Journal of Neuroscience

Internal and external features of the face are represented holistically in face-selective regions of visual cortex.

Publication Date: 2010 Mar 3 PMID: 20203214
Authors: Andrews, T. J. - Davies-Thompson, J. - Kingstone, A. - Young, A. W.
Journal: J Neurosci

The perception and recognition of familiar faces depends critically on an analysis of the internal features of the face (eyes, nose, mouth). We therefore contrasted how information about the internal and external (hair, chin, face outline) features of familiar and unfamiliar faces is represented in face-selective regions. There was a significant response to both the internal and external features of the face when presented in isolation. However, the response to the internal features was greater than the response to the external features. There was significant adaptation to repeated images of either the internal or external features of the face in the fusiform face area (FFA). However, the magnitude of this adaptation was greater for the internal features of familiar faces. Next, we asked whether the internal features of the face are represented independently from the external features. There was a release from adaptation in the FFA to composite images in which the internal features were varied but the external features were unchanged, or when the internal features were unchanged but the external features varied, demonstrating a holistic response. Finally, we asked whether the holistic response to faces could be influenced by the context in which the face was presented. We found that adaptation was still evident to composite images in which the face was unchanged but body features were varied. Together, these findings show that although internal features are important in the neural representation of familiar faces, the face's internal and external features are represented holistically in face-selective regions of the human brain.

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Predictive coding as a model of response properties in cortical area v1.

Publication Date: 2010 Mar 3 PMID: 20203213
Authors: Spratling, M. W.
Journal: J Neurosci

A simple model is shown to account for a large range of V1 classical, and nonclassical, receptive field properties including orientation tuning, spatial and temporal frequency tuning, cross-orientation suppression, surround suppression, and facilitation and inhibition by flankers and textured surrounds. The model is an implementation of the predictive coding theory of cortical function and thus provides a single computational explanation for a diverse range of neurophysiological findings. Furthermore, since predictive coding can be related to the biased competition theory and is a specific example of more general theories of hierarchical perceptual inference, the current results relate V1 response properties to a wider, more unified, framework for understanding cortical function.

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Prefrontal {beta}2 Subunit-Containing and {alpha}7 Nicotinic Acetylcholine Receptors Differentially Control Glutamatergic and Cholinergic Signaling.

Publication Date: 2010 Mar 3 PMID: 20203212
Authors: Parikh, V. - Ji, J. - Decker, M. W. - Sarter, M.
Journal: J Neurosci

One-second-long increases in prefrontal cholinergic activity ("transients") were demonstrated previously to be necessary for the incorporation of cues into ongoing cognitive processes ("cue detection"). Nicotine and, more robustly, selective agonists at alpha4beta2* nicotinic acetylcholine receptors (nAChRs) enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of beta2-containing and alpha7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transients in vivo. Transients were evoked by nicotine, the alpha4beta2* nAChR agonist ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy) pyridine dihydrochloride], or the alpha7 nAChR agonist A-582941 [2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole]. Transients were recorded in mice lacking beta2 or alpha7 nAChRs and in rats after removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of alpha4beta2* nAChRs evokes glutamate release and that the presence of thalamic afferents is necessary for the generation of cholinergic transients. ABT-089-evoked transients were completely abolished in mice lacking beta2* nAChRs. The amplitude, but not the decay rate, of nicotine-evoked transients was reduced by beta2* knock-out. Conversely, in mice lacking the alpha7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of alpha7 nAChR in controlling the duration of release events, stimulation of alpha7 nAChR produced cholinergic transients that lasted 10- to 15-fold longer than those evoked by nicotine. alpha7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal alpha4beta2* nAChRs play a key role in evoking and facilitating the transient glutamatergic-cholinergic interactions that are necessary for cue detection and attentional performance.

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A Role for RhoB in Synaptic Plasticity and the Regulation of Neuronal Morphology.

Publication Date: 2010 Mar 3 PMID: 20203211
Authors: McNair, K. - Spike, R. - Guilding, C. - Prendergast, G. C. - Stone, T. W. - Cobb, S. R. - Morris, B. J.
Journal: J Neurosci

Actin-rich dendritic spines are the locus of excitatory synaptic transmission and plastic events such as long-term potentiation (LTP). Morphological plasticity of spines accompanies activity-dependent changes in synaptic strength. Several Rho GTPase family members are implicated in regulating neuronal and, in particular, spine structure via actin and the actin-binding protein cofilin. However, despite expression in hippocampus and cortex, its ability to modulate actin-regulatory proteins, and its induction during aging, RhoB has been relatively neglected. We previously demonstrated that LTP is associated with specific RhoB activation. Here, we further examined its role in synaptic function using mice with genetic deletion of the RhoB GTPase (RhoB(-/-) mice). Normal basal synaptic transmission accompanied reduced paired-pulse facilitation and post-tetanic potentiation in the hippocampus of RhoB(-/-) mice. Early phase LTP was significantly reduced in RhoB(-/-) animals, whereas the later phase was unaffected. In wild-type mice (RhoB(+/+)), Western blot analysis of potentiated hippocampus showed significant increases in phosphorylated cofilin relative to nonpotentiated slices, which were dramatically impaired in RhoB(-/-) slices. There was also a deficit in phosphorylated Lim kinase levels in the hippocampus from RhoB(-/-) mice. Morphological analysis suggested that lack of RhoB resulted in increased dendritic branching and decreased spine number. Furthermore, an increase in the proportion of stubby relative to thin spines was observed. Moreover, spines demonstrated increased length along with increased head and neck widths. These data implicate RhoB in cofilin regulation and dendritic and spine morphology, highlighting its importance in synaptic plasticity at a structural and functional level.

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Dynamics of Synaptic Transmission between Fast-Spiking Interneurons and Striatal Projection Neurons of the Direct and Indirect Pathways.

Publication Date: 2010 Mar 3 PMID: 20203210
Authors: Planert, H. - Szydlowski, S. N. - Hjorth, J. J. - Grillner, S. - Silberberg, G.
Journal: J Neurosci

The intrastriatal microcircuit is a predominantly inhibitory GABAergic network comprised of a majority of projection neurons [medium spiny neurons (MSNs)] and a minority of interneurons. The connectivity within this microcircuit is divided into two main categories: lateral connectivity between MSNs, and inhibition mediated by interneurons, in particular fast spiking (FS) cells. To understand the operation of striatum, it is essential to have a good description of the dynamic properties of these respective pathways and how they affect different types of striatal projection neurons. We recorded from neuronal pairs, triplets, and quadruplets in slices of rat and mouse striatum and analyzed the dynamics of synaptic transmission between MSNs and FS cells. Retrograde fluorescent labeling and transgenic EGFP (enhanced green fluorescent protein) mice were used to distinguish between MSNs of the direct (striatonigral) and indirect (striatopallidal) pathways. Presynaptic neurons were stimulated with trains of action potentials, and activity-dependent depression and facilitation of synaptic efficacy was recorded from postsynaptic neurons. We found that FS cells provide a strong and homogeneously depressing inhibition of both striatonigral and striatopallidal MSN types. Moreover, individual FS cells are connected to MSNs of both types. In contrast, both MSN types receive sparse and variable, depressing and facilitating synaptic transmission from nearby MSNs. The connection probability was higher for pairs with presynaptic striatopallidal MSNs; however, the variability in synaptic dynamics did not depend on the types of interconnected MSNs. The differences between the two inhibitory pathways were clear in both species and at different developmental stages. Our findings show that the two intrastriatal inhibitory pathways have fundamentally different dynamic properties that are, however, similarly applied to both direct and indirect striatal projections.

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Essential roles of notch signaling in maintenance of neural stem cells in developing and adult brains.

Publication Date: 2010 Mar 3 PMID: 20203209
Authors: Imayoshi, I. - Sakamoto, M. - Yamaguchi, M. - Mori, K. - Kageyama, R.
Journal: J Neurosci

Activation of Notch signaling induces the expression of transcriptional repressor genes such as Hes1, leading to repression of proneural gene expression and maintenance of neural stem/progenitor cells. However, a requirement for Notch signaling in the telencephalon was not clear, because in Hes1;Hes3;Hes5 triple-mutant mice, neural stem/progenitor cells are depleted in most regions of the developing CNS, but not in the telencephalon. Here, we investigated a role for Notch signaling in the telencephalon by generating tamoxifen-inducible conditional knock-out mice that lack Rbpj, an intracellular signal mediator of all Notch receptors. When Rbpj was deleted in the embryonic brain, almost all telencephalic neural stem/progenitor cells prematurely differentiated into neurons and were depleted. When Rbpj was deleted in the adult brain, all neural stem cells differentiated into transit-amplifying cells and neurons. As a result, neurogenesis increased transiently, but 3 months later all neural stem cells were depleted and neurogenesis was totally lost. These results indicated an absolute requirement of Notch signaling for the maintenance of neural stem cells and a proper control of neurogenesis in both embryonic and adult brains.

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Alleviation of neurotoxicity by microglial human siglec-11.

Publication Date: 2010 Mar 3 PMID: 20203208
Authors: Wang, Y. - Neumann, H.
Journal: J Neurosci

Sialic acid-binding Ig superfamily lectins (Siglecs) are members of the Ig superfamily that recognize sialic acid residues of glycoproteins. Siglec-11 is a recently identified human-specific CD33-related Siglec that binds to alpha2,8-linked polysialic acids and is expressed on microglia, the brain resident innate immune cells. Polysialylated neuronal cell adhesion molecule (PSA-NCAM) is a putative ligand of Siglec-11. We observed gene transcription and protein expression of Siglec-11 splice variant 2 in human brain tissue samples by RT-PCR and Western blot analysis. Siglec-11 was detected on microglia in human brain tissue by immunohistochemistry. Human Siglec-11 splice variant 2 was ectopically expressed by a lentiviral vector system in cultured murine microglial cells. Stimulation of Siglec-11 by cross-linking suppressed the lipopolysaccharides (LPS)-induced gene transcription of the proinflammatory mediators interleukin-1beta and nitric oxide synthase-2 in microglia. Furthermore, phagocytosis of apoptotic neuronal material was reduced in Siglec-11 transduced microglia. Expression of PSA-NCAM was detected on microglia and neurons by immunohistochemistry and RT-PCR. Coculture of microglia transduced with Siglec-11 and neurons demonstrated neuroprotective function of Siglec-11. The neuroprotective effect of Siglec-11 was dependent on polysialic acid (PSA) residues on neurons, but independent on PSA on microglia. Thus, data demonstrate that human Siglec-11 ectopically expressed on murine microglia interacts with PSA on neurons, reduces LPS-induced gene transcription of proinflammatory mediators, impairs phagocytosis and alleviates microglial neurotoxicity.

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Cisplatin ototoxicity blocks sensory regeneration in the avian inner ear.

Publication Date: 2010 Mar 3 PMID: 20203207
Authors: Slattery, E. L. - Warchol, M. E.
Journal: J Neurosci

Cisplatin is a chemotherapeutic agent that is widely used in the treatment of solid tumors. Ototoxicity is a common side effect of cisplatin therapy and often leads to permanent hearing loss. The sensory organs of the avian ear are able to regenerate hair cells after aminoglycoside ototoxicity. This regenerative response is mediated by supporting cells, which serve as precursors to replacement hair cells. Given the antimitotic properties of cisplatin, we examined whether the avian ear was also capable of regeneration after cisplatin ototoxicity. Using cell and organ cultures of the chick cochlea and utricle, we found that cisplatin treatment caused apoptosis of both auditory and vestibular hair cells. Hair cell death in the cochlea occurred in a unique pattern, progressing from the low-frequency (distal) region toward the high-frequency (proximal) region. We also found that cisplatin caused a dose-dependent reduction in the proliferation of cultured supporting cells as well as increased apoptosis in those cells. As a result, we observed no recovery of hair cells after ototoxic injury caused by cisplatin. Finally, we explored the potential for nonmitotic hair cell recovery via activation of Notch pathway signaling. Treatment with the gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester failed to promote the direct transdifferentiation of supporting cells into hair cells in cisplatin-treated utricles. Taken together, our data show that cisplatin treatment causes maintained changes to inner ear supporting cells and severely impairs the ability of the avian ear to regenerate either via proliferation or by direct transdifferentiation.

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Error effects in anterior cingulate cortex reverse when error likelihood is high.

Publication Date: 2010 Mar 3 PMID: 20203206
Authors: Jessup, R. K. - Busemeyer, J. R. - Brown, J. W.
Journal: J Neurosci

Strong error-related activity in medial prefrontal cortex (mPFC) has been shown repeatedly with neuroimaging and event-related potential studies for the last several decades. Multiple theories have been proposed to account for error effects, including comparator models and conflict detection models, but the neural mechanisms that generate error signals remain in dispute. Typical studies use relatively low error rates, confounding the expectedness and the desirability of an error. Here we show with a gambling task and functional magnetic resonance imaging that when losses are more frequent than wins, the mPFC error effect disappears, and moreover, exhibits the opposite pattern by responding more strongly to unexpected wins than losses. These findings provide perspective on recent ERP studies and suggest that mPFC error effects result from a comparison between actual and expected outcomes.

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Endogenous neuromagnetic activity for mental hierarchy of timing.

Publication Date: 2010 Mar 3 PMID: 20203205
Authors: Fujioka, T. - Zendel, B. R. - Ross, B.
Journal: J Neurosci

The frontal-striatal circuits, the cerebellum, and motor cortices play crucial roles in processing timing information on second to millisecond scales. However, little is known about the physiological mechanism underlying human's preference to robustly encode a sequence of time intervals into a mental hierarchy of temporal units called meter. This is especially salient in music: temporal patterns are typically interpreted as integer multiples of a basic unit (i.e., the beat) and accommodated into a global context such as march or waltz. With magnetoencephalography and spatial-filtering source analysis, we demonstrated that the time courses of neural activities index a subjectively induced meter context. Auditory evoked responses from hippocampus, basal ganglia, and auditory and association cortices showed a significant contrast between march and waltz metric conditions during listening to identical click stimuli. Specifically, the right hippocampus was activated differentially at 80 ms to the march downbeat (the count one) and approximately 250 ms to the waltz downbeat. In contrast, basal ganglia showed a larger 80 ms peak for march downbeat than waltz. The metric contrast was also expressed in long-latency responses in the right temporal lobe. These findings suggest that anticipatory processes in the hippocampal memory system and temporal computation mechanism in the basal ganglia circuits facilitate endogenous activities in auditory and association cortices through feedback loops. The close interaction of auditory, motor, and limbic systems suggests a distributed network for metric organization in temporal processing and its relevance for musical behavior.

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Control of Rhodopsin's Active Lifetime by Arrestin-1 Expression in Mammalian Rods.

Publication Date: 2010 Mar 3 PMID: 20203204
Authors: Gross, O. P. - Burns, M. E.
Journal: J Neurosci

In rod photoreceptors, deactivation of the light-activated G-protein-coupled receptor rhodopsin (R*) is initiated by phosphorylation and completed through subsequent binding of visual arrestin (Arr1). The in vivo kinetics of these individual interactions have proven difficult to determine with precision since R* lifetime is much shorter than the lifetimes of downstream G-protein and effector molecules. Here, we have used a transgenic mouse line with accelerated downstream deactivation kinetics to reveal the contribution of Arr1 binding to the overall time course of rhodopsin deactivation. Photoresponses revealed that the lifetime of R* is significantly increased in rods that express half of the normal amount of Arr1, in a manner consistent with a twofold decrease in the rate of Arr1 binding across a wide range of flash strengths. A basic model of photoresponse deactivation consistent with established photoreceptor biochemistry shows that R* phosphorylation and Arr1 binding occur with a time constant of approximately 40 ms in wild-type mouse rods, much faster than previous estimates.

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Neocortical Activation of the Hippocampus during Sleep in Infant Rats.

Publication Date: 2010 Mar 3 PMID: 20203203
Authors: Mohns, E. J. - Blumberg, M. S.
Journal: J Neurosci

We recently reported that the majority of hippocampal neurons in newborn rats increase their activity in association with myoclonic twitches, which are indicative of active sleep. Because spindle bursts in the developing somatosensory neocortex occur in response to sensory feedback from myoclonic twitching, we hypothesized that the state-dependent activity of the newborn hippocampus arises from sensory feedback that sequentially activates the neocortex and then hippocampus, constituting an early form of neocortical-hippocampal communication. Here, in unanesthetized 5- to 6-d-old rats, we test this hypothesis by recording simultaneously from forelimb and barrel regions of somatosensory neocortex and dorsal hippocampus during periods of spontaneous sleep and wakefulness and in response to peripheral stimulation. Myoclonic twitches were consistently followed by neocortical spindle bursts, which were in turn consistently followed by bursts of hippocampal unit activity; moreover, spindle burst power was positively correlated with hippocampal unit activity. In addition, exogenous stimulation consistently evoked this neocortical-to-hippocampal sequence of activation. Finally, parahippocampal lesions that disrupted functional connections between the neocortex and hippocampus effectively disrupted the transmission of both spontaneous and evoked neocortical activity to the hippocampus. These findings suggest that sleep-related motor activity contributes to the development of neocortical and hippocampal circuits and provides a foundation on which coordinated activity between these two forebrain structures develops.

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Reconstructing three-dimensional hand movements from noninvasive electroencephalographic signals.

Publication Date: 2010 Mar 3 PMID: 20203202
Authors: Bradberry, T. J. - Gentili, R. J. - Contreras-Vidal, J. L.
Journal: J Neurosci

It is generally thought that the signal-to-noise ratio, the bandwidth, and the information content of neural data acquired via noninvasive scalp electroencephalography (EEG) are insufficient to extract detailed information about natural, multijoint movements of the upper limb. Here, we challenge this assumption by continuously decoding three-dimensional (3D) hand velocity from neural data acquired from the scalp with 55-channel EEG during a 3D center-out reaching task. To preserve ecological validity, five subjects self-initiated reaches and self-selected targets. Eye movements were controlled so they would not confound the interpretation of the results. With only 34 sensors, the correlation between measured and reconstructed velocity profiles compared reasonably well to that reported by studies that decoded hand kinematics from neural activity acquired intracranially. We subsequently examined the individual contributions of EEG sensors to decoding to find substantial involvement of scalp areas over the sensorimotor cortex contralateral to the reaching hand. Using standardized low-resolution brain electromagnetic tomography (sLORETA), we identified distributed current density sources related to hand velocity in the contralateral precentral gyrus, postcentral gyrus, and inferior parietal lobule. Furthermore, we discovered that movement variability negatively correlated with decoding accuracy, a finding to consider during the development of brain-computer interface systems. Overall, the ability to continuously decode 3D hand velocity from EEG during natural, center-out reaching holds promise for the furtherance of noninvasive neuromotor prostheses for movement-impaired individuals.

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Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis.

Publication Date: 2010 Mar 3 PMID: 20203201
Authors: Kronenberg, G. - Gertz, K. - Baldinger, T. - Kirste, I. - Eckart, S. - Yildirim, F. - Ji, S. - Heuser, I. - Schrock, H. - Hortnagl, H. - Sohr, R. - Djoufack, P. C. - Juttner, R. - Glass, R. - Przesdzing, I. - Kumar, J. - Freyer, D. - Hellweg, R. - Kettenmann, H. - Fink, K. B. - Endres, M.
Journal: J Neurosci

Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn(-/-)) mice as a model system for actin filament stabilization. In Gsn(-/-) mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca(2+)](i) increases and exocytotic neurotransmitter release were enhanced in Gsn(-/-) synaptosomes. Importantly, treatment of Gsn(-/-) synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca(2+) influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn(-/-) brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn(-/-) mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca(2+) influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn(-/-) hippocampus is associated with a special vascular niche for neurogenesis.

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Distinct Region-Specific {alpha}-Synuclein Oligomers in A53T Transgenic Mice: Implications for Neurodegeneration.

Publication Date: 2010 Mar 3 PMID: 20203200
Authors: Tsika, E. - Moysidou, M. - Guo, J. - Cushman, M. - Gannon, P. - Sandaltzopoulos, R. - Giasson, B. I. - Krainc, D. - Ischiropoulos, H. - Mazzulli, J. R.
Journal: J Neurosci

Aggregation of alpha-synuclein (alpha-syn), a process that generates oligomeric intermediates, is a common pathological feature of several neurodegenerative disorders. Despite the potential importance of the oligomeric alpha-syn intermediates in neuron function, their biochemical properties and pathobiological functions in vivo remain vastly unknown. Here we used two-dimensional analytical separation and an array of biochemical and cell-based assays to characterize alpha-syn oligomers that are present in the nervous system of A53T alpha-syn transgenic mice. The most prominent species identified were 53 A detergent-soluble oligomers, which preceded neurological symptom onset, and were found at equivalent amounts in regions containing alpha-syn inclusions as well as histologically unaffected regions. These oligomers were resistant to SDS, heat, and urea but were sensitive to proteinase-K digestion. Although the oligomers shared similar basic biochemical properties, those obtained from inclusion-bearing regions were prominently reactive to antibodies that recognize oxidized alpha-syn oligomers, significantly accelerated aggregation of alpha-syn in vitro, and caused primary cortical neuron degeneration. In contrast, oligomers obtained from non-inclusion-bearing regions were not toxic and delayed the in vitro formation of alpha-syn fibrils. These data indicate that specific conformations of alpha-syn oligomers are present in distinct brain regions of A53T alpha-syn transgenic mice. The contribution of these oligomers to the development of neuron dysfunction appears to be independent of their absolute quantities and basic biochemical properties but is dictated by the composition and conformation of the intermediates as well as unrecognized brain-region-specific intrinsic factors.

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Striatal Muscarinic Receptors Promote Activity Dependence of Dopamine Transmission via Distinct Receptor Subtypes on Cholinergic Interneurons in Ventral versus Dorsal Striatum.

Publication Date: 2010 Mar 3 PMID: 20203199
Authors: Threlfell, S. - Clements, M. A. - Khodai, T. - Pienaar, I. S. - Exley, R. - Wess, J. - Cragg, S. J.
Journal: J Neurosci

Striatal dopamine (DA) and acetylcholine (ACh) regulate motivated behaviors and striatal plasticity. Interactions between these neurotransmitters may be important, through synchronous changes in parent neuron activities and reciprocal presynaptic regulation of release. How DA signaling is regulated by striatal muscarinic receptors (mAChRs) is unresolved; contradictory reports indicate suppression or facilitation, implicating several mAChR subtypes on various neurons. We investigated whether mAChR regulation of DA signaling varies with presynaptic activity and identified the mAChRs responsible in sensorimotor- versus limbic-associated striatum. We detected DA in real time at carbon fiber microelectrodes in mouse striatal slices. Broad-spectrum mAChR agonists [oxotremorine-M, APET (arecaidine propargyl ester tosylate)] decreased DA release evoked by low-frequency stimuli (1-10 Hz, four pulses) but increased the sensitivity of DA release to presynaptic activity, even enhancing release by high frequencies (e.g., >25 Hz for four pulses). These bidirectional effects depended on ACh input to striatal nicotinic receptors (nAChRs) on DA axons but not GABA or glutamate input. In caudate-putamen (CPu), knock-out of M(2)- or M(4)-mAChRs (not M(5)) prevented mAChR control of DA, indicating that M(2)- and M(4)-mAChRs are required. In nucleus accumbens (NAc) core or shell, mAChR function was prevented in M(4)-knock-outs, but not M(2)- or M(5)-knock-outs. These data indicate that striatal mAChRs, by inhibiting ACh release from cholinergic interneurons and thus modifying nAChR activity, offer variable control of DA release probability that promotes how DA release reflects activation of dopaminergic axons. Furthermore, different coupling of striatal M(2)/M(4)-mAChRs to the control of DA release in CPu versus NAc suggests targets to influence DA/ACh function differentially between striatal domains.

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A Nonlinear Relationship between Cerebral Serotonin Transporter and 5-HT2A Receptor Binding: An In Vivo Molecular Imaging Study in Humans.

Publication Date: 2010 Mar 3 PMID: 20203198
Authors: Erritzoe, D. - Holst, K. - Frokjaer, V. G. - Licht, C. L. - Kalbitzer, J. - Nielsen, F. A. - Svarer, C. - Madsen, J. - Knudsen, G.
Journal: J Neurosci

Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT(2A)) receptor and the presynaptic serotonin transporter (SERT) are sensitive to chronic changes in cerebral 5-HT levels. Additionally, experimental studies suggest that alterations in either the 5-HT(2A) receptor or SERT level can affect the protein level of the counterpart. The aim of this study was to explore the covariation between cerebral 5-HT(2A) receptor and SERT in vivo in the same healthy human subjects. Fifty-six healthy human subjects with a mean age of 36 +/- 19 years were investigated. The SERT binding was imaged with [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) and 5-HT(2A) receptor binding with [(18)F]altanserin using positron emission tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT(2A) receptor binding. An inverted U-shaped relationship between the 5-HT(2A) receptor and the SERT binding was identified. The observed regional intercorrelation for both the 5-HT(2A) receptor and the SERT cerebral binding suggests that, within the single individual, each marker has a set point adjusted through a common regulator. A quadratic relationship between the two markers is consistent with data from experimental studies of the effect on SERT and 5-HT(2A) receptor binding of chronic changes in 5-HT levels. That is, the observed association between the 5-HT(2A) receptor and SERT binding could be driven by the projection output from the raphe nuclei, but other explanations are also at hand.

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Neuropeptide y suppresses anorexigenic output from the ventromedial nucleus of the hypothalamus.

Publication Date: 2010 Mar 3 PMID: 20203197
Authors: Chee, M. J. - Myers, M. G. Jr - Price, C. J. - Colmers, W. F.
Journal: J Neurosci

Output from the hypothalamic ventromedial nucleus (VMN) is anorexigenic and is supported by the excitatory actions of leptin. The VMN is also highly sensitive to the orexigenic actions of Neuropeptide Y (NPY). We report that NPY robustly inhibits VMN neurons by hyperpolarizing them and decreasing their ability to fire action potentials. This action was mediated by Y(1) receptors coupled to the activation of GIRKs (G-protein-coupled inwardly rectifying potassium channels). Approximately 80% of VMN neurons expressing leptin receptors were sensitive to the actions of NPY, whereas 75% of NPY-sensitive neurons in VMN also responded to glucose by being uniformly inhibited by elevations in glucose. Interestingly, only approximately 36% of NPY-sensitive, leptin receptor b-expressing neurons were also glucosensitive. We suggest that NPY inhibits VMN neurons that are excited by leptin, thereby arresting the anorexigenic tone exerted by VMN neurons. The results further suggest a dynamic interplay between anorexigenic and orexigenic neuromodulators within the VMN to directly affect energy balance.

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Audiovisual functional magnetic resonance imaging adaptation reveals multisensory integration effects in object-related sensory cortices.

Publication Date: 2010 Mar 3 PMID: 20203196
Authors: Doehrmann, O. - Weigelt, S. - Altmann, C. F. - Kaiser, J. - Naumer, M. J.
Journal: J Neurosci

Information integration across different sensory modalities contributes to object recognition, the generation of associations and long-term memory representations. Here, we used functional magnetic resonance imaging adaptation to investigate the presence of sensory integrative effects at cortical levels as early as nonprimary auditory and extrastriate visual cortices, which are implicated in intermediate stages of object processing. Stimulation consisted of an adapting audiovisual stimulus S(1) and a subsequent stimulus S(2) from the same basic-level category (e.g., cat). The stimuli were carefully balanced with respect to stimulus complexity and semantic congruency and presented in four experimental conditions: (1) the same image and vocalization for S(1) and S(2), (2) the same image and a different vocalization, (3) different images and the same vocalization, or (4) different images and vocalizations. This two-by-two factorial design allowed us to assess the contributions of auditory and visual stimulus repetitions and changes in a statistically orthogonal manner. Responses in visual regions of right fusiform gyrus and right lateral occipital cortex were reduced for repeated visual stimuli (repetition suppression). Surprisingly, left lateral occipital cortex showed stronger responses to repeated auditory stimuli (repetition enhancement). Similarly, auditory regions of interest of the right middle superior temporal gyrus and sulcus exhibited repetition suppression to auditory repetitions and repetition enhancement to visual repetitions. Our findings of crossmodal repetition-related effects in cortices of the respective other sensory modality add to the emerging view that in human subjects sensory integrative mechanisms operate on earlier cortical processing levels than previously assumed.

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Differential plasticity of the GABAergic and glycinergic synaptic transmission to rat lumbar motoneurons after spinal cord injury.

Publication Date: 2010 Mar 3 PMID: 20203195
Authors: Sadlaoud, K. - Tazerart, S. - Brocard, C. - Jean-Xavier, C. - Portalier, P. - Brocard, F. - Vinay, L. - Bras, H.
Journal: J Neurosci

Maturation of inhibitory postsynaptic transmission onto motoneurons in the rat occurs during the perinatal period, a time window during which pathways arising from the brainstem reach the lumbar enlargement of the spinal cord. There is a developmental switch in miniature IPSCs (mIPSCs) from predominantly long-duration GABAergic to short-duration glycinergic events. We investigated the effects of a complete neonatal [postnatal day 0 (P0)] spinal cord transection (SCT) on the expression of Glycine and GABA(A) receptor subunits (GlyR and GABA(A)R subunits) in lumbar motoneurons. In control rats, the density of GlyR increased from P1 to P7 to reach a plateau, whereas that of GABA(A)R subunits dropped during the same period. In P7 animals with neonatal SCT (SCT-P7), the GlyR densities were unchanged compared with controls of the same age, while the developmental downregulation of GABA(A)R was prevented. Whole-cell patch-clamp recordings of mIPSCs performed in lumbar motoneurons at P7 revealed that the decay time constant of miniature IPSCs and the proportion of GABAergic events significantly increased after SCT. After daily injections of the 5-HT(2)R agonist DOI, GABA(A)R immunolabeling on SCT-P7 motoneurons dropped down to values reported in control-P7, while GlyR labeling remained stable. A SCT made at P5 significantly upregulated the expression of GABA(A)R 1 week later with little, if any, influence on GlyR. We conclude that the plasticity of GlyR is independent of supraspinal influences whereas that of GABA(A)R is markedly influenced by descending pathways, in particular serotoninergic projections.

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Type 3 deiodinase, a thyroid-hormone-inactivating enzyme, controls survival and maturation of cone photoreceptors.

Publication Date: 2010 Mar 3 PMID: 20203194
Authors: Ng, L. - Lyubarsky, A. - Nikonov, S. S. - Ma, M. - Srinivas, M. - Kefas, B. - St Germain, D. L. - Hernandez, A. - Pugh, E. N. Jr - Forrest, D.
Journal: J Neurosci

Maturation of the mammalian nervous system requires adequate provision of thyroid hormone and mechanisms that enhance tissue responses to the hormone. Here, we report that the development of cones, the photoreceptors for daylight and color vision, requires protection from thyroid hormone by type 3 deiodinase, a thyroid hormone-inactivating enzyme. Type 3 deiodinase, encoded by Dio3, is expressed in the immature mouse retina. In Dio3(-/-) mice, approximately 80% of cones are lost through neonatal cell death. Cones that express opsin photopigments for response to both short (S) and medium-long (M) wavelength light are lost. Rod photoreceptors, which mediate dim light vision, remain essentially intact. Excessive thyroid hormone in wild-type pups also eliminates cones. Cone loss is mediated by cone-specific thyroid hormone receptor beta2 (TRbeta2) as deletion of TRbeta2 rescues cones in Dio3(-/-) mice. However, rescued cones respond to short but not longer wavelength light because TRbeta2 under moderate hormonal stimulation normally induces M opsin and controls the patterning of M and S opsins over the retina. The results suggest that type 3 deiodinase limits hormonal exposure of the cone to levels that safeguard both cone survival and the patterning of opsins that is required for cone function.

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Neurons in Anterior Cingulate Cortex Multiplex Information about Reward and Action.

Publication Date: 2010 Mar 3 PMID: 20203193
Authors: Hayden, B. Y. - Platt, M. L.
Journal: J Neurosci

The dorsal anterior cingulate cortex (dACC) is thought to play a critical role in forming associations between rewards and actions. Currently available physiological data, however, remain inconclusive regarding the question of whether dACC neurons carry information linking particular actions to reward or, instead, encode abstract reward information independent of specific actions. Here we show that firing rates of a majority of dACC neurons in a population studied in an eight-option variably rewarded choice task were sensitive to both saccade direction and reward value. Furthermore, the influences of reward and saccade direction on neuronal activity were approximately equal in magnitude over the range of rewards tested and were statistically independent. Our results indicate that dACC neurons multiplex information about both reward and action, endorsing the idea that this area links motivational outcomes to behavior and undermining the notion that its neurons solely contribute to reward processing in the abstract.

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Amyloid-{beta} Aggregates Cause Alterations of Astrocytic Metabolic Phenotype: Impact on Neuronal Viability.

Publication Date: 2010 Mar 3 PMID: 20203192
Authors: Allaman, I. - Gavillet, M. - Belanger, M. - Laroche, T. - Viertl, D. - Lashuel, H. A. - Magistretti, P. J.
Journal: J Neurosci

Amyloid-beta (Abeta) peptides play a key role in the pathogenesis of Alzheimer's disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Abeta peptides on glucose metabolism in cultured astrocytes. Following Abeta(25-35) exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. Abeta increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of Abeta on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Abeta impair neuronal viability. The effects of the Abeta(25-35) fragment were reproduced by Abeta(1-42) but not by Abeta(1-40). Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that Abeta aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.

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Functional Organization of Vestibular Commissural Connections in Frog.

Publication Date: 2010 Mar 3 PMID: 20203191
Authors: Malinvaud, D. - Vassias, I. - Reichenberger, I. - Rossert, C. - Straka, H.
Journal: J Neurosci

Central vestibular neurons receive substantial inputs from the contralateral labyrinth through inhibitory and excitatory brainstem commissural pathways. The functional organization of these pathways was studied by a multi-methodological approach in isolated frog whole brains. Retrogradely labeled vestibular commissural neurons were primarily located in the superior vestibular nucleus in rhombomeres 2/3 and the medial and descending vestibular nucleus in rhombomeres 5-7. Restricted projections to contralateral vestibular areas, without collaterals to other classical vestibular targets, indicate that vestibular commissural neurons form a feedforward push-pull circuitry. Electrical stimulation of the contralateral coplanar semicircular canal nerve evoked in canal-related second-order vestibular neurons (2 degrees VN) commissural IPSPs ( approximately 70%) and EPSPs ( approximately 30%) with mainly ( approximately 70%) disynaptic onset latencies. The dynamics of commissural responses to electrical pulse trains suggests mediation predominantly by tonic vestibular neurons that activate in all tonic 2 degrees VN large-amplitude IPSPs with a reversal potential of -74 mV. In contrast, phasic 2 degrees VN exhibited either nonreversible, small-amplitude IPSPs ( approximately 40%) of likely dendritic origin or large-amplitude commissural EPSPs ( approximately 60%). IPSPs with disynaptic onset latencies were exclusively GABAergic (mainly GABA(A) receptor-mediated) but not glycinergic, compatible with the presence of GABA-immunopositive ( approximately 20%) and the absence of glycine-immunopositive vestibular commissural neurons. In contrast, IPSPs with longer, oligosynaptic onset latencies were GABAergic and glycinergic, indicating that both pharmacological types of local inhibitory neurons were activated by excitatory commissural fibers. Conservation of major morpho-physiological and pharmacological features of the vestibular commissural pathway suggests that this phylogenetically old circuitry plays an essential role for the processing of bilateral angular head acceleration signals in vertebrates.

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Critical Period for Inhibitory Plasticity in RodentBinocular V1.

Publication Date: 2010 Mar 3 PMID: 20203190
Authors: Maffei, A. - Lambo, M. E. - Turrigiano, G. G.
Journal: J Neurosci

Postnatal cortical circuit development is characterized by windows of heightened plasticity that contribute to the acquisition of mature connectivity and function. What drives the transition between different critical plasticity windows is not known. Here we show that a switch in sign of inhibitory plasticity correlates with the reported transition between the precritical period (pre-CP) and the critical period (CP) for ocular dominance plasticity (ODP). In layer 4 of binocular visual cortex (V1b), depression of inhibitory synapses onto pyramidal neurons is induced when rats are monocularly deprived for 2 d at the end of the third postnatal week (pre-CP), whereas potentiation is induced if the monocular deprivation is started in the fourth postnatal week (CP). The magnitude of potentiation increases with deprivations started close to the peak of the CP for ODP. The direction of inhibitory plasticity depends on the differential manipulation of circuits activated by the two eyes. During development, these two forms of plasticity shift the balance between excitation and inhibition of the circuit in opposite directions, whereas the excitatory synaptic drive remains unaffected. Inhibitory plasticity is thus fundamental in modulating cortical circuit refinement and might be one of the mechanisms promoting ocular dominance shifts.

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Training of Working Memory Impacts Structural Connectivity.

Publication Date: 2010 Mar 3 PMID: 20203189
Authors: Takeuchi, H. - Sekiguchi, A. - Taki, Y. - Yokoyama, S. - Yomogida, Y. - Komuro, N. - Yamanouchi, T. - Suzuki, S. - Kawashima, R.
Journal: J Neurosci

Working memory is the limited capacity storage system involved in the maintenance and manipulation of information over short periods of time. Individual capacity of working memory is associated with the integrity of white matter in the frontoparietal regions. It is unknown to what extent the integrity of white matter underlying the working memory system is plastic. Using voxel-based analysis (VBA) of fractional anisotropy (FA) measures of fiber tracts, we investigated the effect of working memory training on structural connectivity in an interventional study. The amount of working memory training correlated with increased FA in the white matter regions adjacent to the intraparietal sulcus and the anterior part of the body of the corpus callosum after training. These results showed training-induced plasticity in regions that are thought to be critical in working memory. As changes in myelination lead to FA changes in diffusion tensor imaging, a possible mechanism for the observed FA change is increased myelination after training. Observed structural changes may underlie previously reported improvement of working memory capacity, improvement of other cognitive functions, and altered functional activity following working memory training.

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Temporal Sequence of Attentional Modulation in the Lateral Intraparietal Area and Middle Temporal Area during Rapid Covert Shifts of Attention.

Publication Date: 2010 Mar 3 PMID: 20203188
Authors: Herrington, T. M. - Assad, J. A.
Journal: J Neurosci

In the visual system, spatial attention enhances sensory responses to stimuli at attended locations relative to unattended locations. Which brain structures direct the locus of attention, and how is attentional modulation delivered to structures in the visual system? We trained monkeys on an attention-switch task designed to precisely measure the onset of attentional modulation during rapid shifts of spatial attention. Here we show that attentional modulation appears substantially earlier in the lateral intraparietal area (LIP) than in an anatomically connected lower visual area, the middle temporal area. This temporal sequence of attentional latencies demonstrates that endogenous changes of state can occur in higher visual areas before lower visual areas and satisfies a critical prediction of the hypothesis that LIP is a source of top-down attentional signals to early visual cortex.

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{micro}-Opioid Receptor Endocytosis Prevents Adaptations in Ventral Tegmental Area GABA Transmission Induced during Naloxone-Precipitated Morphine Withdrawal.

Publication Date: 2010 Mar 3 PMID: 20203187
Authors: Madhavan, A. - He, L. - Stuber, G. D. - Bonci, A. - Whistler, J. L.
Journal: J Neurosci

Chronic morphine drives adaptations in synaptic transmission thought to underlie opiate dependence. Here we examine the role of mu-opioid receptor (MOR) trafficking in one of these adaptations, specifically, changes in GABA transmission in the ventral tegmental area (VTA). To address this question, we used a knock-in mouse, RMOR (for recycling MOR), in which genetic change in the MOR promotes morphine-induced receptor desensitization and endocytosis in GABA interneurons of the VTA. In wild-type mice (postnatal days 23-28) chronic morphine (10 mg/kg, s.c., twice daily for 5 d), induced a cAMP-dependent increase in the probability of GABA release onto VTA dopamine neurons. The increased GABA release frequency correlated with physical dependence on morphine measured by counting somatic signs of morphine withdrawal, such as, tremors, jumps, rears, wet-dog shakes, and grooming behavior precipitated by subcutaneous administration of naloxone (NLX) (2 mg/kg). This adaptation in GABA release was prevented in RMOR mice given the same morphine treatment, implicating MOR trafficking in this morphine-induced change in plasticity. Importantly, treatment with the cAMP activity inhibitor rp-cAMPS [(R)-adenosine, cyclic 3',5'-(hydrogenphosphorothioate) triethylammonium] (50 ng/0.5 mul), directly to the VTA, attenuated somatic withdrawal signs to systemic morphine produced by intra-VTA NLX (500 ng/0.5 mul), directly tying enhanced cAMP-driven GABA release to naloxone-precipitated morphine withdrawal in the VTA.

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Nurture versus Nature: Long-Term Impact of Forced Right-Handedness on Structure of Pericentral Cortex and Basal Ganglia.

Publication Date: 2010 Mar 3 PMID: 20203186
Authors: Kloppel, S. - Mangin, J. F. - Vongerichten, A. - Frackowiak, R. S. - Siebner, H. R.
Journal: J Neurosci

Does a conflict between inborn motor preferences and educational standards during childhood impact the structure of the adult human brain? To examine this issue, we acquired high-resolution T1-weighted magnetic resonance scans of the whole brain in adult "converted" left-handers who had been forced as children to become dextral writers. Analysis of sulcal surfaces revealed that consistent right- and left-handers showed an interhemispheric asymmetry in the surface area of the central sulcus with a greater surface contralateral to the dominant hand. This pattern was reversed in the converted group who showed a larger surface of the central sulcus in their left, nondominant hemisphere, indicating plasticity of the primary sensorimotor cortex caused by forced use of the nondominant hand. Voxel-based morphometry showed a reduction of gray matter volume in the middle part of the left putamen in converted left-handers relative to both consistently handed groups. A similar trend was found in the right putamen. Converted subjects with at least one left-handed first-degree relative showed a correlation between the acquired right-hand advantage for writing and the structural changes in putamen and pericentral cortex. Our results show that a specific environmental challenge during childhood can shape the macroscopic structure of the human basal ganglia. The smaller than normal putaminal volume differs markedly from previously reported enlargement of cortical gray matter associated with skill acquisition. This indicates a differential response of the basal ganglia to early environmental challenges, possibly related to processes of pruning during motor development.

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Opposing effects of contextual surround in human early visual cortex revealed by functional magnetic resonance imaging with continuously modulated visual stimuli.

Publication Date: 2010 Mar 3 PMID: 20203185
Authors: Tajima, S. - Watanabe, M. - Imai, C. - Ueno, K. - Asamizuya, T. - Sun, P. - Tanaka, K. - Cheng, K.
Journal: J Neurosci

Spatial context in vision has profound effects on neural responses and perception. Recent animal studies suggest that the effect of surround on a central stimulus can dramatically change its character depending on the contrast of the center stimulus, but such a drastic change has not been demonstrated in the human visual cortex. To examine the dependency of the surround effect on the contrast of the center stimulus, we conducted an functional magnetic resonance imaging experiment by using a low or a high contrast in the center region while the surround contrast was sinusoidally modulated between the two contrasts. We found that the blood oxygen level-dependent response in human V1 corresponding to the center region was differentially modulated by the surround contrast, depending crucially on the center contrast: whereas a suppressive effect was observed in conditions in which the center contrast was high, a facilitative effect was seen in conditions where the center contrast was low.

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MicroRNA-183 Family Members Regulate Sensorineural Fates in the Inner Ear.

Publication Date: 2010 Mar 3 PMID: 20203184
Authors: Li, H. - Kloosterman, W. - Fekete, D. M.
Journal: J Neurosci

Members of the microRNA (miRNA) 183 family (miR-183, miR-96, and miR-182) are expressed abundantly in specific sensory cell types in the eye, nose, and inner ear. In the inner ear, expression is robust in the mechanosensory hair cells and weak in the associated statoacoustic ganglion (SAG) neurons; both cell types can share a common lineage during development. Recently, dominant-progressive hearing loss in humans and mice was linked to mutations in the seed region of miR-96, with associated defects in both development and maintenance of hair cells in the mutant mice. To understand how the entire triplet functions in the development of mechanosensory hair cells and neurons of the inner ear, we manipulated the levels of these miRNAs in zebrafish embryos using synthesized miRNAs and antisense morpholino oligonucleotides (MOs). Overexpression of miR-96 or miR-182 induces duplicated otocysts, ectopic or expanded sensory patches, and extra hair cells, whereas morphogenesis of the SAG is adversely affected to different degrees. In contrast, knockdown of miR-183, miR-96, and miR-182 causes reduced numbers of hair cells in the inner ear, smaller SAGs, defects in semicircular canals, and abnormal neuromasts on the posterior lateral line. However, the prosensory region of the posterior macula, where the number of hair cells is reduced by approximately 50%, is not significantly impaired. Our findings suggest both distinct and common roles for the three miRNAs in cell-fate determination in the inner ear, and these principles might apply to development of other sensory organs.

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Phosducin Regulates Transmission at thePhotoreceptor-to-ON-Bipolar Cell Synapse.

Publication Date: 2010 Mar 3 PMID: 20203183
Authors: Herrmann, R. - Lobanova, E. S. - Hammond, T. - Kessler, C. - Burns, M. E. - Frishman, L. J. - Arshavsky, V. Y.
Journal: J Neurosci

The rate of synaptic transmission between photoreceptors and bipolar cells has been long known to depend on conditions of ambient illumination. However, the molecular mechanisms that mediate and regulate transmission at this ribbon synapse are poorly understood. We conducted electroretinographic recordings from dark- and light-adapted mice lacking the abundant photoreceptor-specific protein phosducin and found that the ON-bipolar cell responses in these animals have a reduced light sensitivity in the dark-adapted state. Additional desensitization of their responses, normally caused by steady background illumination, was also diminished compared with wild-type animals. This effect was observed in both rod- and cone-driven pathways, with the latter affected to a larger degree. The underlying mechanism is likely to be photoreceptor specific because phosducin is not expressed in other retina neurons and transgenic expression of phosducin in rods of phosducin knock-out mice rescued the rod-specific phenotype. The underlying mechanism functions downstream from the phototransduction cascade, as evident from the sensitivity of phototransduction in phosducin knock-out rods being affected to a much lesser degree than b-wave responses. These data indicate that a major regulatory component responsible for setting the sensitivity of signal transmission between photoreceptors and ON-bipolar cells is confined to photoreceptors and that phosducin participates in the underlying molecular mechanism.

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Cooperation and Competition among Frontal Eye Field Neurons during Visual Target Selection.

Publication Date: 2010 Mar 3 PMID: 20203182
Authors: Cohen, J. Y. - Crowder, E. A. - Heitz, R. P. - Subraveti, C. R. - Thompson, K. G. - Woodman, G. F. - Schall, J. D.
Journal: J Neurosci

The role of spike rate versus timing codes in visual target selection is unclear. We simultaneously recorded activity from multiple frontal eye field neurons and asked whether they interacted to select targets from distractors during visual search. When both neurons in a pair selected the target and had overlapping receptive fields (RFs), they cooperated more than when one or neither neuron in the pair selected the target, measured by positive spike timing correlations using joint peristimulus time histogram analysis. The amount of cooperation depended on the location of the search target: it was higher when the target was inside both neurons' RFs than when it was inside one RF but not the other, or outside both RFs. Elevated spike timing coincidences occurred at the time of attentional selection of the target as measured by average modulation of discharge rates. We observed competition among neurons with spatially non-overlapping RFs, measured by negative spike timing correlations. Thus, we provide evidence for dynamic and task-dependent cooperation and competition among frontal eye field neurons during visual target selection.

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Fenretinide promotes functional recovery and tissue protection after spinal cord contusion injury in mice.

Publication Date: 2010 Mar 3 PMID: 20203181
Authors: Lopez-Vales, R. - Redensek, A. - Skinner, T. A. - Rathore, K. I. - Ghasemlou, N. - Wojewodka, G. - Desanctis, J. - Radzioch, D. - David, S.
Journal: J Neurosci

The inflammatory response is thought to contribute to secondary damage after spinal cord injury (SCI). Polyunsaturated fatty acids (PUFAs) play an important role in the onset and resolution of inflammation. Arachidonic acid (AA), an omega-6 PUFA, contributes to the initiation of inflammatory responses, whereas docosahexaenoic acid (DHA), an omega-3 PUFA, has antiinflammatory effects. Therefore, decreasing AA and increasing DHA levels after SCI might be expected to attenuate inflammation after SCI and promote tissue protection and functional recovery. We show here that daily oral administration of fenretinide after spinal cord contusion injury led to a significant decrease in AA and an increase in DHA levels in plasma and injured spinal cord tissue. This was accompanied by a significant reduction in tissue damage and improvement in locomotor recovery. Fenretinide also reduced the expression of proinflammatory genes and the levels of oxidative stress markers after SCI. In addition, in vitro studies demonstrated that fenretinide reduced TNF-alpha (tumor necrosis factor-alpha) expression by reactive microglia. These results demonstrate that fenretinide treatment after SCI can reduce inflammation and tissue damage in the spinal cord and improve locomotor recovery. These beneficial effects may be mediated via the ability of fenretinide to modulate PUFA homeostasis. Since fenretinide is currently in clinical trials for the treatment of cancers, this drug might be a good candidate for the treatment of acute SCI in humans.

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Striatal prediction error modulates cortical coupling.

Publication Date: 2010 Mar 3 PMID: 20203180
Authors: den Ouden, H. E. - Daunizeau, J. - Roiser, J. - Friston, K. J. - Stephan, K. E.
Journal: J Neurosci

Both perceptual inference and motor responses are shaped by learned probabilities. For example, stimulus-induced responses in sensory cortices and preparatory activity in premotor cortex reflect how (un)expected a stimulus is. This is in accordance with predictive coding accounts of brain function, which posit a fundamental role of prediction errors for learning and adaptive behavior. We used functional magnetic resonance imaging and recent advances in computational modeling to investigate how (failures of) learned predictions about visual stimuli influence subsequent motor responses. Healthy volunteers discriminated visual stimuli that were differentially predicted by auditory cues. Critically, the predictive strengths of cues varied over time, requiring subjects to continuously update estimates of stimulus probabilities. This online inference, modeled using a hierarchical Bayesian learner, was reflected behaviorally: speed and accuracy of motor responses increased significantly with predictability of the stimuli. We used nonlinear dynamic causal modeling to demonstrate that striatal prediction errors are used to tune functional coupling in cortical networks during learning. Specifically, the degree of striatal trial-by-trial prediction error activity controls the efficacy of visuomotor connections and thus the influence of surprising stimuli on premotor activity. This finding substantially advances our understanding of striatal function and provides direct empirical evidence for formal learning theories that posit a central role for prediction error-dependent plasticity.

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Variability of visual responses of superior colliculus neurons depends on stimulus velocity.

Publication Date: 2010 Mar 3 PMID: 20203179
Authors: Mochol, G. - Wojcik, D. K. - Wypych, M. - Wrobel, A. - Waleszczyk, W. J.
Journal: J Neurosci

Visually responding neurons in the superficial, retinorecipient layers of the cat superior colliculus receive input from two primarily parallel information processing channels, Y and W, which is reflected in their velocity response profiles. We quantified the time-dependent variability of responses of these neurons to stimuli moving with different velocities by Fano factor (FF) calculated in discrete time windows. The FF for cells responding to low-velocity stimuli, thus receiving W inputs, increased with the increase in the firing rate. In contrast, the dynamics of activity of the cells responding to fast moving stimuli, processed by Y pathway, correlated negatively with FF whether the response was excitatory or suppressive. These observations were tested against several types of surrogate data. Whereas Poisson description failed to reproduce the variability of all collicular responses, the inclusion of secondary structure to the generating point process recovered most of the observed features of responses to fast moving stimuli. Neither model could reproduce the variability of low-velocity responses, which suggests that, in this case, more complex time dependencies need to be taken into account. Our results indicate that Y and W channels may differ in reliability of responses to visual stimulation. Apart from previously reported morphological and physiological differences of the cells belonging to Y and W channels, this is a new feature distinguishing these two pathways.

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Phosphorylation at S87 Is Enhanced in Synucleinopathies, Inhibits {alpha}-Synuclein Oligomerization, and Influences Synuclein-Membrane Interactions.

Publication Date: 2010 Mar 3 PMID: 20203178
Authors: Paleologou, K. E. - Oueslati, A. - Shakked, G. - Rospigliosi, C. C. - Kim, H. Y. - Lamberto, G. R. - Fernandez, C. O. - Schmid, A. - Chegini, F. - Gai, W. P. - Chiappe, D. - Moniatte, M. - Schneider, B. L. - Aebischer, P. - Eliezer, D. - Zweckstetter, M. - Masliah, E. - Lashuel, H. A.
Journal: J Neurosci

Increasing evidence suggests that phosphorylation may play an important role in the oligomerization, fibrillogenesis, Lewy body (LB) formation, and neurotoxicity of alpha-synuclein (alpha-syn) in Parkinson disease. Herein we demonstrate that alpha-syn is phosphorylated at S87 in vivo and within LBs. The levels of S87-P are increased in brains of transgenic (TG) models of synucleinopathies and human brains from Alzheimer disease (AD), LB disease (LBD), and multiple system atrophy (MSA) patients. Using antibodies against phosphorylated alpha-syn (S129-P and S87-P), a significant amount of immunoreactivity was detected in the membrane in the LBD, MSA, and AD cases but not in normal controls. In brain homogenates from diseased human brains and TG animals, the majority of S87-P alpha-syn was detected in the membrane fractions. A battery of biophysical methods were used to dissect the effect of S87 phosphorylation on the structure, aggregation, and membrane-binding properties of monomeric alpha-syn. These studies demonstrated that phosphorylation at S87 expands the structure of alpha-syn, increases its conformational flexibility, and blocks its fibrillization in vitro. Furthermore, phosphorylation at S87, but not S129, results in significant reduction of alpha-syn binding to membranes. Together, our findings provide novel mechanistic insight into the role of phosphorylation at S87 and S129 in the pathogenesis of synucleinopathies and potential roles of phosphorylation in alpha-syn normal biology.

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Calcium and Cyclic AMP Promote Axonal Regeneration in Caenorhabditis elegans and Require DLK-1 Kinase.

Publication Date: 2010 Mar 3 PMID: 20203177
Authors: Ghosh-Roy, A. - Wu, Z. - Goncharov, A. - Jin, Y. - Chisholm, A. D.
Journal: J Neurosci

Axons of adult Caenorhabditis elegans neurons undergo robust regenerative growth after laser axotomy. Here we show that axotomy of PLM sensory neurons triggers axonal calcium waves whose amplitude correlates with the extent of regeneration. Genetic elevation of Ca(2+) or cAMP accelerates formation of a growth cone from the injured axon. Elevated Ca(2+) or cAMP also facilitates apparent fusion of axonal fragments and promotes branching to postsynaptic targets. Conversely, inhibition of voltage-gated calcium channels or calcium release from internal stores reduces regenerative growth. We identify the fusogen EFF-1 as critical for axon fragment fusion and the basic leucine zipper domain (bZip) protein CREB (cAMP response element-binding protein) as a key effector for branching. The effects of elevated Ca(2+) or cAMP on regrowth require the MAPKKK (mitogen-activated protein kinase kinase kinase) DLK-1. Increased cAMP signaling can partly bypass the requirement for the bZip protein CEBP-1, a downstream factor of the DLK-1 kinase cascade. These findings reveal the relationship between Ca(2+)/cAMP signaling and the DLK-1 MAPK (mitogen-activated protein kinase) cascade in regeneration.

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Striatal Activity during Intentional Switching Depends on Pattern Stability.

Publication Date: 2010 Mar 3 PMID: 20203176
Authors: De Luca, C. - Jantzen, K. J. - Comani, S. - Bertollo, M. - Kelso, J. A.
Journal: J Neurosci

The theoretical framework of coordination dynamics posits complementary neural mechanisms to maintain complex behavioral patterns under circumstances that may render them unstable and to voluntarily switch between behaviors if changing internal or external conditions so demand. A candidate neural structure known to play a role in both the selection and maintenance of intentional behavior is the basal ganglia. Here, we use functional magnetic resonance imaging to explore the role of basal ganglia in intentional switching between bimanual coordination patterns that are known to differ in their stability as a function of movement rate. Key measures of pattern dynamics and switching were used to map behavior onto the associated neural circuitry to determine the relation between specific behavioral variables and activated brain areas. Results show that putamen activity is highly sensitive to pattern stability: greater activity was observed in bilateral putamen when subjects were required to switch from a more to a less stable pattern than vice versa. Since putamen activity correlated with pattern stability both before and during the switching process, its role may be to select desired actions and inhibit competing ones through parametric modulation of the intrinsic dynamics. Though compatible with recent computational models of basal ganglia function, our results further suggest that pattern stability determines how the basal ganglia efficiently and successfully select among response alternatives.

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Ubiquitination acutely regulates presynaptic neurotransmitter release in Mammalian neurons.

Publication Date: 2010 Mar 3 PMID: 20203175
Authors: Rinetti, G. V. - Schweizer, F. E.
Journal: J Neurosci

The ubiquitin proteasome system (UPS) plays a crucial role in modulating synaptic physiology both presynaptically and postsynaptically, but the regulatory mechanisms remain obscure. To determine acute effects of proteasome inhibition on neurotransmission, we performed whole-cell voltage-clamp recordings from cultured rodent hippocampal neurons. We find that proteasome inhibitors induce a strikingly fast, severalfold increase in the frequency of both miniature (mini) and spontaneous synaptic currents at excitatory and inhibitory synapses. The lack of change in mini amplitude and kinetics indicates a presynaptic site of action. This effect does not depend on increased levels of presynaptic proteins, previously suggested as proteasomal targets. Furthermore, blockade of the UPS using E1-activating enzyme inhibitors also increases mini frequency, demonstrating that accumulation of ubiquitinated proteins is not required. Overall, these data suggest that the UPS not only orchestrates protein turnover, but also dynamically regulates the activity state of presynaptic proteins, thus crucially shaping synaptic transmission.

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Heart-type fatty acid binding protein regulates dopamine D2 receptor function in mouse brain.

Publication Date: 2010 Feb 24 PMID: 20181611
Authors: Shioda, N. - Yamamoto, Y. - Watanabe, M. - Binas, B. - Owada, Y. - Fukunaga, K.
Journal: J Neurosci

Fatty acid binding proteins (FABPs) are essential for energy production and long-chain polyunsaturated fatty acid-related signaling in the brain and other tissues. Of various FABPs, heart-type fatty acid binding protein (H-FABP, FABP3) is highly expressed in neurons of mature brain and plays a role in arachidonic acid incorporation into brain and heart cells. However, the precise function of H-FABP in brain remains unclear. We previously demonstrated that H-FABP is associated with the dopamine D(2) receptor long isoform (D2LR) in vitro. Here, we confirm that H-FABP binds to dopamine D(2) receptor (D2R) in brain extracts and colocalizes immunohistochemically with D2R in the dorsal striatum. We show that H-FABP is highly expressed in acetylcholinergic interneurons and terminals of glutamatergic neurons in the dorsal striatum of mouse brain but absent in dopamine neuron terminals and spines in the same region. H-FABP knock-out (KO) mice showed lower responsiveness to methamphetamine-induced sensitization and enhanced haloperidol-induced catalepsy compared with wild-type mice, indicative of D2R dysfunction. Consistent with the latter, aberrant increased acetylcholine (ACh) release and depolarization-induced glutamate (Glu) release were observed in the dorsal striatum of H-FABP KO mice. Furthermore, phosphorylation of CaMKII (Ca(2+)/calmodulin-dependent protein kinase II) and ERK (extracellular signal-regulated kinase) was significantly increased in the dorsal striatum. We confirmed elevated ERK phosphorylation following quinpirole-mediated D2R stimulation in H-FABP-overexpressing SHSY-5Y human neuroblastoma cells. Together, H-FABP is highly expressed in ACh interneurons and glutamatergic terminals, thereby regulating dopamine D2R function in the striatum.

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Temporal cortex neurons encode articulated actions as slow sequences of integrated poses.

Publication Date: 2010 Feb 24 PMID: 20181610
Authors: Singer, J. M. - Sheinberg, D. L.
Journal: J Neurosci

Form and motion processing pathways of the primate visual system are known to be interconnected, but there has been surprisingly little investigation of how they interact at the cellular level. Here we explore this issue with a series of three electrophysiology experiments designed to reveal the sources of action selectivity in monkey temporal cortex neurons. Monkeys discriminated between actions performed by complex, richly textured, rendered bipedal figures and hands. The firing patterns of neurons contained enough information to discriminate the identity of the character, the action performed, and the particular conjunction of action and character. This suggests convergence of motion and form information within single cells. Form and motion information in isolation were both sufficient to drive action discrimination within these neurons, but removing form information caused a greater disruption to the original response. Finally, we investigated the temporal window across which visual information is integrated into a single pose (or, equivalently, the timing with which poses are differentiated). Temporal cortex neurons under normal conditions represent actions as sequences of poses integrated over approximately 120 ms. They receive both motion and form information, however, and can use either if the other is absent.

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Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat.

Publication Date: 2010 Feb 24 PMID: 20181609
Authors: Wakabayashi, Y. - Nakada, T. - Murata, K. - Ohkura, S. - Mogi, K. - Navarro, V. M. - Clifton, D. K. - Mori, Y. - Tsukamura, H. - Maeda, K. - Steiner, R. A. - Okamura, H.
Journal: J Neurosci

Gonadotropin-releasing hormone (GnRH) neurons in the basal forebrain are the final common pathway through which the brain regulates reproduction. GnRH secretion occurs in a pulsatile manner, and indirect evidence suggests the kisspeptin neurons in the arcuate nucleus (ARC) serve as the central pacemaker that drives pulsatile GnRH secretion. The purpose of this study was to investigate the possible coexpression of kisspeptin, neurokinin B (NKB), and dynorphin A (Dyn) in neurons of the ARC of the goat and evaluate their potential roles in generating GnRH pulses. Using double and triple labeling, we confirmed that all three neuropeptides are coexpressed in the same population of neurons. Using electrophysiological techniques to record multiple-unit activity (MUA) in the medial basal hypothalamus, we found that bursts of MUA occurred at regular intervals in ovariectomized animals and that these repetitive bursts (volleys) were invariably associated with discrete pulses of luteinizing hormone (LH) (and by inference GnRH). Moreover, the frequency of MUA volleys was reduced by gonadal steroids, suggesting that the volleys reflect the rhythmic discharge of steroid-sensitive neurons that regulate GnRH secretion. Finally, we observed that central administration of Dyn-inhibit MUA volleys and pulsatile LH secretion, whereas NKB induced MUA volleys. These observations are consistent with the hypothesis that kisspeptin neurons in the ARC drive pulsatile GnRH and LH secretion, and suggest that NKB and Dyn expressed in those neurons are involved in the process of generating the rhythmic discharge of kisspeptin.

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Bral1: its role in diffusion barrier formation and conduction velocity in the CNS.

Publication Date: 2010 Feb 24 PMID: 20181608
Authors: Bekku, Y. - Vargova, L. - Goto, Y. - Vorisek, I. - Dmytrenko, L. - Narasaki, M. - Ohtsuka, A. - Fassler, R. - Ninomiya, Y. - Sykova, E. - Oohashi, T.
Journal: J Neurosci

At the nodes of Ranvier, excitable axon membranes are exposed directly to the extracellular fluid. Cations are accumulated and depleted in the local extracellular nodal region during action potential propagation, but the impact of the extranodal micromilieu on signal propagation still remains unclear. Brain-specific hyaluronan-binding link protein, Bral1, colocalizes and forms complexes with negatively charged extracellular matrix (ECM) proteins, such as versican V2 and brevican, at the nodes of Ranvier in the myelinated white matter. The link protein family, including Bral1, appears to be the linchpin of these hyaluronan-bound ECM complexes. Here we report that the hyaluronan-associated ECM no longer shows a nodal pattern and that CNS nerve conduction is markedly decreased in Bral1-deficient mice even though there were no differences between wild-type and mutant mice in the clustering or transition of ion channels at the nodes or in the tissue morphology around the nodes of Ranvier. However, changes in the extracellular space diffusion parameters, measured by the real-time iontophoretic method and diffusion-weighted magnetic resonance imaging (MRI), suggest a reduction in the diffusion hindrances in the white matter of mutant mice. These findings provide a better understanding of the mechanisms underlying the accumulation of cations due to diffusion barriers around the nodes during saltatory conduction, which further implies the importance of the Bral1-based extramilieu for neuronal conductivity.

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Notch signaling influences neuroprotective and proliferative properties of mature Muller glia.

Publication Date: 2010 Feb 24 PMID: 20181607
Authors: Ghai, K. - Zelinka, C. - Fischer, A. J.
Journal: J Neurosci

Notch signaling is known to play important roles during retinal development. Recently, Notch signaling has been shown to be active in proliferating Muller glia in acutely damaged chick retina (Hayes et al., 2007). However, the roles of Notch in mature, undamaged retina remain unknown. Thus, the purpose of this study was to determine the role of the Notch-signaling pathway in the postnatal retina. Here we show that components of the Notch-signaling pathway are expressed in most Muller glia at low levels in undamaged retina. The expression of Notch-related genes varies during early postnatal development and across regions, with higher expression in peripheral versus central retina. Blockade of Notch activity with a small molecule inhibitor before damage was protective to retinal interneurons (amacrine and bipolar cells) and projection neurons (ganglion cells). In the absence of damage, Notch is upregulated in retinas treated with insulin and FGF2; the combination of these factors is known to stimulate the proliferation and dedifferentiation of Muller glia (Fischer et al., 2002b). Inhibition of Notch signaling during FGF2 treatment reduces levels of the downstream effectors of the MAPK-signaling pathway-p38 MAPK and pCREB in Muller glia. Further, inhibition of Notch activity potently inhibits FGF2-induced proliferation of Muller glia. Together, our data indicate that Notch signaling is downstream of, and is required for, FGF2/MAPK signaling to drive the proliferation of Muller glia. In addition, our data suggest that low levels of Notch signaling in Muller glia diminish the neuroprotective activities of these glial cells.

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In vivo intracellular recording suggests that gray matter astrocytes in mature cerebral cortex and hippocampus are electrophysiologically homogeneous.

Publication Date: 2010 Feb 24 PMID: 20181606
Authors: Mishima, T. - Hirase, H.
Journal: J Neurosci

Previous anatomical and in vitro electrophysiology studies suggest that astrocytes are heterogeneous in physiology, morphology, and biochemical content. However, the extent to which this diversity applies to in vivo conditions is largely unknown. To characterize and classify the physiological and morphological properties of cerebral cortical and hippocampal astrocytes in the intact brain, we performed in vivo intracellular recordings from single astrocytes using anesthetized mature rats. Astrocytes were classified based on their glial fibrillary acidic protein (GFAP) immunoreactivity and cell body locations. We analyzed morphometric measures such as the occupied volume and polarity, as well as physiological characteristics such as the mean membrane potential. These measurements did not show obvious segregation into subpopulations, suggesting that gray matter astrocytes in the cortex and hippocampus are composed of a homogeneous population in mature animals. The membrane potential of astrocytes in both cortex and hippocampus fluctuated within a few millivolts in the presence of spontaneous network activity. These membrane potential fluctuations of an astrocyte showed a significant variability that depended on the local field potential state and cell body location. We attribute the variability of the membrane potential fluctuations to local potassium concentration changes due to neuronal activity.

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Whisker-related axonal patterns and plasticity of layer 2/3 neurons in the mouse barrel cortex.

Publication Date: 2010 Feb 24 PMID: 20181605
Authors: Sehara, K. - Toda, T. - Iwai, L. - Wakimoto, M. - Tanno, K. - Matsubayashi, Y. - Kawasaki, H.
Journal: J Neurosci

Elucidating neuronal circuits and their plasticity in the cerebral cortex is one of the important questions in neuroscience research. Here we report novel axonal trajectories and their plasticity in the mouse somatosensory barrel cortex. We selectively visualized layer 2/3 neurons using in utero electroporation and examined the axonal trajectories of layer 2/3 neurons. We found that the axons of layer 2/3 neurons preferentially run in the septal regions of layer 4 and named this axonal pattern "barrel nets." The intensity of green fluorescent protein in the septal regions was markedly higher compared with that in barrel hollows. Focal in utero electroporation revealed that the axons in barrel nets were indeed derived from layer 2/3 neurons in the barrel cortex. During development, barrel nets became visible at postnatal day 10, which was well after the initial appearance of barrels. When whisker follicles were cauterized within 3 d after birth, the whisker-related pattern of barrel nets was altered, suggesting that cauterization of whisker follicles results in developmental plasticity of barrel nets. Our results uncover the novel axonal trajectories of layer 2/3 neurons with whisker-related patterns and their developmental plasticity in the mouse somatosensory cortex. Barrel nets should be useful for investigating the pattern formation and axonal reorganization of intracortical neuronal circuits.

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Homer 1a gates the induction mechanism for endocannabinoid-mediated synaptic plasticity.

Publication Date: 2010 Feb 24 PMID: 20181604
Authors: Roloff, A. M. - Anderson, G. R. - Martemyanov, K. A. - Thayer, S. A.
Journal: J Neurosci

At hippocampal excitatory synapses, endocannabinoids (eCBs) mediate two forms of retrograde synaptic inhibition that are induced by postsynaptic depolarization or activation of metabotropic glutamate receptors (mGluRs). The homer family of molecular scaffolds provides spatial organization to regulate postsynaptic signaling cascades, including those activated by mGluRs. Expression of the homer 1a (H1a) immediate-early gene produces a short homer protein that lacks the domain required for homer oligomerization, enabling it to uncouple homer assemblies. Here, we report that H1a differentially modulates two forms of eCB-mediated synaptic plasticity, depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE). EPSCs were recorded from cultured hippocampal neurons and DSE evoked by a 15 s depolarization to 0 mV and MSE evoked by a type I mGluR agonist. Expression of H1a enhanced DSE and inhibited MSE at the same synapse. Many physiologically important stimuli initiate H1a expression including brain-derived neurotrophic factor (BDNF). Treating hippocampal cultures with BDNF increased transcription of H1a and uncoupled homer 1c-GFP (green fluorescent protein) clusters. BDNF treatment blocked MSE and enhanced DSE. Thus, physiological changes in H1a expression gate the induction pathway for eCB-mediated synaptic plasticity by uncoupling mGluR from eCB production.

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Prefrontal inositol triphosphate is molecular correlate of working memory in nonhuman primates.

Publication Date: 2010 Feb 24 PMID: 20181603
Authors: Lopez-Tellez, J. F. - Lopez-Aranda, M. F. - Navarro-Lobato, I. - Masmudi-Martin, M. - Montanez, E. M. - Calvo, E. B. - Khan, Z. U.
Journal: J Neurosci

Working memory (WM) is a process of actively maintaining information in the mind for a relatively short period of time, and prefrontal cortex (PFC) has been thought to play a central role in its function. However, our understanding of underlying molecular events that translate into WM behavior remains elusive. To shed light on this issue, we have used three distinct nonhuman primate models of WM where each model represents three WM conditions: normal control, WM-deficient, and recuperated to normal from WM deficiency. Based on the hypothesis that there is a common molecular substrate for the coding of WM behavior, we have studied the relationship of these animals' performance on a WM task with their PFC levels of molecular components associated with Gq-phospholipase C and cAMP pathways, with the idea of identifying the footprints of such biomolecules. We observed that in all of the primate models WM deficiency was strongly related to the reduced concentration of IP(3) in PFC, whereas recuperation of WM-deficient animals to normal condition was associated with the normalization in IP(3) level. However, this correlation was absent or weak for cAMP, active protein kinase A, dopamine D(1) receptor, and Gq protein. In addition, WM deficiency related not only to pharmacological conditions but also to aging. Thus, it is suggested that optimal IP(3) activity is essential for normal WM function and the maintenance of intracellular IP(3)-mediated Ca(2+) level in PFC may serve as biochemical substrate for the expression of WM behavior.

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Attentional modulation of MT neurons with single or multiple stimuli in their receptive fields.

Publication Date: 2010 Feb 24 PMID: 20181602
Authors: Lee, J. - Maunsell, J. H.
Journal: J Neurosci

Descriptions of how attention modulates neuronal responses suggest that the strength of its effects depends on stimulus conditions. Attention to an isolated stimulus in the receptive field of an individual neuron typically produces a moderate enhancement of the cell's response, but neuronal responses are often strongly modulated when attention is shifted between multiple stimuli that lie within the receptive field. However, previous reports have not compared these stimulus effects under equivalent conditions, so differences in task difficulty could have been responsible for much of the difference. Consequently, the quantitative effects of stimulus conditions have remained unknown, and it has not been possible to address the question of whether the differences that have been observed could be explained by a single mechanism. We measured the attentional modulation of the responses of 70 single neurons in area MT of two rhesus monkeys using a task designed to keep attention stable across different stimulus configurations. We found that attentional modulation was indeed much stronger when more than one stimulus was within the receptive field. Nevertheless, the broad range of attentional modulations seen across the different conditions could be readily explained by single mechanism. The neurophysiological data from all stimulus conditions were well fit by a model in which attention acts via a response normalization mechanism (Lee and Maunsell, 2009). Collectively, these results validate previous impressions of the effects of stimulus configuration on attentional modulation, and add support to hypothesis that attention modulation depends on a response normalization mechanism.

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Absence of an external germinal layer in zebrafish and shark reveals a distinct, anamniote ground plan of cerebellum development.

Publication Date: 2010 Feb 24 PMID: 20181601
Authors: Chaplin, N. - Tendeng, C. - Wingate, R. J.
Journal: J Neurosci

The granule cell layer of the cerebellum comprises the largest population of neurons in the vertebrate CNS. In amniotes, its precursors undergo a unique phase of transit amplification, regulated by Sonic hedgehog. They do so within a prominent but transient secondary proliferative epithelium, the external germinal layer, which is formed by tangential migration of precursor cells from the rhombic lip. This behavior is a hallmark of bird and mammal cerebellum development. Despite its significance for both development and disease, it is unclear whether an external germinal layer is a requirement for granule cell production or an expedient of transit amplification. Evidence for its existence in more basal vertebrates is contradictory. We therefore examined cerebellum development in the zebrafish, specifically in relation to the expression of the basic helix-loop-helix gene Atonal 1, which definitively characterizes granule cell precursors. The expression of Atoh1a-Atoh1c, in combination with patterns of proliferation and fate maps, define precursor pools at the rhombic lip and cerebellar midline but demonstrate that an external germinal layer is absent. Sonic hedgehog signaling is correspondingly absent in the zebrafish cerebellum. Sustained roof-plate-derived signals suggest that, in the absence of transit amplification, primary granule cell precursor pools are maintained throughout development. To determine whether this pattern is specific to zebrafish or reflects a more general anamniote organization, we examined the expression of similar genes in the dogfish, Scylliorhinus canicula. We show that these anamniotes share a common ground plan of granule cell production that does not include an external germinal layer.

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Contribution of dopamine D1 and D2 receptors to amygdala activity in human.

Publication Date: 2010 Feb 24 PMID: 20181600
Authors: Takahashi, H. - Takano, H. - Kodaka, F. - Arakawa, R. - Yamada, M. - Otsuka, T. - Hirano, Y. - Kikyo, H. - Okubo, Y. - Kato, M. - Obata, T. - Ito, H. - Suhara, T.
Journal: J Neurosci

Several animal studies have demonstrated functional roles of dopamine (DA) D1 and D2 receptors in amygdala activity. However, the contribution of DA D1 and D2 receptors to amygdala response induced by affective stimuli in human is unknown. To investigate the contribution of DA receptor subtypes to amygdala reactivity in human, we conducted a multimodal in vivo neuroimaging study in which DA D1 and D2 receptor bindings in the amygdala were measured with positron emission tomography (PET), and amygdala response induced by fearful faces was assessed by functional magnetic resonance imaging (fMRI) in healthy volunteers. We used multimodality voxelwise correlation analysis between fMRI signal and DA receptor binding measured by PET. DA D1 binding in the amygdala was positively correlated with amygdala signal change in response to fearful faces, but DA D2 binding in the amygdala was not related to amygdala signal change. DA D1 receptors might play a major role in enhancing amygdala response when sensory inputs are affective.

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Macaque parieto-insular vestibular cortex: responses to self-motion and optic flow.

Publication Date: 2010 Feb 24 PMID: 20181599
Authors: Chen, A. - DeAngelis, G. C. - Angelaki, D. E.
Journal: J Neurosci

The parieto-insular vestibular cortex (PIVC) is thought to contain an important representation of vestibular information. Here we describe responses of macaque PIVC neurons to three-dimensional (3D) vestibular and optic flow stimulation. We found robust vestibular responses to both translational and rotational stimuli in the retroinsular (Ri) and adjacent secondary somatosensory (S2) cortices. PIVC neurons did not respond to optic flow stimulation, and vestibular responses were similar in darkness and during visual fixation. Cells in the upper bank and tip of the lateral sulcus (Ri and S2) responded to sinusoidal vestibular stimuli with modulation at the first harmonic frequency and were directionally tuned. Cells in the lower bank of the lateral sulcus (mostly Ri) often modulated at the second harmonic frequency and showed either bimodal spatial tuning or no tuning at all. All directions of 3D motion were represented in PIVC, with direction preferences distributed approximately uniformly for translation, but showing a preference for roll rotation. Spatiotemporal profiles of responses to translation revealed that half of PIVC cells followed the linear velocity profile of the stimulus, one-quarter carried signals related to linear acceleration (in the form of two peaks of direction selectivity separated in time), and a few neurons followed the derivative of linear acceleration (jerk). In contrast, mainly velocity-coding cells were found in response to rotation. Thus, PIVC comprises a large functional region in macaque areas Ri and S2, with robust responses to 3D rotation and translation, but is unlikely to play a significant role in visual/vestibular integration for self-motion perception.

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Smelling sounds: olfactory-auditory sensory convergence in the olfactory tubercle.

Publication Date: 2010 Feb 24 PMID: 20181598
Authors: Wesson, D. W. - Wilson, D. A.
Journal: J Neurosci

Historical and psychophysical literature has demonstrated a perceptual interplay between olfactory and auditory stimuli-the neural mechanisms of which are not understood. Here, we report novel findings revealing that the early olfactory code is subjected to auditory cross-modal influences. In vivo extracellular recordings from the olfactory tubercle, a trilaminar structure within the basal forebrain, of anesthetized mice revealed that olfactory tubercle single units selectively respond to odors-with 65% of units showing significant odor-evoked activity. Remarkably, 19% of olfactory tubercle single units also showed robust responses to an auditory tone. Furthermore, 29% of single units tested displayed supraadditive or suppressive responses to the simultaneous presentation of odor and tone, suggesting cross-modal modulation. In contrast, olfactory bulb units did not show significant responses to tone presentation nor modulation of odor-evoked activity by tone-suggesting a lack of olfactory-auditory convergence upstream from the olfactory tubercle. Thus, the tubercle presents itself as a source for direct multimodal convergence within an early stage of odor processing and may serve as a seat for psychophysical interactions between smells and sounds.

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Novel embryonic neuronal migration and proliferation defects in Dcx mutant mice are exacerbated by Lis1 reduction.

Publication Date: 2010 Feb 24 PMID: 20181597
Authors: Pramparo, T. - Youn, Y. H. - Yingling, J. - Hirotsune, S. - Wynshaw-Boris, A.
Journal: J Neurosci

Heterozygous LIS1 mutations and males with loss of the X-linked DCX result in lissencephaly, a neuronal migration defect. LIS1 regulates nuclear translocation and mitotic division of neural progenitor cells, while the role of DCX in cortical development remains poorly understood. Here, we uncovered novel neuronal migration and proliferation defects in the Dcx mutant embryonic brains. Although cortical organization was fairly well preserved, Dcx(ko/Y) neurons displayed defective migration velocities similar to Lis1(+/ko) neurons when characterized by time-lapse video-microscopy of embryonic cortical slices. Dcx(ko/Y) migrating neurons displayed novel multidirectional movements with abnormal morphology and increased branching. Surprisingly, Dcx(ko/Y) radial glial cells displayed spindle orientation abnormalities similar to Lis1(+/ko) cells that in turn lead to moderate proliferation defects both in vivo and in vitro. We found functional genetic interaction of the two genes, with the combined effects of Lis1 haploinsufficiency and Dcx knock-out leading to more severe neuronal migration and proliferation phenotypes in the Lis1(+/ko);Dcx(ko/Y) male double mutant compared with the single mutants, resulting in cortical disorganization and depletion of the progenitor pool. Thus, we provide definitive evidence for a critical role for Dcx in neuronal migration and neurogenesis, as well as for the in vivo genetic interaction of the two genes most commonly involved in human neuronal migration defects.

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Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinal cord injury.

Publication Date: 2010 Feb 24 PMID: 20181596
Authors: Cao, Q. - He, Q. - Wang, Y. - Cheng, X. - Howard, R. M. - Zhang, Y. - DeVries, W. H. - Shields, C. B. - Magnuson, D. S. - Xu, X. M. - Kim, D. H. - Whittemore, S. R.
Journal: J Neurosci

Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC(+)) OLs, and CNTF significantly increased the percentage of APC(+) OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI.

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Proteomic identification of binding partners for the brain metabolite lanthionine ketimine (LK) and documentation of LK effects on microglia and motoneuron cell cultures.

Publication Date: 2010 Feb 24 PMID: 20181595
Authors: Hensley, K. - Christov, A. - Kamat, S. - Zhang, X. C. - Jackson, K. W. - Snow, S. - Post, J.
Journal: J Neurosci

Lanthionine ketimine (LK) represents a poorly understood class of thioethers present in mammalian CNS. Previous work has indicated high-affinity interaction of LK with synaptosomal membrane protein(s), but neither LK binding partners nor specific bioactivities have been reported. In this study, LK was chemically synthesized and used as an affinity agent to capture binding partners from mammalian brain lysate. Liquid chromatography with electrospray ionization-mass spectrometry of electrophoretically separated, LK-bound proteins identified polypeptides implicated in axon remodeling or vesicle trafficking and diseases including Alzheimer's disease and schizophrenia: collapsin response mediator protein-2/dihydropyrimidinase-like protein-2 (CRMP2/DRP2/DPYSL2), myelin basic protein, and syntaxin-binding protein-1 (STXBP1/Munc-18). Also identified was the recently discovered glutathione-binding protein lanthionine synthetase-like protein-1. Functional consequences of LK:CRMP2 interactions were probed through immunoprecipitation studies using brain lysate wherein LK was found to increase CRMP2 coprecipitation with its partner neurofibromin-1 but decreased CRMP2 coprecipitation with beta-tubulin. Functional studies of NSC-34 motor neuron-like cells indicated that a cell-permeable LK-ester, LKE, was nontoxic and protective against oxidative challenge with H(2)O(2). LKE-treated NSC-34 cells significantly increased neurite number and length in a serum concentration-dependent manner, consistent with a CRMP2 interaction. Finally, LKE antagonized the activation of EOC-20 microglia by inflammogens. The results are discussed with reference to possible biochemical origins, paracrine functions, neurological significance, and pharmacological potential of lanthionyl compounds.

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NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death.

Publication Date: 2010 Feb 24 PMID: 20181594
Authors: Alano, C. C. - Garnier, P. - Ying, W. - Higashi, Y. - Kauppinen, T. M. - Swanson, R. A.
Journal: J Neurosci

Poly(ADP-ribose)-1 (PARP-1) is a key mediator of cell death in excitotoxicity, ischemia, and oxidative stress. PARP-1 activation leads to cytosolic NAD(+) depletion and mitochondrial release of apoptosis-inducing factor (AIF), but the causal relationships between these two events have been difficult to resolve. Here, we examined this issue by using extracellular NAD(+) to restore neuronal NAD(+) levels after PARP-1 activation. Exogenous NAD(+) was found to enter neurons through P2X(7)-gated channels. Restoration of cytosolic NAD(+) by this means prevented the glycolytic inhibition, mitochondrial failure, AIF translocation, and neuron death that otherwise results from extensive PARP-1 activation. Bypassing the glycolytic inhibition with the metabolic substrates pyruvate, acetoacetate, or hydroxybutyrate also prevented mitochondrial failure and neuron death. Conversely, depletion of cytosolic NAD(+) with NAD(+) glycohydrolase produced a block in glycolysis inhibition, mitochondrial depolarization, AIF translocation, and neuron death, independent of PARP-1 activation. These results establish NAD(+) depletion as a causal event in PARP-1-mediated cell death and place NAD(+) depletion and glycolytic failure upstream of mitochondrial AIF release.

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Stimulus predictability reduces responses in primary visual cortex.

Publication Date: 2010 Feb 24 PMID: 20181593
Authors: Alink, A. - Schwiedrzik, C. M. - Kohler, A. - Singer, W. - Muckli, L.
Journal: J Neurosci

In this functional magnetic resonance imaging study we tested whether the predictability of stimuli affects responses in primary visual cortex (V1). The results of this study indicate that visual stimuli evoke smaller responses in V1 when their onset or motion direction can be predicted from the dynamics of surrounding illusory motion. We conclude from this finding that the human brain anticipates forthcoming sensory input that allows predictable visual stimuli to be processed with less neural activation at early stages of cortical processing.

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Acquisition and performance of goal-directed instrumental actions depends on ERK signaling in distinct regions of dorsal striatum in rats.

Publication Date: 2010 Feb 24 PMID: 20181592
Authors: Shiflett, M. W. - Brown, R. A. - Balleine, B. W.
Journal: J Neurosci

The performance of goal-directed actions relies on an animal's previous knowledge of the outcomes or consequences that result from its actions. Additionally, a sensorimotor learning process linking environmental stimuli with actions influences instrumental performance by selecting actions for additional evaluation. These distinct decision-making processes in rodents depend on separate subregions of the dorsal striatum. Whereas the posterior dorsomedial striatum (pDMS) is required for the encoding of actions with their outcomes or consequences, the dorsolateral striatum (DLS) mediates action selection based on sensorimotor learning. However, the molecular mechanisms within these brain regions that support learning and performance of goal-directed behavior are not known. Here we show that activation of extracellular signal-regulated kinase (ERK) in the dorsal striatum has a critical role in learning and performance of instrumental goal-directed behavior in rodents. We observed an increase in p42 ERK (ERK2) activation in both the pDMS and DLS during both the acquisition and performance of recently acquired instrumental goal-directed actions. Furthermore, disruption of ERK activation in the pDMS prevented both the acquisition of action-outcome associations, as well as the performance of goal-directed actions guided by previously acquired associations, whereas disruption of ERK activation in the DLS disrupted instrumental performance but left instrumental action-outcome learning intact. These results provide evidence of a critical, region-specific role for ERK signaling in the dorsal striatum during the acquisition of instrumental learning and suggest that processes sensitive to ERK signaling within these striatal subregions interact to control instrumental performance after initial acquisition.

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Dopamine-dependent tuning of striatal inhibitory synaptogenesis.

Publication Date: 2010 Feb 24 PMID: 20181591
Authors: Goffin, D. - Ali, A. B. - Rampersaud, N. - Harkavyi, A. - Fuchs, C. - Whitton, P. S. - Nairn, A. C. - Jovanovic, J. N.
Journal: J Neurosci

Dopaminergic projections to the striatum, crucial for the correct functioning of this brain region in adulthood, are known to be established early in development, but their role is currently uncharacterized. We demonstrate here that dopamine, by activating D(1)- and/or D(2)-dopamine receptors, decreases the number of functional GABAergic synapses formed between the embryonic precursors of the medium spiny neurons, the principal output neurons of the striatum, with associated changes in spontaneous synaptic activity. Activation of these receptors reduces the size of postsynaptic GABA(A) receptor clusters and their overall cell-surface expression, without affecting the total number of clusters or the size or number of GABAergic nerve terminals. These changes result from an increased internalization of GABA(A) receptors, and are mediated by distinct signaling pathways converging at the level of GABA(A) receptors to cause a transient PP2A/PP1-dependent dephosphorylation. Thus, tonic D(1)- and D(2)-receptor activity limits the extent of collateral inhibitory synaptogenesis between medium spiny neurons, revealing a novel role of dopamine in controlling the development of intrinsic striatal microcircuits.

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The inferior parietal lobule and recognition memory: expectancy violation or successful retrieval?

Publication Date: 2010 Feb 24 PMID: 20181590
Authors: O'Connor, A. R. - Han, S. - Dobbins, I. G.
Journal: J Neurosci

Functional neuroimaging studies of episodic recognition demonstrate an increased lateral parietal response for studied versus new materials, often termed a retrieval success effect. Using a novel memory analog of attentional cueing, we manipulated the correspondence between anticipated and actual recognition evidence by presenting valid or invalid anticipatory cues (e.g., "likely old") before recognition judgments. Although a superior parietal region demonstrated the retrieval success pattern, a larger inferior parietal lobule (IPL) region tracked the validity of the memory cueing (invalid cueing > valid cueing) and no retrieval success-sensitive lateral parietal region was insensitive to cueing. The invalid cueing response occurred even for correctly identified new items unlikely to trigger substantive episodic retrieval. Within the IPL, although supramarginal and angular gyrus (SMG; AG) regions both demonstrated invalid cueing amplitude elevations, each region differentially coupled with distinct cortical networks when unexpectedly old items were encountered; a connectivity pattern also observed at rest in the same subjects. These findings jointly suggest that the lateral parietal response during recognition does not signify the recovery of episodic content, but is a marker of the violation of memory expectations. A second independent dataset confirmed this interpretation by demonstrating that SMG activation tracked the decision biases of observers, not their accuracy, with increased activation for nondominant recognition judgments. The expectancy violation interpretation of the lateral parietal recognition response is consistent with the literature on visual search and oddball paradigms and suggests that damage to these regions should impair memory-linked orienting behavior and not retrieval per se.

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Astrocyte-mediated hepatocyte growth factor/scatter factor supplementation restores GABAergic interneurons and corrects reversal learning deficits in mice.

Publication Date: 2010 Feb 24 PMID: 20181589
Authors: Bissonette, G. B. - Bae, M. H. - Suresh, T. - Jaffe, D. E. - Powell, E. M.
Journal: J Neurosci

Many psychiatric and neurological disorders present persistent neuroanatomical abnormalities in multiple brain regions that may reflect a common origin for a developmental disturbance. In mammals, many of the local GABAergic inhibitory interneurons arise from a single subcortical source. Perturbations in the ontogeny of the GABAergic interneurons may be reflected in the adult by interneuron deficits in both frontal cerebral cortical and striatal regions. Disrupted GABAergic circuitry has been reported in patients with schizophrenia and frontal lobe epilepsy and may contribute to their associated impairments in behavioral flexibility. The present study demonstrates that one type of behavioral flexibility, reversal learning, is dependent upon proper numbers of GABAergic interneurons. Mice with abnormal interneuron ontogeny have reduced numbers of parvalbumin-expressing GABAergic local interneurons in the orbitofrontal cortical and striatal regions and impaired reversal leaning. Using a genetic approach, both the anatomical and functional deficiencies are restored with exogenous postnatal growth factor supplementation. These results show that GABAergic local circuitry is critical for modulating behavioral flexibility and that birth defects can be corrected by replenishing crucial growth factors.

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Inactivation of the central but not the basolateral nucleus of the amygdala disrupts learning in response to overexpectation of reward.

Publication Date: 2010 Feb 24 PMID: 20181588
Authors: Haney, R. Z. - Calu, D. J. - Takahashi, Y. K. - Hughes, B. W. - Schoenbaum, G.
Journal: J Neurosci

The amygdala is critical for associating predictive cues with primary rewarding and aversive outcomes. This is particularly evident in tasks in which information about expected outcomes is required for normal responding. Here we used a pavlovian overexpectation task to test whether outcome signaling by amygdala might also be necessary for changing those representations in the face of unexpected outcomes. Rats were trained to associate several different cues with a food reward. After learning, two of the cues were presented together, in compound, followed by the same reward. Before each compound training session, rats received infusions of 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide or saline into either the basolateral (ABL) or central nucleus (CeN) of amygdala. We found that infusions into CeN abolished the normal decline in responding to the compounded cue in a later probe test, whereas infusions into ABL had no effect. These results are inconsistent with the proposal that signaling of information about expected outcomes by ABL contributes to learning, at least in this setting, and instead implicate the CeN in this process, perhaps attributable to the hypothesized involvement of this area in attention and variations in stimulus processing.

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The coxsackievirus-adenovirus receptor reveals complex homophilic and heterophilic interactions on neural cells.

Publication Date: 2010 Feb 24 PMID: 20181587
Authors: Patzke, C. - Max, K. E. - Behlke, J. - Schreiber, J. - Schmidt, H. - Dorner, A. A. - Kroger, S. - Henning, M. - Otto, A. - Heinemann, U. - Rathjen, F. G.
Journal: J Neurosci

The coxsackievirus-adenovirus receptor (CAR) is a member of the Ig superfamily strongly expressed in the developing nervous system. Our histological investigations during development reveal an initial uniform distribution of CAR on all neural cells with a concentration on membranes that face the margins of the nervous system (e.g., the basal laminae and the ventricular side). At more advanced stages, CAR becomes downregulated and restricted to specific regions including areas rich in axonal and dendritic surfaces. To study the function of CAR on neural cells, we used the fiber knob of the adenovirus, extracellular CAR domains, blocking antibodies to CAR, as well as CAR-deficient neural cells. Blocking antibodies were found to inhibit neurite extension in retina organ and retinal explant cultures, whereas the application of the recombinant fiber knob of the adenovirus subtype Ad2 or extracellular CAR domains promoted neurite extension and adhesion to extracellular matrices. We observed a promiscuous interaction of CAR with extracellular matrix glycoproteins, which was deduced from analytical ultracentrifugation experiments, affinity chromatography, and adhesion assays. The membrane proximal Ig domain of CAR, termed D2, was found to bind to a fibronectin fragment, including the heparin-binding domain 2, which promotes neurite extension of wild type, but not of CAR-deficient neural cells. In contrast to heterophilic interactions, homophilic association of CAR involves both Ig domains, as was revealed by ultracentrifugation, chemical cross-linking, and adhesion studies. The results of these functional and binding studies are correlated to a U-shaped homodimer of the complete extracellular domains of CAR detected by x-ray crystallography.

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Cyclosporin A has direct effects on adult neural precursor cells.

Publication Date: 2010 Feb 24 PMID: 20181586
Authors: Hunt, J. - Cheng, A. - Hoyles, A. - Jervis, E. - Morshead, C. M.
Journal: J Neurosci

Multipotent, self-renewing neural stem cells and their progeny [collectively referred to as neural precursor cells (NPCs)] represent a population of cells with great promise for CNS repair. To effectively harness their potential for therapeutic applications, the factors that regulate NPC behavior and/or fate must be well understood. The ability of immunomodulatory molecules to affect NPC behavior is of interest because of recent work elucidating the complex interactions between the immune system and nervous system. Herein, we examined the effects of cyclosporin A, a commonly used immunosuppressive molecule, on NPC proliferation kinetics, survival, and fate using in vitro assays at the population level and at the single-cell level. The use of pure populations of NPCs revealed a direct effect of cyclosporin A on cell survival, resulting in increased numbers and larger colonies, with no effect on proliferation kinetics. Cyclosporin A did not alter the differentiation profile of NPC colonies, indicating that it did not promote selective survival of a particular neural lineage. Additionally, we observed decreased cell-cell adhesions in developing cyclosporin A-treated NPC colonies. Consistent with the in vitro observations, in vivo administration of cyclosporin A to adult animals increased the numbers of NPCs within the neurogenic niche lining the lateral ventricles. Together, our findings establish that cyclosporin A has direct effects on NPCs both in vitro and in vivo, making it a promising candidate molecule for developing clinically relevant strategies to stimulate NPCs for brain repair.

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Lack of Mid1, the mouse ortholog of the Opitz syndrome gene, causes abnormal development of the anterior cerebellar vermis.

Publication Date: 2010 Feb 24 PMID: 20181585
Authors: Lancioni, A. - Pizzo, M. - Fontanella, B. - Ferrentino, R. - Napolitano, L. M. - De Leonibus, E. - Meroni, G.
Journal: J Neurosci

Opitz G/BBB syndrome (OS) is a genetic disorder characterized by midline developmental defects. Male patients with the X-linked form of OS, caused by loss-of-function mutations in the MID1 gene, show high variability of the clinical signs. MID1 encodes a ubiquitin ligase that controls phosphatase 2A, but its role in the pathogenesis of the disease is still unclear. Here, we report a mouse line carrying a nonfunctional ortholog of the human MID1 gene, Mid1. Mid1-null mice show the brain anatomical defect observed in patients (i.e., hypoplasia of the anterior portion of the medial cerebellum, the vermis). We found that the presence of this defect correlates with motor coordination and procedural and nonassociative learning impairments. The defect is limited to the most anterior lobes of the vermis, the region of the developing cerebellum adjacent to the dorsal midbrain. Analyses at midgestation reveal that lack of Mid1 causes the shortening of the posterior dorsal midbrain, the rostralization of the midbrain/cerebellum boundary, and the downregulation of a key player in the development of this region, Fgf17. Thus, lack of Mid1 causes a misspecification of the midbrain/cerebellar boundary that results in an abnormal development of the most anterior cerebellar lobes. This animal model provides a tool for additional in vivo studies of the physiological and pathological role of the Mid1 gene and a system to investigate the development and function of anterior cerebellar domains.

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Diverse voltage-sensitive dyes modulate GABAA receptor function.

Publication Date: 2010 Feb 24 PMID: 20181584
Authors: Mennerick, S. - Chisari, M. - Shu, H. J. - Taylor, A. - Vasek, M. - Eisenman, L. N. - Zorumski, C. F.
Journal: J Neurosci

Voltage-sensitive dyes are important tools for assessing network and single-cell excitability, but an untested premise in most cases is that the dyes do not interfere with the parameters (membrane potential, excitability) that they are designed to measure. We found that popular members of several different families of voltage-sensitive dyes modulate GABA(A) receptor with maximum efficacy and potency similar to clinically used GABA(A) receptor modulators. Di-4-ANEPPS and DiBAC4(3) potentiated GABA function with micromolar and high nanomolar potency, respectively, and yielded strong maximum effects similar to barbiturates and neurosteroids. Newer blue oxonols had biphasic effects on GABA(A) receptor function at nanomolar and micromolar concentrations, with maximum potentiation comparable to that of saturating benzodiazepine effects. ANNINE-6 and ANNINE-6plus had no detectable effect on GABA(A) receptor function. Even dyes with no activity on GABA(A) receptors at baseline induced photodynamic enhancement of GABA(A) receptors. The basal effects of dyes were sufficient to prolong IPSCs and to dampen network activity in multielectrode array recordings. Therefore, the dual effects of voltage-sensitive dyes on GABAergic inhibition require caution in dye use for studies of excitability and network activity.

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Reconciling coherent oscillation with modulation of irregular spiking activity in selective attention: gamma-range synchronization between sensory and executive cortical areas.

Publication Date: 2010 Feb 24 PMID: 20181583
Authors: Ardid, S. - Wang, X. J. - Gomez-Cabrero, D. - Compte, A.
Journal: J Neurosci

In this computational work, we investigated gamma-band synchronization across cortical circuits associated with selective attention. The model explicitly instantiates a reciprocally connected loop of spiking neurons between a sensory-type (area MT) and an executive-type (prefrontal/parietal) cortical circuit (the source area for top-down attentional signaling). Moreover, unlike models in which neurons behave as clock-like oscillators, in our model single-cell firing is highly irregular (close to Poisson), while local field potential exhibits a population rhythm. In this "sparsely synchronized oscillation" regime, the model reproduces and clarifies multiple observations from behaving animals. Top-down attentional inputs have a profound effect on network oscillatory dynamics while only modestly affecting single-neuron spiking statistics. In addition, attentional synchrony modulations are highly selective: interareal neuronal coherence occurs only when there is a close match between the preferred feature of neurons, the attended feature, and the presented stimulus, a prediction that is experimentally testable. When interareal coherence was abolished, attention-induced gain modulations of sensory neurons were slightly reduced. Therefore, our model reconciles the rate and synchronization effects, and suggests that interareal coherence contributes to large-scale neuronal computation in the brain through modest enhancement of rate modulations as well as a pronounced attention-specific enhancement of neural synchrony.

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Critical involvement of postsynaptic protein kinase activation in long-term potentiation at hippocampal mossy fiber synapses on CA3 interneurons.

Publication Date: 2010 Feb 24 PMID: 20181582
Authors: Galvan, E. J. - Cosgrove, K. E. - Mauna, J. C. - Card, J. P. - Thiels, E. - Meriney, S. D. - Barrionuevo, G.
Journal: J Neurosci

Hippocampal mossy fiber (MF) synapses on area CA3 lacunosum-moleculare (L-M) interneurons are capable of undergoing a Hebbian form of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) induced by the same type of high-frequency stimulation (HFS) that induces LTP at MF synapses on pyramidal cells. LTP of MF input to L-M interneurons occurs only at synapses containing mostly calcium-impermeable (CI)-AMPA receptors (AMPARs). Here, we demonstrate that HFS-induced LTP at these MF-interneuron synapses requires postsynaptic activation of protein kinase A (PKA) and protein kinase C (PKC). Brief extracellular stimulation of PKA with forskolin (FSK) alone or in combination with 1-Methyl-3-isobutylxanthine (IBMX) induced a long-lasting synaptic enhancement at MF synapses predominantly containing CI-AMPARs. However, the FSK/IBMX-induced potentiation in cells loaded with the specific PKA inhibitor peptide PKI(6-22) failed to be maintained. Consistent with these data, delivery of HFS to MFs synapsing onto L-M interneurons loaded with PKI(6-22) induced posttetanic potentiation (PTP) but not LTP. Hippocampal sections stained for the catalytic subunit of PKA revealed abundant immunoreactivity in interneurons located in strata radiatum and L-M of area CA3. We also found that extracellular activation of PKC with phorbol 12,13-diacetate induced a pharmacological potentiation of the isolated CI-AMPAR component of the MF EPSP. However, HFS delivered to MF synapses on cells loaded with the PKC inhibitor chelerythrine exhibited PTP followed by a significant depression. Together, our data indicate that MF LTP in L-M interneurons at synapses containing primarily CI-AMPARs requires some of the same signaling cascades as does LTP of glutamatergic input to CA3 or CA1 pyramidal cells.

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Interaction between Ephrins and mGlu5 metabotropic glutamate receptors in the induction of long-term synaptic depression in the hippocampus.

Publication Date: 2010 Feb 24 PMID: 20181581
Authors: Piccinin, S. - Cinque, C. - Calo, L. - Molinaro, G. - Battaglia, G. - Maggi, L. - Nicoletti, F. - Melchiorri, D. - Eusebi, F. - Massey, P. V. - Bashir, Z. I.
Journal: J Neurosci

We applied the group-I metabotropic glutamate (mGlu) receptor agonist, 3,5-dihydroxyphenylglycine (DHPG), to neonatal or adult rat hippocampal slices at concentrations (10 microM) that induced a short-term depression (STD) of excitatory synaptic transmission at the Schaffer collateral/CA1 synapses. DHPG-induced STD was entirely mediated by the activation of mGlu5 receptors because it was abrogated by the mGlu5 receptor antagonist, MPEP [2-methyl-6-(phenylethynyl)pyridine], but not by the mGlu1 receptor antagonist, CPCCOEt [7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester]. Knowing that ephrin-Bs functionally interact with group-I mGlu receptors (Calo et al., 2005), we examined whether pharmacological activation of ephrin-Bs could affect DHPG-induced STD. We activated ephrin-Bs using their cognate receptor, EphB1, under the form of a preclustered EphB1/Fc chimera. Addition of clustered EphB1/Fc alone to the slices induced a small but nondecremental depression of excitatory synaptic transmission, which differed from the depression induced by 10 microM DHPG. Surprisingly, EphB1/Fc-induced synaptic depression was abolished by MPEP (but not by CPCCOEt) suggesting that it required the endogenous activation of mGlu5 receptors. In addition, coapplication of DHPG and EphB1/Fc, resulted in a large and nondecremental long-term depression. The effect of clustered EphB1/Fc was specific because it was not mimicked by unclustered EphB1/Fc or clustered EphA1/Fc. These findings raise the intriguing possibility that changes in synaptic efficacy mediated by mGlu5 receptors are under the control of the ephrin/Eph receptor system, and that the neuronal actions of ephrins can be targeted by drugs that attenuate mGlu5 receptor signaling.

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Origin and molecular specification of globus pallidus neurons.

Publication Date: 2010 Feb 24 PMID: 20181580
Authors: Nobrega-Pereira, S. - Gelman, D. - Bartolini, G. - Pla, R. - Pierani, A. - Marin, O.
Journal: J Neurosci

The mechanisms controlling the assembly of brain nuclei are poorly understood. In the forebrain, it is typically assumed that the formation of nuclei follows a similar sequence of events that in the cortex. In this structure, projection neurons are generated sequentially from common progenitor cells and migrate radially to reach their final destination, whereas interneurons are generated remotely and arrive to the cortex through tangential migration. Using the globus pallidus as a model to study the formation of forebrain nuclei, we found that the development of this basal ganglia structure involves the generation of several distinct classes of projection neurons from relatively distant progenitor pools, which then assemble together through tangential migration. Our results thus suggest that tangential migration in the forebrain is not limited to interneurons, as previously thought, but also involves projection neurons and reveal that the assembly of forebrain nuclei is more complex than previously anticipated.

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The progenitor zone of the ventral medial ganglionic eminence requires Nkx2-1 to generate most of the globus pallidus but few neocortical interneurons.

Publication Date: 2010 Feb 24 PMID: 20181579
Authors: Flandin, P. - Kimura, S. - Rubenstein, J. L.
Journal: J Neurosci

We show that most globus pallidus neurons, but very few neocortical interneurons, are generated from the ventral medial ganglionic eminence and dorsal preoptic area based on fate mapping using an Shh-Cre allele. The Shh-expressing subpallial lineage produces parvalbumin(+) GABAergic neurons, ChAT(+) cholinergic neurons, and oligodendrocytes. Loss of Nkx2-1 function from the Shh-expressing domain eliminated most globus pallidus neurons, whereas most cortical and striatal interneurons continued to be generated, except for striatal cholinergic neurons. Finally, our analysis provided evidence for a novel cellular component (Nkx2-1(-);Npas1(+)) of the globus pallidus.

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Histamine and orexin in the control of arousal, locomotion, and motivation.

Publication Date: 2010 Feb 24 PMID: 20181578
Authors: Burgess, C. R.
Journal: J Neurosci

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CaMKK-CaMKI signaling pathways differentially control axon and dendrite elongation in cortical neurons.

Publication Date: 2010 Feb 24 PMID: 20181577
Authors: Neal, A. P. - Molina-Campos, E. - Marrero-Rosado, B. - Bradford, A. B. - Fox, S. M. - Kovalova, N. - Hannon, H. E.
Journal: J Neurosci

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Norepinephrine directly activates adult hippocampal precursors via beta3-adrenergic receptors.

Publication Date: 2010 Feb 17 PMID: 20164362
Authors: Jhaveri, D. J. - Mackay, E. W. - Hamlin, A. S. - Marathe, S. V. - Nandam, L. S. - Vaidya, V. A. - Bartlett, P. F.
Journal: J Neurosci

Adult hippocampal neurogenesis is a critical form of cellular plasticity that is greatly influenced by neural activity. Among the neurotransmitters that are widely implicated in regulating this process are serotonin and norepinephrine, levels of which are modulated by stress, depression and clinical antidepressants. However, studies to date have failed to address a direct role for either neurotransmitter in regulating hippocampal precursor activity. Here we show that norepinephrine but not serotonin directly activates self-renewing and multipotent neural precursors, including stem cells, from the hippocampus of adult mice. Mechanistically, we provide evidence that beta(3)-adrenergic receptors, which are preferentially expressed on a Hes5-expressing precursor population in the subgranular zone (SGZ), mediate this norepinephrine-dependent activation. Moreover, intrahippocampal injection of a selective beta(3)-adrenergic receptor agonist in vivo increases the number of proliferating cells in the SGZ. Similarly, systemic injection of the beta-adrenergic receptor agonist isoproterenol not only results in enhancement of proliferation in the SGZ but also leads to an increase in the percentage of nestin/glial fibrillary acidic protein double-positive neural precursors in vivo. Finally, using a novel ex vivo "slice-sphere" assay that maintains an intact neurogenic niche, we demonstrate that antidepressants that selectively block the reuptake of norepinephrine, but not serotonin, robustly increase hippocampal precursor activity via beta-adrenergic receptors. These findings suggest that the activation of neurogenic precursors and stem cells via beta(3)-adrenergic receptors could be a potent mechanism to increase neuronal production, providing a putative target for the development of novel antidepressants.

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Neuronal stability and drift across periods of sleep: premotor activity patterns in a vocal control nucleus of adult zebra finches.

Publication Date: 2010 Feb 17 PMID: 20164361
Authors: Rauske, P. L. - Chi, Z. - Dave, A. S. - Margoliash, D.
Journal: J Neurosci

How stable are neural activity patterns compared across periods of sleep? We evaluated this question in adult zebra finches, whose premotor neurons in the nucleus robustus arcopallialis (RA) exhibit sequences of bursts during daytime singing that are characterized by precise timing relative to song syllables. Each burst has a highly regulated pattern of spikes. We assessed these spike patterns in singing that occurred before and after periods of sleep. For about half of the neurons, one or more premotor bursts had changed after sleep, an average of 20% of all bursts across all RA neurons. After sleep, modified bursts were characterized by a discrete, albeit modest, loss of spikes with compensatory increases in spike intervals, but not changes in timing relative to the syllable. Changes in burst structure followed both interrupted bouts of sleep (1.5-3 h) and full nights of sleep, implicating sleep and not circadian cycle as mediating these effects. Changes in burst structure were also observed during the day, but far less frequently. In cases where multiple bursts in the sequence changed in a single cell, the sequence position of those bursts tended to cluster together. Bursts that did not show discrete changes in structure also showed changes in spike counts, but not biased toward losses. We hypothesize that changes in burst patterns during sleep represent active sculpting of the RA network, supporting auditory feedback-mediated song maintenance.

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Phase response curve analysis of a full morphological globus pallidus neuron model reveals distinct perisomatic and dendritic modes of synaptic integration.

Publication Date: 2010 Feb 17 PMID: 20164360
Authors: Schultheiss, N. W. - Edgerton, J. R. - Jaeger, D.
Journal: J Neurosci

Synchronization of globus pallidus (GP) neurons and cortically entrained oscillations between GP and other basal ganglia nuclei are key features of the pathophysiology of Parkinson's disease. Phase response curves (PRCs), which tabulate the effects of phasic inputs within a neuron's spike cycle on output spike timing, are efficient tools for predicting the emergence of synchronization in neuronal networks and entrainment to periodic input. In this study we apply physiologically realistic synaptic conductance inputs to a full morphological GP neuron model to determine the phase response properties of the soma and different regions of the dendritic tree. We find that perisomatic excitatory inputs delivered throughout the interspike interval advance the phase of the spontaneous spike cycle yielding a type I PRC. In contrast, we demonstrate that distal dendritic excitatory inputs can either delay or advance the next spike depending on whether they occur early or late in the spike cycle. We find this latter pattern of responses, summarized by a biphasic (type II) PRC, was a consequence of dendritic activation of the small conductance calcium-activated potassium current, SK. We also evaluate the spike-frequency dependence of somatic and dendritic PRC shapes, and we demonstrate the robustness of our results to variations of conductance densities, distributions, and kinetic parameters. We conclude that the distal dendrite of GP neurons embodies a distinct dynamical subsystem that could promote synchronization of pallidal networks to excitatory inputs. These results highlight the need to consider different effects of perisomatic and dendritic inputs in the control of network behavior.

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Coordination between extrinsic extracellular matrix cues and intrinsic responses to orient the centrosome in polarizing cerebellar granule neurons.

Publication Date: 2010 Feb 17 PMID: 20164359
Authors: Gupta, S. K. - Meiri, K. F. - Mahfooz, K. - Bharti, U. - Mani, S.
Journal: J Neurosci

Successful axon targeting during development is critically dependent on directionality of axon extension and requires coordination between the extrinsic cues that provide spatial information to the axon and the intrinsic responses that regulate structural specification of the axon during neuronal polarization. How these responses are coordinated is unclear but are known to involve aligning the centrosome with the base of the emerging axon. We have used a novel in vitro micropatterning assay that spatially segregates the extrinsic cues used by polarizing cerebellar granule cells to orient axon extension and used it to investigate the signaling mechanisms responsible for coordinating centrosome positioning with intrinsic responses. The results show that, when laminin and/or vitronectin are used as spatially restricted cues in association with substrate-associated sonic hedgehog, they are sufficient to induce cell cycle arrest, that laminin and vitronectin then induce integrin-mediated signaling that upregulates phosphoinositide-3 kinase and PKC function to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3) that is associated with the centrosome, that this PIP3 can interact with PKC-phosphorylated growth-associated protein GAP-43, and that PKC-phosphorylated GAP-43 in turn is required for positioning Par6, Cdc42, and IQGAP1, all intrinsic response components, in proximity to the centrosome, such that, in the absence of GAP-43, they are mislocalized and microtubules are not oriented appropriately. We conclude from these results that GAP-43 plays an important role in coordinating extrinsic signaling and intrinsic responses in polarizing cerebellar granule neurons.

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Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors.

Publication Date: 2010 Feb 17 PMID: 20164358
Authors: Dravid, S. M. - Burger, P. B. - Prakash, A. - Geballe, M. T. - Yadav, R. - Le, P. - Vellano, K. - Snyder, J. P. - Traynelis, S. F.
Journal: J Neurosci

We have studied relative efficacies of NR1 agonists glycine and d-cycloserine (DCS), and found efficacy to be dependent on the NR2 subunit. DCS shows partial agonism at NR1/NR2B but has higher relative efficacy than glycine at NR1/NR2C receptor. Molecular dynamics (MD) simulations of the NR1/NR2B and NR1/NR2C agonist binding domain dimer suggest only subtle differences in the interactions of DCS with NR1 binding site residues relative to glycine. The most pronounced differences were observed in the NR1/NR2C simulation between the orientation of helices F and G of the NR1 subunit. Interestingly, Helix F was previously proposed to influence receptor gating and to adopt an orientation depending on agonist efficacy. MD simulations and site-directed mutagenesis further suggest a role for residues at the agonist binding domain dimer interface in regulating DCS efficacy. To relate the structural rearrangements to receptor gating, we recorded single-channel currents from outside-out patches containing a single active NR1/NR2C receptor. DCS increased the mean open time and open probability of NR1/NR2C receptors compared with glycine. Maximum likelihood fitting of a gating model for NR1/NR2C receptor activation to the single-channel data suggests that DCS specifically accelerates the rate constant governing a fast gating step and reduces the closing rate. These changes appear to reflect a decreased activation energy for a pregating step and increased stability of the open states. We suggest that the higher efficacy of DCS at NR1/NR2C receptors involves structural rearrangements at the dimer interface and an effect on NR1/NR2C receptor pregating conformational changes.

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Contribution of the global subunit structure and stargazin on the maturation of AMPA receptors.

Publication Date: 2010 Feb 17 PMID: 20164357
Authors: Shanks, N. F. - Maruo, T. - Farina, A. N. - Ellisman, M. H. - Nakagawa, T.
Journal: J Neurosci

Subunit assembly governs regulation of AMPA receptor (AMPA-R) synaptic delivery and determines biophysical parameters of the ion channel. However, little is known about the molecular pathways of this process. Here, we present single-particle EM three-dimensional structures of dimeric biosynthetic intermediates of the GluA2 subunit of AMPA-Rs. Consistent with the structures of intact tetramers, the N-terminal domains of the biosynthetic intermediates form dimers. Transmembrane domains also dimerize despite the two ligand-binding domains (LBDs) being separated. A significant difference was detected between the dimeric structures of the wild type and the L504Y mutant, a point mutation that blocks receptor trafficking and desensitization. In contrast to the wild type, whose LBD is separated, the LBD of the L504Y mutant was detected as a single density. Our results provide direct structural evidence that separation of the LBD within the intact dimeric subunits is critical for efficient tetramerization in the endoplasmic reticulum and further trafficking of AMPA-Rs. The contribution of stargazin on the subunit assembly of AMPA-R was examined. Our data suggest that stargazin affects AMPA-R trafficking at a later stage of receptor maturation.

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Presynaptic GABA(B) receptors regulate experience-dependent development of inhibitory short-term plasticity.

Publication Date: 2010 Feb 17 PMID: 20164356
Authors: Takesian, A. E. - Kotak, V. C. - Sanes, D. H.
Journal: J Neurosci

Short-term changes in synaptic gain support information processing throughout the CNS, yet we know little about the developmental regulation of such plasticity. Here we report that auditory experience is necessary for the normal maturation of synaptic inhibitory short-term plasticity (iSTP) in the auditory cortex, and that presynaptic GABA(B) receptors regulate this development. Moderate or severe hearing loss was induced in gerbils, and iSTP was characterized by measuring inhibitory synaptic current amplitudes in response to repetitive stimuli. We reveal a profound developmental shift of iSTP from depressing to facilitating after the onset of hearing. Even moderate hearing loss prevented this shift. This iSTP change was mediated by a specific class of inhibitory interneurons, the low-threshold spiking cells. Further, using paired recordings, we reveal that presynaptic GABA(B) receptors at interneuron-pyramidal connections regulate iSTP in an experience-dependent manner. This novel synaptic mechanism may support the emergence of mature temporal processing in the auditory cortex.

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Diacylglycerol lipase is not involved in depolarization-induced suppression of inhibition at unitary inhibitory connections in mouse hippocampus.

Publication Date: 2010 Feb 17 PMID: 20164355
Authors: Min, R. - Testa-Silva, G. - Heistek, T. S. - Canto, C. B. - Lodder, J. C. - Bisogno, T. - Di Marzo, V. - Brussaard, A. B. - Burnashev, N. - Mansvelder, H. D.
Journal: J Neurosci

Endocannabinoids control hippocampal inhibitory synaptic transmission through activation of presynaptic CB(1) receptors. During depolarization-induced suppression of inhibition (DSI), endocannabinoids are synthesized upon postsynaptic depolarization. The endocannabinoid 2-arachidonoylglycerol (2-AG) may mediate hippocampal DSI. Currently, the best studied pathway for biosynthesis of 2-AG involves the enzyme diacylglycerol lipase (DAGL). However, whether DAGL is necessary for hippocampal DSI is controversial and was not systematically addressed. Here, we investigate DSI at unitary connections between CB(1) receptor-containing interneurons and pyramidal neurons in CA1. We found that the novel DAGL inhibitor OMDM-188, as well as the established inhibitor RHC-80267, did not affect DSI. As reported previously, effects of the DAGL inhibitor tetrahydrolipstatin depended on the application method: postsynaptic intracellular application left DSI intact, while incubation blocked DSI. We show that all DAGL inhibitors tested block slow self-inhibition in neocortical interneurons, which involves DAGL. We conclude that DAGL is not involved in DSI at unitary connections in hippocampus.

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Saccade suppression by electrical microstimulation in monkey caudate nucleus.

Publication Date: 2010 Feb 17 PMID: 20164354
Authors: Watanabe, M. - Munoz, D. P.
Journal: J Neurosci

It has been suggested that the caudate nucleus, the input stage of the basal ganglia, facilitates and suppresses saccade initiation based on its anatomical characteristics. Although the involvement of the caudate nucleus in saccade facilitation has been shown previously, it is still unclear whether the caudate nucleus is also involved in saccade suppression. Here, we revealed the direct involvement of the caudate nucleus in saccade suppression by electrical microstimulation in behaving monkeys. We delivered microstimulation to the caudate nucleus while monkeys performed the prosaccade (look toward a peripheral visual stimulus) and antisaccade (look away from the stimulus) paradigm. The reaction times of contralateral saccades were prolonged on both prosaccade and antisaccade trials. The suppression effects on reaction times were stronger on prosaccade trials compared with antisaccade trials. The analysis of reaction time distributions using the linear approach to threshold with ergodic rate model (LATER model) revealed that microstimulation prolonged reaction times by reducing the rate of rise to the threshold for saccade initiation. Microstimulation also worsened correct performance rates for contralateral saccades. The same microstimulation prolonged and/or shortened the reaction times of ipsilateral saccades, although the effects were not as consistent as those on contralateral saccades. We conclude that caudate signals are sufficient to suppress contralateral saccades and influence saccadic decision by controlling contralateral and ipsilateral saccade commands at the same time.

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Hippocampal gamma oscillations increase with memory load.

Publication Date: 2010 Feb 17 PMID: 20164353
Authors: van Vugt, M. K. - Schulze-Bonhage, A. - Litt, B. - Brandt, A. - Kahana, M. J.
Journal: J Neurosci

Although the hippocampus plays a crucial role in encoding and retrieval of contextually mediated episodic memories, considerable controversy surrounds the role of the hippocampus in short-term or working memory. To examine both hippocampal and neocortical contributions to working memory function, we recorded electrocorticographic activity from widespread cortical and subcortical sites as 20 neurosurgical patients performed working memory tasks. These recordings revealed significant increases in 48-90 Hz gamma oscillatory power with memory load for two classes of stimuli: letters and faces. Sites exhibiting gamma increases with memory load appeared primarily in the hippocampus and medial temporal lobe. These findings implicate gamma oscillatory activity in the maintenance of both letters and faces in working memory and provide the first direct evidence for modulation of hippocampal gamma oscillations as humans perform a working memory task.

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EEG measures index neural and cognitive recovery from sleep deprivation.

Publication Date: 2010 Feb 17 PMID: 20164352
Authors: Mander, B. A. - Reid, K. J. - Baron, K. G. - Tjoa, T. - Parrish, T. B. - Paller, K. A. - Gitelman, D. R. - Zee, P. C.
Journal: J Neurosci

Sleep deprivation impairs many cognitive abilities, but these impairments can be reversed after a certain quantity and quality of sleep. The ability to inhibit responding is particularly susceptible to disruption after prolonged wakefulness. How recovery sleep (RS) alters brain activity, leading to improved performance on a variety of cognitive tasks, remains unclear. This issue was examined in the current study using spectral analysis of electroencephalogram (EEG) data during sleep. These measures of sleep physiology were acquired after both normal sleep (NS) and RS, and were related to measures of inhibitory control and concurrent brain activity. Subjects were nine young adults who underwent functional magnetic resonance imaging twice, after 9 h of NS and after 10 h of RS that followed 38 h of being awake. A multiple regression model was used to examine differences between conditions in (1) EEG spectral power during sleep, (2) probability of successful inhibition in a go/no-go task, and (3) activation within a region of right prefrontal cortex during the task. Performance recovery, as indexed by reduced performance differences between conditions, was predicted by increased delta power and decreased sigma power in RS compared with NS. These EEG variables predicted most of the variance in inhibitory performance difference between conditions. Regressions also suggested that RS improved performance because of changes in brain function including prefrontal regions that resulted from delta rebound. We thus propose that slow waves, reflected in delta power during RS, act to restore brain function, thereby improving cognitive performance that entails response inhibition.

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Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation.

Publication Date: 2010 Feb 17 PMID: 20164351
Authors: Foster, K. A. - McLaughlin, N. - Edbauer, D. - Phillips, M. - Bolton, A. - Constantine-Paton, M. - Sheng, M.
Journal: J Neurosci

NMDA receptors (NMDARs) are critical mediators of activity-dependent synaptic plasticity, but the differential roles of NR2A- versus NR2B-containing NMDARs have been controversial. Here, we investigate the roles of NR2A and NR2B in long-term potentiation (LTP) in organotypic hippocampal slice cultures using RNA interference (RNAi) and overexpression, to complement pharmacological approaches. In young slices, when NR2B is the predominant subunit expressed, LTP is blocked by the NR2B-selective antagonist Ro25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol]. As slices mature and NR2A expression rises, activation of NR2B receptors became no longer necessary for LTP induction. LTP was blocked, however, by RNAi knockdown of NR2B, and this was rescued by coexpression of an RNAi-resistant NR2B (NR2B*) cDNA. Interestingly, a chimeric NR2B subunit in which the C-terminal cytoplasmic tail was replaced by that of NR2A failed to rescue LTP, whereas the reverse chimera, NR2A channel with NR2B tail, was able to restore LTP. Thus, expression of NR2B with its intact cytoplasmic tail is required for LTP induction, at an age when channel activity of NR2B-NMDARs is not required for LTP. Overexpression of wild-type NR2A failed to rescue LTP in neurons transfected with the NR2B-RNAi construct, despite restoring NMDA-EPSC amplitude to a similar level as NR2B*. Surprisingly, an NR2A construct lacking its entire C-terminal cytoplasmic tail regained its ability to restore LTP. Together, these data suggest that the NR2B subunit plays a critical role for LTP, presumably by recruiting relevant molecules important for LTP via its cytoplasmic tail. In contrast, NR2A is not essential for LTP, and its cytoplasmic tail seems to carry inhibitory factors for LTP.

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Distinct functional contributions of primary sensory and association areas to audiovisual integration in object categorization.

Publication Date: 2010 Feb 17 PMID: 20164350
Authors: Werner, S. - Noppeney, U.
Journal: J Neurosci

Multisensory interactions have been demonstrated in a distributed neural system encompassing primary sensory and higher-order association areas. However, their distinct functional roles in multisensory integration remain unclear. This functional magnetic resonance imaging study dissociated the functional contributions of three cortical levels to multisensory integration in object categorization. Subjects actively categorized or passively perceived noisy auditory and visual signals emanating from everyday actions with objects. The experiment included two 2 x 2 factorial designs that manipulated either (1) the presence/absence or (2) the informativeness of the sensory inputs. These experimental manipulations revealed three patterns of audiovisual interactions. (1) In primary auditory cortices (PACs), a concurrent visual input increased the stimulus salience by amplifying the auditory response regardless of task-context. Effective connectivity analyses demonstrated that this automatic response amplification is mediated via both direct and indirect [via superior temporal sulcus (STS)] connectivity to visual cortices. (2) In STS and intraparietal sulcus (IPS), audiovisual interactions sustained the integration of higher-order object features and predicted subjects' audiovisual benefits in object categorization. (3) In the left ventrolateral prefrontal cortex (vlPFC), explicit semantic categorization resulted in suppressive audiovisual interactions as an index for multisensory facilitation of semantic retrieval and response selection. In conclusion, multisensory integration emerges at multiple processing stages within the cortical hierarchy. The distinct profiles of audiovisual interactions dissociate audiovisual salience effects in PACs, formation of object representations in STS/IPS and audiovisual facilitation of semantic categorization in vlPFC. Furthermore, in STS/IPS, the profiles of audiovisual interactions were behaviorally relevant and predicted subjects' multisensory benefits in performance accuracy.

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Stored-trace reactivation in rat prefrontal cortex is correlated with down-to-up state fluctuation density.

Publication Date: 2010 Feb 17 PMID: 20164349
Authors: Johnson, L. A. - Euston, D. R. - Tatsuno, M. - McNaughton, B. L.
Journal: J Neurosci

Spontaneous reactivation of previously stored patterns of neural activity occurs in hippocampus and neocortex during non-rapid eye movement (NREM) sleep. Notable features of the neocortical local field potential during NREM sleep are high-amplitude, low-frequency thalamocortical oscillations including K-complexes, low-voltage spindles, and high-voltage spindles. Using combined neuronal ensemble and local field potential recordings, we show that prefrontal stored-trace reactivation is correlated with the density of down-to-up state transitions of the population of simultaneously recorded cells, as well as K-complexes and low-voltage spindles in the local field potential. This result strengthens the connection between reactivation and learning, as these same NREM sleep features have been correlated with memory. Although memory trace reactivation is correlated with low-voltage spindles, it is not correlated with high-voltage spindles, indicating that despite their similar frequency characteristics, these two oscillations serve different functions.

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Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation.

Publication Date: 2010 Feb 17 PMID: 20164348
Authors: Wu, H. Y. - Hudry, E. - Hashimoto, T. - Kuchibhotla, K. - Rozkalne, A. - Fan, Z. - Spires-Jones, T. - Xie, H. - Arbel-Ornath, M. - Grosskreutz, C. L. - Bacskai, B. J. - Hyman, B. T.
Journal: J Neurosci

Amyloid beta (Abeta)-containing plaques are surrounded by dystrophic neurites in the Alzheimer's disease (AD) brain, but whether and how plaques induce these neuritic abnormalities remain unknown. We tested the hypothesis that soluble oligomeric assemblies of Abeta, which surround plaques, induce calcium-mediated secondary cascades that lead to dystrophic changes in local neurites. We show that soluble Abeta oligomers lead to activation of the calcium-dependent phosphatase calcineurin (CaN) (PP2B), which in turn activates the transcriptional factor nuclear factor of activated T cells (NFAT). Activation of these signaling pathways, even in the absence of Abeta, is sufficient to produce a virtual phenocopy of Abeta-induced dystrophic neurites, dendritic simplification, and dendritic spine loss in both neurons in culture and in the adult mouse brain. Importantly, the morphological deficits in the vicinity of Abeta deposits in a mouse model of AD are ameliorated by CaN inhibition, supporting the hypothesis that CaN-NFAT are aberrantly activated by Abeta and that CaN-NFAT activation is responsible for disruption of neuronal structure near plaques. In accord with this, we also detect increased levels of an active form of CaN and NFATc4 in the nuclear fraction from the cortex of patients with AD. Thus, Abeta appears to mediate the neurodegeneration of AD, at least in part, by activation of CaN and subsequent NFAT-mediated downstream cascades.

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Suppression of the intrinsic apoptosis pathway by synaptic activity.

Publication Date: 2010 Feb 17 PMID: 20164347
Authors: Leveille, F. - Papadia, S. - Fricker, M. - Bell, K. F. - Soriano, F. X. - Martel, M. A. - Puddifoot, C. - Habel, M. - Wyllie, D. J. - Ikonomidou, C. - Tolkovsky, A. M. - Hardingham, G. E.
Journal: J Neurosci

Synaptic activity promotes resistance to diverse apoptotic insults, the mechanism behind which is incompletely understood. We show here that a coordinated downregulation of core components of the intrinsic apoptosis pathway by neuronal activity forms a key part of the underlying mechanism. Activity-dependent protection against apoptotic insults is associated with inhibition of cytochrome c release in most but not all neurons, indicative of anti-apoptotic signaling both upstream and downstream of this step. We find that enhanced firing activity suppresses expression of the proapoptotic BH3-only member gene Puma in a NMDA receptor-dependent, p53-independent manner. Puma expression is sufficient to induce cytochrome c loss and neuronal apoptosis. Puma deficiency protects neurons against apoptosis and also occludes the protective effect of synaptic activity, while blockade of physiological NMDA receptor activity in the developing mouse brain induces neuronal apoptosis that is preceded by upregulation of Puma. However, enhanced activity can also confer resistance to Puma-induced apoptosis, acting downstream of cytochrome c release. This mechanism is mediated by transcriptional suppression of apoptosome components Apaf-1 and procaspase-9, and limiting caspase-9 activity, since overexpression of procaspase-9 accelerates the rate of apoptosis in active neurons back to control levels. Synaptic activity does not exert further significant anti-apoptotic effects downstream of caspase-9 activation, since an inducible form of caspase-9 overrides the protective effect of synaptic activity, despite activity-induced transcriptional suppression of caspase-3. Thus, suppression of apoptotic gene expression may synergize with other activity-dependent events such as enhancement of antioxidant defenses to promote neuronal survival.

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Homeostatic regulation of synaptic excitability: tonic GABA(A) receptor currents replace I(h) in cortical pyramidal neurons of HCN1 knock-out mice.

Publication Date: 2010 Feb 17 PMID: 20164346
Authors: Chen, X. - Shu, S. - Schwartz, L. C. - Sun, C. - Kapur, J. - Bayliss, D. A.
Journal: J Neurosci

Homeostatic control of synaptic efficacy is often mediated by dynamic regulation of excitatory synaptic receptors. Here, we report a novel form of homeostatic synaptic plasticity based on regulation of shunt currents that control dendritosomatic information transfer. In cortical pyramidal neurons from wild-type mice, HCN1 channels underlie a dendritic hyperpolarization-activated cationic current (I(h)) that serves to limit temporal summation of synaptic inputs. In HCN1 knock-out mice, as expected, I(h) is reduced in pyramidal neurons and its effects on synaptic summation are strongly diminished. Unexpectedly, we found a markedly enhanced bicuculline- and L-655,708-sensitive background GABA(A) current in these cells that could be attributed to selective upregulation of GABA(A) alpha5 subunit expression in the cortex of HCN1 knock-out mice. Strikingly, despite diminished I(h), baseline sublinear summation of evoked EPSPs was unchanged in pyramidal neurons from HCN1 knock-out mice; however, blocking tonic GABA(A) currents with bicuculline enhanced synaptic summation more strongly in pyramidal cells from HCN1 knock-out mice than in those cells from wild-type mice. Increasing tonic GABA(A) receptor conductance in the context of reduced I(h), using computational or pharmacological approaches, restored normal baseline synaptic summation, as observed in neurons from HCN1 knock-out mice. These data indicate that upregulation of alpha5 subunit-mediated GABA(A) receptor tonic current compensates quantitatively for loss of dendritic I(h) in cortical pyramidal neurons from HCN1 knock-out mice to maintain normal synaptic summation; they further imply that dendritosomatic synaptic efficacy is a controlled variable for homeostatic regulation of cortical neuron excitability in vivo.

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Cilia organize ependymal planar polarity.

Publication Date: 2010 Feb 17 PMID: 20164345
Authors: Mirzadeh, Z. - Han, Y. G. - Soriano-Navarro, M. - Garcia-Verdugo, J. M. - Alvarez-Buylla, A.
Journal: J Neurosci

Multiciliated epithelial cells, called ependymal cells, line the ventricles in the adult brain. Most ependymal cells are born prenatally and are derived from radial glia. Ependymal cells have a remarkable planar polarization that determines orientation of ciliary beating and propulsion of CSF. Disruption of ependymal ciliary beating, by injury or disease, results in aberrant CSF circulation and hydrocephalus, a common disorder of the CNS. Very little is known about the mechanisms guiding ependymal planar polarity and whether this organization is acquired during ependymal cell development or is already present in radial glia. Here we show that basal bodies in ependymal cells in the lateral ventricle walls of adult mice are polarized in two ways: (1) rotational; angle of individual basal bodies with respect to their long axis and (2) translational; the position of basal bodies on the apical surface of the cell. Conditional ablation of motile cilia disrupted rotational orientation, but translational polarity was largely preserved. In contrast, translational polarity was dramatically affected when radial glial primary cilia were ablated earlier in development. Remarkably, radial glia in the embryo have a translational polarity that predicts the orientation of mature ependymal cells. These results suggest that ependymal planar cell polarity is a multistep process initially organized by primary cilia in radial glia and then refined by motile cilia in ependymal cells.

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Activation of the T1 neuronal circuit is necessary and sufficient to induce sexually dimorphic mating behavior in Drosophila melanogaster.

Publication Date: 2010 Feb 17 PMID: 20164344
Authors: Ronderos, D. S. - Smith, D. P.
Journal: J Neurosci

The molecular and cellular events mediating complex behaviors in animals are largely unknown. Elucidating the circuits underlying behaviors in simple model systems may shed light on how these circuits function. In drosophila, courtship behavior provides a tractable model for studying the underlying basis of innate behavior. The male-specific pheromone 11-cis-vaccenyl acetate (cVA) modulates courtship behavior and is detected by T1 neurons, located on the antenna of male and female flies. The T1 neurons express the odorant receptor Or67d and are exquisitely tuned to cVA pheromone. However, cVA-induced changes in mating behavior have also been reported upon manipulation of olfactory neurons expressing odorant receptor Or65a. These findings raise the issue of whether multiple olfactory-driven circuits underlie cVA-induced behavioral responses and what role these circuits play in behavior. Here, we engineered flies in which the Or67d circuit is specifically activated in the absence of cVA to determine the role of this circuit in behavior. We created transgenic flies that express a dominant-active, pheromone-independent variant of the extracellular pheromone receptor, LUSH. We found that, similar to the behaviors elicited by cVA, engineered male flies have dramatically reduced courtship, whereas engineered females showed enhanced courtship. cVA exposure did not enhance the dominant LUSH-triggered effects on behavior in the engineered flies. Finally, we show the effects of both cVA and dominant LUSH on courtship are reversed by genetically removing Or67d. These findings demonstrate that the T1/Or67d circuit is necessary and sufficient to mediate sexually dimorphic courtship behaviors.

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eIF2alpha Phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation.

Publication Date: 2010 Feb 17 PMID: 20164343
Authors: Jiang, Z. - Belforte, J. E. - Lu, Y. - Yabe, Y. - Pickel, J. - Smith, C. B. - Je, H. S. - Lu, B. - Nakazawa, K.
Journal: J Neurosci

Protein synthesis inhibitor antibiotics are widely used to produce amnesia, and have been recognized to inhibit general or global mRNA translation in the basic translational machinery. For instance, anisomycin interferes with protein synthesis by inhibiting peptidyl transferase or the 80S ribosomal function. Therefore, de novo general or global protein synthesis has been thought to be necessary for long-term memory formation. However, it is unclear which mode of translation-gene-specific translation or general/global translation-is actually crucial for the memory consolidation process in mammalian brains. Here, we generated a conditional transgenic mouse strain in which double-strand RNA-dependent protein kinase (PKR)-mediated phosphorylation of eIF2alpha, a key translation initiation protein, was specifically increased in hippocampal CA1 pyramidal cells by the chemical inducer AP20187. Administration of AP20187 significantly increased activating transcription factor 4 (ATF4) translation and concomitantly suppressed CREB-dependent pathways in CA1 cells; this led to impaired hippocampal late-phase LTP and memory consolidation, with no obvious reduction in general translation. Conversely, inhibition of general translation by low-dose anisomycin failed to block hippocampal-dependent memory consolidation. Together, these results indicated that CA1-restricted genetic manipulation of particular mRNA translations is sufficient to impair the consolidation and that consolidation of memories in CA1 pyramidal cells through eIF2alpha dephosphorylation depends more on transcription/translation of particular genes than on overall levels of general translation. The present study sheds light on the critical importance of gene-specific translations for hippocampal memory consolidation.

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Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice.

Publication Date: 2010 Feb 17 PMID: 20164342
Authors: Kolber, B. J. - Boyle, M. P. - Wieczorek, L. - Kelley, C. L. - Onwuzurike, C. C. - Nettles, S. A. - Vogt, S. K. - Muglia, L. J.
Journal: J Neurosci

During development, early-life stress, such as abuse or trauma, induces long-lasting changes that are linked to adult anxiety and depressive behavior. It has been postulated that altered expression of corticotropin-releasing hormone (CRH) can at least partially account for the various effects of stress on behavior. In accord with this hypothesis, evidence from pharmacological and genetic studies has indicated the capacity of differing levels of CRH activity in different brain areas to produce behavioral changes. Furthermore, stress during early life or adulthood causes an increase in CRH release in a variety of neural sites. To evaluate the temporal and spatial specificity of the effect of early-life CRH exposure on adult behavior, the tetracycline-off system was used to produce mice with forebrain-restricted inducible expression of CRH. After transient elevation of CRH during development only, behavioral testing in adult mice revealed a persistent anxiogenic and despair-like phenotype. These behavioral changes were not associated with alterations in adult circadian or stress-induced corticosterone release but were associated with changes in CRH receptor type 1 expression. Furthermore, the despair-like changes were normalized with antidepressant treatment. Overall, these studies suggest that forebrain-restricted CRH signaling during development can permanently alter stress adaptation leading to increases in maladaptive behavior in adulthood.

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Stochastic transitions between neural states in taste processing and decision-making.

Publication Date: 2010 Feb 17 PMID: 20164341
Authors: Miller, P. - Katz, D. B.
Journal: J Neurosci

Noise, which is ubiquitous in the nervous system, causes trial-to-trial variability in the neural responses to stimuli. This neural variability is in turn a likely source of behavioral variability. Using Hidden Markov modeling, a method of analysis that can make use of such trial-to-trial response variability, we have uncovered sequences of discrete states of neural activity in gustatory cortex during taste processing. Here, we advance our understanding of these patterns in two ways. First, we reproduce the experimental findings in a formal model, describing a network that evinces sharp transitions between discrete states that are deterministically stable given sufficient noise in the network; as in the empirical data, the transitions occur at variable times across trials, but the stimulus-specific sequence is itself reliable. Second, we demonstrate that such noise-induced transitions between discrete states can be computationally advantageous in a reduced, decision-making network. The reduced network produces binary outputs, which represent classification of ingested substances as palatable or nonpalatable, and the corresponding behavioral responses of "spit" or "swallow". We evaluate the performance of the network by measuring how reliably its outputs follow small biases in the strengths of its inputs. We compare two modes of operation: deterministic integration ("ramping") versus stochastic decision-making ("jumping"), the latter of which relies on state-to-state transitions. We find that the stochastic mode of operation can be optimal under typical levels of internal noise and that, within this mode, addition of random noise to each input can improve optimal performance when decisions must be made in limited time.

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Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors.

Publication Date: 2010 Feb 17 PMID: 20164340
Authors: Steullet, P. - Cabungcal, J. H. - Kulak, A. - Kraftsik, R. - Chen, Y. - Dalton, T. P. - Cuenod, M. - Do, K. Q.
Journal: J Neurosci

Elevated oxidative stress and alteration in antioxidant systems, including glutathione (GSH) decrease, are observed in schizophrenia. Genetic and functional data indicate that impaired GSH synthesis represents a susceptibility factor for the disorder. Here, we show that a genetically compromised GSH synthesis affects the morphological and functional integrity of hippocampal parvalbumin-immunoreactive (PV-IR) interneurons, known to be affected in schizophrenia. A GSH deficit causes a selective decrease of PV-IR interneurons in CA3 and dendate gyrus (DG) of the ventral but not dorsal hippocampus and a concomitant reduction of beta/gamma oscillations. Impairment of PV-IR interneurons emerges at the end of adolescence/early adulthood as oxidative stress increases or cumulates selectively in CA3 and DG of the ventral hippocampus. Such redox dysregulation alters stress and emotion-related behaviors but leaves spatial abilities intact, indicating functional disruption of the ventral but not dorsal hippocampus. Thus, a GSH deficit affects PV-IR interneuron's integrity and neuronal synchrony in a region- and time-specific manner, leading to behavioral phenotypes related to psychiatric disorders.

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Acute in vivo genetic rescue demonstrates that phosphorylation of RIM1alpha serine 413 is not required for mossy fiber long-term potentiation.

Publication Date: 2010 Feb 17 PMID: 20164339
Authors: Yang, Y. - Calakos, N.
Journal: J Neurosci

While presynaptic, protein kinase A (PKA)-dependent, long-term plasticity has been described in numerous brain regions, the target(s) of PKA and the molecular mechanisms leading to sustained changes in neurotransmitter release remain elusive. Here, we acutely reconstitute mossy fiber long-term potentiation (mfLTP) de novo in the mature brains of mutant mice that normally lack this form of plasticity. These results demonstrate that RIM1alpha, a presynaptic scaffold protein and a potential PKA target, can support mfLTP independent of a role in brain development. Using this approach, we study two mutations of RIM1alpha (S413A and V415P) and conclude that PKA-phosphorylation-dependent signaling by RIM1alpha serine 413 is not required for mfLTP, consistent with conclusions reached from the study of RIM1alpha S413A knockin mice. Together, these results provide insights into the mechanism of mossy fiber LTP and demonstrate a useful acute approach to genetically manipulate mossy fiber synapses in the mature brain.

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Brain-derived neurotrophic factor regulates hedonic feeding by acting on the mesolimbic dopamine system.

Publication Date: 2010 Feb 17 PMID: 20164338
Authors: Cordeira, J. W. - Frank, L. - Sena-Esteves, M. - Pothos, E. N. - Rios, M.
Journal: J Neurosci

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, play prominent roles in food intake regulation through central mechanisms. However, the neural circuits underlying their anorexigenic effects remain largely unknown. We showed previously that selective BDNF depletion in the ventromedial hypothalamus (VMH) of mice resulted in hyperphagic behavior and obesity. Here, we sought to ascertain whether its regulatory effects involved the mesolimbic dopamine system, which mediates motivated and reward-seeking behaviors including consumption of palatable food. We found that expression of BDNF and TrkB mRNA in the ventral tegmental area (VTA) of wild-type mice was influenced by consumption of palatable, high-fat food (HFF). Moreover, amperometric recordings in brain slices of mice depleted of central BDNF uncovered marked deficits in evoked release of dopamine in the nucleus accumbens (NAc) shell and dorsal striatum but normal secretion in the NAc core. Mutant mice also exhibited dramatic increases in HFF consumption, which were exacerbated when access to HFF was restricted. However, mutants displayed enhanced responses to D(1) receptor agonist administration, which normalized their intake of HFF in a 4 h food intake test. Finally, in contrast to deletion of Bdnf in the VMH of mice, which resulted in increased intake of standard chow, BDNF depletion in the VTA elicited excessive intake of HFF but not of standard chow and increased body weights under HFF conditions. Our findings indicate that the effects of BDNF on eating behavior are neural substrate-dependent and that BDNF influences hedonic feeding via positive modulation of the mesolimbic dopamine system.

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Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system.

Publication Date: 2010 Feb 17 PMID: 20164337
Authors: Zibetti, C. - Adamo, A. - Binda, C. - Forneris, F. - Toffolo, E. - Verpelli, C. - Ginelli, E. - Mattevi, A. - Sala, C. - Battaglioli, E.
Journal: J Neurosci

A variety of chromatin remodeling complexes are thought to orchestrate transcriptional programs that lead neuronal precursors from earliest commitment to terminal differentiation. Here we show that mammalian neurons have a specialized chromatin remodeling enzyme arising from a neurospecific splice variant of LSD1/KDM1, histone lysine specific demethylase 1, whose demethylase activity on Lys4 of histone H3 has been related to gene repression. We found that alternative splicing of LSD1 transcript generates four full-length isoforms from combinatorial retention of two identified exons: the 4 aa exon E8a is internal to the amine oxidase domain, and its inclusion is restricted to the nervous system. Remarkably, the expression of LSD1 splice variants is dynamically regulated throughout cortical development, particularly during perinatal stages, with a progressive increase of LSD1 neurospecific isoforms over the ubiquitous ones. Notably, the same LSD1 splice dynamics can be fairly recapitulated in cultured cortical neurons. Functionally, LSD1 isoforms display in vitro a comparable demethylase activity, yet the inclusion of the sole exon E8a reduces LSD1 repressor activity on a reporter gene. Additional distinction among isoforms is supported by the knockdown of neurospecific variants in cortical neurons resulting in the inhibition of neurite maturation, whereas overexpression of the same variants enhances it. Instead, perturbation of LSD1 isoforms that are devoid of the neurospecific exon elicits no morphogenic effect. Collectively, results demonstrate that the arousal of neuronal LSD1 isoforms pacemakes early neurite morphogenesis, conferring a neurospecific function to LSD1 epigenetic activity.

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Overexpression of serum response factor restores ocular dominance plasticity in a model of fetal alcohol spectrum disorders.

Publication Date: 2010 Feb 17 PMID: 20164336
Authors: Paul, A. P. - Pohl-Guimaraes, F. - Krahe, T. E. - Filgueiras, C. C. - Lantz, C. L. - Colello, R. J. - Wang, W. - Medina, A. E.
Journal: J Neurosci

Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in fetal alcohol spectrum disorders (FASD). Recently, we showed that third trimester alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity. For instance, a few days of monocular deprivation results in a robust reduction of cortical regions responsive to the deprived eye in normal animals, but not in ferrets exposed early to alcohol. This plasticity deficit can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. PDE1 inhibition can increase cAMP and cGMP levels, activating transcription factors such as the cAMP response element binding protein (CREB) and the serum response factor (SRF). SRF is important for many plasticity processes such as LTP, LTD, spine motility, and axonal pathfinding. Here we attempt to rescue OD plasticity in alcohol-treated ferrets using a Sindbis viral vector to express a constitutively active form of SRF during the period of monocular deprivation. Using optical imaging of intrinsic signals and single-unit recordings, we observed that overexpression of a constitutively active form of SRF, but neither its dominant-negative nor GFP, restored OD plasticity in alcohol-treated animals. Surprisingly, this restoration was observed throughout the extent of the primary visual cortex and most cells infected by the virus were positive for GFAP rather than NeuN. This finding suggests that overexpression of SRF in astrocytes may reduce the deficits in neuronal plasticity seen in models of FASD.

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A G-protein-coupled neuropeptide Y-like receptor suppresses behavioral and sensory response to multiple stressful stimuli in Drosophila.

Publication Date: 2010 Feb 17 PMID: 20164335
Authors: Xu, J. - Li, M. - Shen, P.
Journal: J Neurosci

Recent studies suggest that human neuropeptide Y (NPY) plays a prominent role in management of stress response and emotion, and higher NPY levels observed in combat-exposed veterans may help coping with posttraumatic stress. Neuropeptide F (NPF), the counterpart of NPY in Drosophila melanogaster, also displays parallel activities, including promotion of resilience to diverse stressors and prevention of uncontrolled aggressive behavior. However, it remains unclear how NPY family peptides modulate physical and emotional responses to various stressors. Here we show that NPFR1, a G-protein-coupled NPF receptor, exerts an inhibitory effect on larval aversion to diverse stressful stimuli mediated by different subtypes of fly and mammalian transient receptor potential (TRP) family channels. Imaging analysis in larval sensory neurons and cultured human cells showed that NPFR1 attenuates Ca(2+) influx mediated by fly TRPA and rat TRPV1 channels. Our findings suggest that suppression of TRP channel-mediated neural excitation by the conserved NPF/NPFR1 system may be a major mechanism for attaining its broad anti-stress function.

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Deletion of GRK1 causes retina degeneration through a transducin-independent mechanism.

Publication Date: 2010 Feb 17 PMID: 20164334
Authors: Fan, J. - Sakurai, K. - Chen, C. K. - Rohrer, B. - Wu, B. X. - Yau, K. W. - Kefalov, V. - Crouch, R. K.
Journal: J Neurosci

Rpe65(-/-) mice are unable to produce 11-cis-retinal, the chromophore of visual pigments. Consequently, the pigment is present as the apoprotein opsin with a minute level of pigment containing 9-cis-retinal as chromophore. Notably, a 10-20% fraction of this opsin is mono-phosphorylated independently of light conditions. To determine the role of rhodopsin kinase (GRK1) in phosphorylating this opsin and to test whether eliminating this phosphorylation would accelerate photoreceptor degeneration, we generated the Rpe65(-/-)Grk1(-/-) mouse. The retinae of Rpe65(-/-)Grk1(-/-) mice had negligible opsin phosphorylation, extensive degeneration with decreased opsin levels, and diminished light-evoked rod responses relative to Rpe65(-/-) mice. These data show that opsin phosphorylation in the Rpe65(-/-) mouse is due to the action of GRK1 and is neuroprotective. However, despite the higher activity of unphosphorylated opsin, the severe loss of opsin in the rapidly degenerating Rpe65(-/-)Grk1(-/-) mice resulted in lower overall opsin activity and in higher rod sensitivity compared with Rpe65(-/-) mice. In Rpe65(-/-)Grk1(-/-)Gnat1(-/-) mice where transduction activation was blocked, degeneration was only partially prevented. Therefore, increased opsin activity in the absence of phosphorylation was not the only mechanism for the accelerated retinal degeneration. Finally, the deletion of GRK1 triggered retinal degeneration in Grk1(-/-) mice after 1 month, even in the absence of apo-opsin. This degeneration was independent of light conditions and occurred even in the absence of transducin in Grk1(-/-)Gnat1(-/-) mice. Taken together, our results demonstrate a light-independent mechanism for retinal degeneration in the absence of GRK1, suggesting a second, not previously recognized role for that kinase.

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Distinct value signals in anterior and posterior ventromedial prefrontal cortex.

Publication Date: 2010 Feb 17 PMID: 20164333
Authors: Smith, D. V. - Hayden, B. Y. - Truong, T. K. - Song, A. W. - Platt, M. L. - Huettel, S. A.
Journal: J Neurosci

The core feature of an economic exchange is a decision to trade one good for another, based on a comparison of relative value. Economists have long recognized, however, that the value an individual ascribes to a good during decision making (i.e., their relative willingness to trade for that good) does not always map onto the reward they actually experience. Here, we show that experienced value and decision value are represented in distinct regions of ventromedial prefrontal cortex (VMPFC) during the passive consumption of rewards. Participants viewed two categories of rewards-images of faces that varied in their attractiveness and monetary gains and losses-while being scanned using functional magnetic resonance imaging. An independent market task, in which participants exchanged some of the money that they had earned for brief views of attractive faces, determined the relative decision value associated with each category. We found that activation of anterior VMPFC increased with increasing experienced value, but not decision value, for both reward categories. In contrast, activation of posterior VMPFC predicted each individual's relative decision value for face and monetary stimuli. These results indicate not only that experienced value and decision value are represented in distinct regions of VMPFC, but also that decision value signals are evident even in the absence of an overt choice task. We conclude that decisions are made by comparing neural representations of the value of different goods encoded in posterior VMPFC in a common, relative currency.

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Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B.

Publication Date: 2010 Feb 17 PMID: 20164332
Authors: Horresh, I. - Bar, V. - Kissil, J. L. - Peles, E.
Journal: J Neurosci

Caspr and Caspr2 regulate the formation of distinct axonal domains around the nodes of Ranvier. Caspr is required for the generation of a membrane barrier at the paranodal junction (PNJ), whereas Caspr2 serves as a membrane scaffold that clusters Kv1 channels at the juxtaparanodal region (JXP). Both Caspr and Caspr2 interact with protein 4.1B, which may link the paranodal and juxtaparanodal adhesion complexes to the axonal cytoskeleton. To determine the role of protein 4.1B in the function of Caspr proteins, we examined the ability of transgenic Caspr and Caspr2 mutants lacking their 4.1-binding sequence (d4.1) to restore Kv1 channel clustering in Caspr- and Caspr2-null mice, respectively. We found that Caspr-d4.1 was localized to the PNJ and is able to recruit the paranodal adhesion complex components contactin and NF155 to this site. Nevertheless, in axons expressing Caspr-d4.1, Kv1 channels were often detected at paranodes, suggesting that the interaction of Caspr with protein 4.1B is necessary for the generation of an efficient membrane barrier at the PNJ. We also found that the Caspr2-d4.1 transgene did not accumulate at the JXP, even though it was targeted to the axon, demonstrating that the interaction with protein 4.1B is required for the accumulation of Caspr2 and Kv1 channels at the juxtaparanodal axonal membrane. In accordance, we show that Caspr2 and Kv1 channels are not clustered at the JXP in 4.1B-null mice. Our results thus underscore the functional importance of protein 4.1B in the organization of peripheral myelinated axons.

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Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons.

Publication Date: 2010 Feb 17 PMID: 20164331
Authors: Williams, K. W. - Margatho, L. O. - Lee, C. E. - Choi, M. - Lee, S. - Scott, M. M. - Elias, C. F. - Elmquist, J. K.
Journal: J Neurosci

Acute leptin administration results in a depolarization and concomitant increase in the firing rate of a subpopulation of arcuate proopiomelanocortin (POMC) cells. This rapid activation of POMC cells has been implicated as a cellular correlate of leptin effects on energy balance. In contrast to leptin, insulin inhibits the activity of some POMC neurons. Several studies have described a "cross talk" between leptin and insulin within the mediobasal hypothalamus via the intracellular enzyme, phosphoinositol-3-kinase (PI3K). Interestingly, both insulin and leptin regulate POMC cellular activity by activation of PI3K; however, it is unclear whether leptin and insulin effects are observed in similar or distinct populations of POMC cells. We therefore used dual label immunohistochemistry/in situ hybridization and whole-cell patch-clamp electrophysiology to map insulin and leptin responsive arcuate POMC neurons. Leptin-induced Fos activity within arcuate POMC neurons was localized separate from POMC neurons that express insulin receptor. Moreover, acute responses to leptin and insulin were largely segregated in distinct subpopulations of POMC cells. Collectively, these data suggest that cross talk between leptin and insulin occurs within a network of cells rather than within individual POMC neurons.

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Neural correlates of variations in event processing during learning in basolateral amygdala.

Publication Date: 2010 Feb 17 PMID: 20164330
Authors: Roesch, M. R. - Calu, D. J. - Esber, G. R. - Schoenbaum, G.
Journal: J Neurosci

The discovery that dopamine neurons signal errors in reward prediction has demonstrated that concepts empirically derived from the study of animal behavior can be used to understand the neural implementation of reward learning. Yet the learning theory models linked to phasic dopamine activity treat attention to events such as cues and rewards as static quantities; other models, such as Pearce-Hall, propose that learning might be influenced by variations in processing of these events. A key feature of these accounts is that event processing is modulated by unsigned rather than signed reward prediction errors. Here we tested whether neural activity in rat basolateral amygdala conforms to this pattern by recording single units in a behavioral task in which rewards were unexpectedly delivered or omitted. We report that neural activity at the time of reward is providing an unsigned error signal with characteristics consistent with those postulated by these models. This neural signal increased immediately after a change in reward, and stronger firing was evident whether the value of the reward increased or decreased. Further, as predicted by these models, the change in firing developed over several trials as expectations for reward were repeatedly violated. This neural signal was correlated with faster orienting to predictive cues after changes in reward, and abolition of the signal by inactivation of basolateral amygdala disrupted this change in orienting and retarded learning in response to changes in reward. These results suggest that basolateral amygdala serves a critical function in attention for learning.

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Inhibition of FK506 binding proteins reduces alpha-synuclein aggregation and Parkinson's disease-like pathology.

Publication Date: 2010 Feb 17 PMID: 20164329
Authors: Gerard, M. - Deleersnijder, A. - Daniels, V. - Schreurs, S. - Munck, S. - Reumers, V. - Pottel, H. - Engelborghs, Y. - Van den Haute, C. - Taymans, J. M. - Debyser, Z. - Baekelandt, V.
Journal: J Neurosci

alpha-Synuclein (alpha-SYN) is a key player in the pathogenesis of Parkinson's disease (PD). In pathological conditions, the protein is present in a fibrillar, aggregated form inside cytoplasmic inclusions called Lewy bodies. Members of the FK506 binding protein (FKBP) family are peptidyl-prolyl isomerases that were shown recently to accelerate the aggregation of alpha-SYN in vitro. We now established a neuronal cell culture model for synucleinopathy based on oxidative stress-induced alpha-SYN aggregation and apoptosis. Using high-content analysis, we examined the role of FKBPs in aggregation and apoptotic cell death. FK506, a specific inhibitor of this family of proteins, inhibited alpha-SYN aggregation and neuronal cell death in this synucleinopathy model dose dependently. Knockdown of FKBP12 or FKBP52 reduced the number of alpha-SYN aggregates and protected against cell death, whereas overexpression of FKBP12 or FKBP52 accelerated both aggregation of alpha-SYN and cell death. Thus, FK506 likely targets FKBP members in the cell culture model. Furthermore, oral administration of FK506 after viral vector-mediated overexpression of alpha-SYN in adult mouse brain significantly reduced alpha-SYN aggregate formation and neuronal cell death. Our data explain previously described neuroregenerative and neuroprotective effects of immunophilin ligands and validate FKBPs as a novel drug target for the causative treatment of PD.

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Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease.

Publication Date: 2010 Feb 17 PMID: 20164328
Authors: Hernandez, C. M. - Kayed, R. - Zheng, H. - Sweatt, J. D. - Dineley, K. T.
Journal: J Neurosci

Early Alzheimer's disease (AD) is marked by cholinergic hypofunction, neuronal marker loss, and decreased nicotinic acetylcholine receptor (nAChR) density from the cortex and hippocampus. alpha7 nAChRs expressed on cholinergic projection neurons and target regions have been implicated in neuroprotection against beta-amyloid (Abeta) toxicity and maintenance of the septohippocampal phenotype. We tested the role that alpha7 nAChRs perform in the etiology of early AD by genetically deleting the alpha7 nAChR subunit from the Tg2576 mouse model for AD and assessing animals for cognitive function and septohippocampal integrity. Thus, Tg2576 mice transgenic for mutant human amyloid precursor protein (APP) were crossed with alpha7 nAChR knock-out mice (A7KO) to render an animal with elevated Abeta in the absence of alpha7 nAChRs (A7KO-APP). We found that learning and memory deficits seen in 5-month-old APP mice are more severe in the A7KO-APP animals. Analyses of animals in early-stage preplaque cognitive decline revealed signs of neurodegeneration in A7KO-APP hippocampus as well as loss of cholinergic functionality in the basal forebrain and hippocampus. These changes occurred concomitant with the appearance of a dodecameric oligomer of Abeta that was absent from all other genotypic groups, generating the hypothesis that increased soluble oligomeric Abeta may underlie additional impairment of A7KO-APP cognitive function. Thus, alpha7 nAChRs in a mouse model for early-stage AD appear to serve a neuroprotective role through maintenance of the septohippocampal cholinergic phenotype and preservation of hippocampal integrity possibly through influences on Abeta accumulation and oligomerization.

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Neuronal nitric oxide synthase alteration accounts for the role of 5-HT1A receptor in modulating anxiety-related behaviors.

Publication Date: 2010 Feb 17 PMID: 20164327
Authors: Zhang, J. - Huang, X. Y. - Ye, M. L. - Luo, C. X. - Wu, H. Y. - Hu, Y. - Zhou, Q. G. - Wu, D. L. - Zhu, L. J. - Zhu, D. Y.
Journal: J Neurosci

Increasing evidence suggests that 5-HT(1A) receptor (5-HT(1A)R) is implicated in anxiety disorders. However, the mechanism underlying the role of 5-HT(1A)R in these diseases remains unknown. Here, we show that 5-HT(1A)R-selective agonist 8-OH-DPAT and selective serotonin reuptake inhibitor (SSRI) fluoxetine downregulated hippocampal neuronal nitric oxide synthase (nNOS) expression, whereas 5-HT(1A)R-selective antagonist NAN-190 upregulated hippocampal nNOS expression. By assessing anxiety-related behaviors using the novelty suppressed feeding, open-field, and elevated plus maze tests, we show that mice lacking nNOS gene [knock-out (KO)] or treated with nNOS-selective inhibitor 7-nitroindazole (7-NI; i.p., 30 mg/kg/d for 28 d; or intrahippocampal microinjection, 16.31 microg/1.0 microl) displayed an anxiolytic-like phenotype, implicating nNOS in anxiety. We also show that, in wild-type (WT) mice, administrations of 8-OH-DPAT (i.p., 0.1 mg/kg/d) or fluoxetine (i.p., 10 mg/kg/d) for 28 d caused anxiolytic-like effects, whereas NAN-190 (i.p., 0.3 mg/kg/d for 28 d) caused anxiogenic-like effects. In KO mice, however, these drugs were ineffective. Moreover, intrahippocampal infusion of 8-OH-DPAT (45.963 microg/100 microl) using 14 d osmotic minipump produced anxiolytic effects. Intrahippocampal microinjection of 7-NI (16.31 microg/1.0 microl) abolished the anxiogenic-like effects of intrahippocampal NAN-190 (4.74 microg/1.0 microl). Additionally, NAN-190 decreased and 8-OH-DPAT increased phosphorylated cAMP response element-binding protein (CREB) levels in WT mice but not in KO mice. Blockade of hippocampal CREB phosphorylation by microinjection of H89 (5.19 microg/1.0 microl), a PKA (protein kinase A) inhibitor, abolished the anxiolytic-like effects of 7-NI (i.p., 30 mg/kg/d for 21 d). These findings indicate that both hippocampal nNOS and CREB activity mediate the anxiolytic effects of 5-HT(1A)R agonists and SSRIs.

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Genetically determined differences in brain response to a primary food reward.

Publication Date: 2010 Feb 17 PMID: 20164326
Authors: Felsted, J. A. - Ren, X. - Chouinard-Decorte, F. - Small, D. M.
Journal: J Neurosci

Combining genetic and neuroimaging techniques may elucidate the biological underpinnings of individual differences in neurophysiology and potential vulnerabilities to disease. The TaqIA A1 variant is associated with diminished dopamine D(2) receptor density, higher body mass, and food reinforcement. It also moderates the relationship between brain response to food and future weight gain. This suggests that the polymorphism is associated with a fundamental difference in the neurophysiology of food that may predispose toward overeating. An alternative possibility is that factors, such as impulsivity, eating style, reward drive, and perception, which may covary with the polymorphism, influence reward coding and eating behavior. To distinguish between these alternatives, we used functional magnetic resonance imaging to measure neural response to the ingestion of palatable and caloric milkshakes in healthy subjects with (A1+; n = 13) and without (A1-; n = 13) the TaqIA A1 allele. The groups were selected from a larger group to be matched for linked individual factors such as age, gender, education, body mass index, impulsivity, eating style, and perceptual responses to the milkshake. We demonstrate an interaction between genotype (A1+ vs A1-) and stimulus (milkshake vs a tasteless/odorless baseline) in the midbrain, thalamus, and orbital frontal cortex; whereas A1- shows increased responses to milkshake, A1+ shows decreased responses to milkshake relative to baseline. This interaction occurs despite similar ratings of milkshake pleasantness, intensity, and familiarity. We therefore conclude that there is a specific association between the TaqIA A1 polymorphism and brain response during ingestion of a palatable food.

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Hormonal modulation of sensorimotor integration.

Publication Date: 2010 Feb 17 PMID: 20164325
Authors: DeLong, N. D. - Nusbaum, M. P.
Journal: J Neurosci

Neuronal circuits commonly receive simultaneous inputs from descending, ascending, and hormonal systems. Thus far, however, most such inputs have been studied individually to determine their influence on a given circuit. Here, we examine the integrated action of the hormone crustacean cardioactive peptide (CCAP) and the gastropyloric receptor (GPR) proprioceptor neuron on the biphasic gastric mill (chewing) rhythm driven by the projection neuron modulatory commissural neuron 1 (MCN1) in the isolated crab stomatogastric ganglion. In control saline, GPR stimulation selectively prolongs the gastric mill retractor phase, via presynaptic inhibition of MCN1. In the absence of GPR stimulation, CCAP does not alter retraction duration and modestly prolongs protraction. Here, we show, using computational modeling and dynamic-clamp manipulations, that the presence of CCAP weakens or eliminates the GPR effect on the gastric mill rhythm. This CCAP action results from its ability to activate the same modulator-activated conductance (G(MI)) as MCN1 in the gastric mill circuit neuron lateral gastric (LG). Because GPR prolongs retraction by weakening MCN1 activation of G(MI) in LG, the parallel G(MI) activation by CCAP reduces the impact of GPR regulation of this conductance. The CCAP-activated G(MI) thus counteracts the GPR-mediated decrease in the MCN1-activated G(MI) in LG and reduces the GPR ability to regulate the gastric mill rhythm. Consequently, although CCAP neither changes retraction duration nor alters GPR inhibition of MCN1, its activation of a modulator-activated conductance in a pivotal downstream circuit neuron enables CCAP to weaken or eliminate sensory regulation of motor circuit output.

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fMRI-Guided transcranial magnetic stimulation reveals that the superior temporal sulcus is a cortical locus of the McGurk effect.

Publication Date: 2010 Feb 17 PMID: 20164324
Authors: Beauchamp, M. S. - Nath, A. R. - Pasalar, S.
Journal: J Neurosci

A compelling example of auditory-visual multisensory integration is the McGurk effect, in which an auditory syllable is perceived very differently depending on whether it is accompanied by a visual movie of a speaker pronouncing the same syllable or a different, incongruent syllable. Anatomical and physiological studies in human and nonhuman primates have suggested that the superior temporal sulcus (STS) is involved in auditory-visual integration for both speech and nonspeech stimuli. We hypothesized that the STS plays a critical role in the creation of the McGurk percept. Because the location of multisensory integration in the STS varies from subject to subject, the location of auditory-visual speech processing in the STS was first identified in each subject with fMRI. Then, activity in this region of the STS was disrupted with single-pulse transcranial magnetic stimulation (TMS) as subjects rated their percept of McGurk and non-McGurk stimuli. Across three experiments, TMS of the STS significantly reduced the likelihood of the McGurk percept but did not interfere with perception of non-McGurk stimuli. TMS of the STS was effective at disrupting the McGurk effect only in a narrow temporal window from 100 ms before auditory syllable onset to 100 ms after onset, and TMS of a control location did not influence perception of McGurk or control stimuli. These results demonstrate that the STS plays a critical role in the McGurk effect and auditory-visual integration of speech.

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Dynamic clamp: alteration of response properties and creation of virtual realities in neurophysiology.

Publication Date: 2010 Feb 17 PMID: 20164323
Authors: Economo, M. N. - Fernandez, F. R. - White, J. A.
Journal: J Neurosci

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A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors.

Publication Date: 2010 Feb 10 PMID: 20147565
Authors: Jeon, J. - Dencker, D. - Wortwein, G. - Woldbye, D. P. - Cui, Y. - Davis, A. A. - Levey, A. I. - Schutz, G. - Sager, T. N. - Mork, A. - Li, C. - Deng, C. X. - Fink-Jensen, A. - Wess, J.
Journal: J Neurosci

Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M(1)-M(5) mAChRs). Like other mAChR subtypes, the M(4) mAChR is widely expressed in different regions of the forebrain. Interestingly, M(4) mAChRs are coexpressed with D(1) dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M(4) mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M(4) mAChRs only in D(1) dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes, including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes were accompanied by a lack of muscarinic inhibition of D(1) dopamine receptor-mediated cAMP stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M(4) mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance.

MeSH Categories: Amphetamine/pharmacology, Animals, Antipsychotic Agents/pharmacology, Behavior, Animal/drug effects/*physiology, Central Nervous System Stimulants/pharmacology, Cocaine/pharmacology, Corpus Striatum/metabolism, Cyclic AMP/biosynthesis, Dopamine/*physiology, Mice, Mice, Mutant Strains, Motor Activity/drug effects, Neurons/*physiology, Nucleus Accumbens/metabolism, Receptor, Muscarinic M4/genetics/*metabolism, Receptors, Dopamine D1/agonists/biosynthesis

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Multisegmental A{delta}- and C-fiber input to neurons in lamina I and the lateral spinal nucleus.

Publication Date: 2010 Feb 10 PMID: 20147564
Authors: Pinto, V. - Szucs, P. - Lima, D. - Safronov, B. V.
Journal: J Neurosci

Spinal lamina I and the lateral spinal nucleus (LSN) receive and integrate nociceptive primary afferent inputs to project through diverse ascending pathways. The pattern of the afferent supply of individual lamina I and LSN neurons through different segmental dorsal roots is poorly understood. Therefore, we recorded responses of lamina I and LSN neurons in spinal segments L4 and L3 to stimulation of six ipsilateral dorsal roots (L1-L6). The neurons were viewed through the overlying white matter in the isolated spinal cord preparation using the oblique infrared LED illumination technique. Orientation of myelinated fibers in the white matter was used as a criterion to distinguish between the LSN and lamina I. Both types of neurons received mixed (monosynaptic and polysynaptic) excitatory Adelta- and C-fiber input from up to six dorsal roots, with only less than one-third of it arising from the corresponding segmental root. The largest mixed input arose from the dorsal root of the neighboring caudal segment. Lamina I and LSN neurons could fire spikes upon the stimulation of up to six different dorsal roots. We also found that individual lamina I neurons can receive converging monosynaptic Adelta- and/or C-fiber inputs from up to six segmental roots. This study shows that lamina I and LSN neurons function as intersegmental integrators of primary afferent inputs. We suggest that broad monosynaptic convergence of Adelta- and C-afferents onto a lamina I neuron is important for the somatosensory processing.

MeSH Categories: Animals, Female, Lumbosacral Region, Male, Nerve Fibers, Myelinated/*physiology, Nerve Fibers, Unmyelinated/*physiology, Neurons/*physiology, Rats, Rats, Wistar, Spinal Cord/*physiology, Spinal Nerve Roots/physiology

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Keeping it together: mechanisms of intersegmental coordination for a flexible locomotor behavior.

Publication Date: 2010 Feb 10 PMID: 20147563
Authors: Puhl, J. G. - Mesce, K. A.
Journal: J Neurosci

The coordination of multiple neural oscillators is key for the generation of productive locomotor movements. In the medicinal leech, we determined that activation and coordination of the segmental crawl oscillators, or unit burst generators, are dependent on signals descending from the cephalic ganglion. In nearly intact animals, removing descending input (reversibly with a sucrose block) prevented overt crawling, but not swimming. Cephalic depolarization was sufficient for coordination. To determine whether descending signals were necessary for the generation and maintenance of posterior-directed intersegmental phase delays, we induced fictive crawling in isolated whole nerve cords using dopamine (DA) and blocked descending inputs. After blockade, we observed a significant loss of intersegmental coordination. Appropriate phase delays were also absent in DA-treated chains of ganglia. In chains, when one ganglion was removed from its neighbors, crawling in that ganglion emerged robust and stable, underscoring that these oscillators operate best with either all or none of their intersegmental inputs. To study local oscillator coupling, we induced fictive crawling (with DA) in a single oscillator within a chain. Although appropriate intersegmental phase delays were always absent, when one ganglion was treated with DA, neighboring ganglia began to show crawl-like bursting, with motoneuron spikes/burst greatest in untreated posterior ganglia. We further determined that this local excitatory drive excluded the swim-gating cell, 204. In conclusion, both long-distance descending and local interoscillator coupling contribute to crawling. This dual contribution helps to explain the inherent flexibility of crawling, and provides a foundation for understanding other dynamic locomotor behaviors across animal groups.

MeSH Categories: Animals, Dopamine/pharmacology, Electrophysiology, Ganglia, Invertebrate/anatomy & histology/drug effects/physiology, Leeches/anatomy & histology/*physiology, Motor Activity

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The P2Y2 receptor sensitizes mouse bladder sensory neurons and facilitates purinergic currents.

Publication Date: 2010 Feb 10 PMID: 20147562
Authors: Chen, X. - Molliver, D. C. - Gebhart, G. F.
Journal: J Neurosci

Sensitization of bladder afferents is an underlying contributor to the development and maintenance of painful bladder syndrome/interstitial cystitis. Extracellular purines and pyrimidines (e.g., ATP and UTP), released during bladder distension or from damaged cells after tissue insult, are thought to play an important role in bladder physiological and pathological states by actions at ionotropic P2X and metabotropic P2Y receptors. In the present study, we examined the ability of P2Y receptors to sensitize and modulate P2X-mediated responses in mouse bladder sensory neurons. UTP (a P2Y(2) and P2Y(4) agonist) increased excitability of bladder neurons by depolarizing resting membrane potential, increasing action potential firing, and facilitating responses to suprathreshold current injection as well as to P2X agonist application. These effects of UTP on bladder neuron excitability were blocked by the P2Y(2) receptor antagonist suramin. UTP also facilitated bladder neuron homomeric P2X(2) sustained currents and homomeric P2X(3) fast currents. The facilitatory effect of UTP on P2X(2) sustained currents was mediated by a G-protein-coupled P2Y(2) receptor/PKC pathway, whereas the effect of UTP on P2X(3) fast currents was G-protein independent. We also examined P2X and P2Y receptor expression in bladder neurons. P2Y(2) and P2Y(4) transcripts were detected in approximately 50 and approximately 20% of bladder neurons, respectively. Approximately 50% of P2X(2)- and P2X(3)-positive bladder neurons expressed P2Y(2) transcripts, whereas < or =25% of the same bladder neurons expressed P2Y(4) transcripts. These results support involvement of P2Y(2) receptors in bladder sensation, suggesting an important contribution to bladder neuron excitability and hypersensitivity.

MeSH Categories: Action Potentials, Animals, Male, Membrane Potentials, Mice, Mice, Inbred C57BL, Receptors, Purinergic P2/agonists/antagonists & inhibitors/*physiology, Sensory Receptor Cells/drug effects/*physiology, Suramin/pharmacology, Uridine Triphosphate/pharmacology, Urinary Bladder/drug effects/*innervation/*physiology

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High-frequency stimulation of the subthalamic nucleus and L-3,4-dihydroxyphenylalanine inhibit in vivo serotonin release in the prefrontal cortex and hippocampus in a rat model of Parkinson's disease.

Publication Date: 2010 Feb 10 PMID: 20147561
Authors: Navailles, S. - Benazzouz, A. - Bioulac, B. - Gross, C. - De Deurwaerdere, P.
Journal: J Neurosci

High-frequency stimulation of the subthalamic nucleus (STN-HFS) and l-3,4-dihydroxyphenylalanine (l-DOPA) medication are the most used therapeutic approaches in Parkinson's disease (PD), but their beneficial motor effects are burdened by the emergence of cognitive and depressive disorders. Although a reduced serotonergic function has been linked to the psychiatric effects of antiparkinsonian treatments, biochemical evidence supporting this hypothesis is still lacking. By using a microdialysis approach in anesthetized rats, we investigated the ability of STN-HFS (130 Hz, 30 muA, 20 min) and l-DOPA (6-12 mg/kg) to change extracellular levels of serotonin (5-HT) monitored simultaneously in the prefrontal cortex (PFC) and hippocampus (HIPP), two brain regions involved in the regulation of mood and cognition that receive a distinct 5-HT innervation. The results show that STN-HFS inhibited 5-HT levels in the PFC and HIPP of sham-lesioned and 6-hydroxydopamine (6-OHDA)-lesioned rats. The effect elicited by STN-HFS was blocked by the administration of the 5-HT(1A) agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin. l-DOPA (6 and 12 mg/kg) reduced 5-HT levels in the PFC and HIPP of 6-OHDA rats. STN-HFS did not further decrease 5-HT levels induced by l-DOPA, but attenuated l-DOPA-induced dopamine release in the PFC and HIPP. These neurochemical data show that STN-HFS inhibits 5-HT release by modulating serotonergic neuron activity, while the decrease in 5-HT levels induced by l-DOPA may include its direct action inside serotonergic neurons. These results support the premise that antiparkinsonian treatments reduce central serotonergic transmission, which may favor the development of nonmotor side effects in PD.

MeSH Categories: Animals, Antiparkinson Agents/*therapeutic use, Combined Modality Therapy, Deep Brain Stimulation, Extracellular Space/metabolism, Hippocampus/*metabolism, Hydroxyindoleacetic Acid/metabolism, Levodopa/*therapeutic use, Male, Microdialysis, Oxidopamine, Parkinson Disease, Secondary/chemically induced/*metabolism/therapy, Prefrontal Cortex/*metabolism, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT1A/agonists, Serotonin/*metabolism, Subthalamic Nucleus/*physiopathology

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A probabilistic strategy for understanding action selection.

Publication Date: 2010 Feb 10 PMID: 20147560
Authors: Kim, B. - Basso, M. A.
Journal: J Neurosci

Brain regions involved in transforming sensory signals into movement commands are the likely sites where decisions are formed. Once formed, a decision must be read out from the activity of populations of neurons to produce a choice of action. How this occurs remains unresolved. We recorded from four superior colliculus neurons simultaneously while monkeys performed a target selection task. We implemented three models to gain insight into the computational principles underlying population coding of action selection. We compared the population vector average (PVA)/optimal linear estimator (OLE) and winner-takes-all (WTA) models and a Bayesian model, maximum a posteriori estimate (MAP), to determine which predicted choices most often. The probabilistic model predicted more trials correctly than both the WTA and the PVA. The MAP model predicted 81.88%, whereas WTA predicted 71.11% and PVA/OLE predicted the least number of trials at 55.71 and 69.47%. Recovering MAP estimates using simulated, nonuniform priors that correlated with monkeys' choice performance, improved the accuracy of the model by 2.88%. A dynamic analysis revealed that the MAP estimate evolved over time and the posterior probability of the saccade choice reached a maximum at the time of the saccade. MAP estimates also scaled with choice performance accuracy. Although there was overlap in the prediction abilities of all the models, we conclude that movement choice from populations of neurons may be best understood by considering frameworks based on probability.

MeSH Categories: Animals, Bayes Theorem, *Choice Behavior, Macaca mulatta, Models, Neurological, Models, Statistical, Neurons/physiology, *Saccades, Superior Colliculi/physiology

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Mechanisms underlying lateral GABAergic feedback onto rod bipolar cells in rat retina.

Publication Date: 2010 Feb 10 PMID: 20147559
Authors: Chavez, A. E. - Grimes, W. N. - Diamond, J. S.
Journal: J Neurosci

GABAergic feedback inhibition from amacrine cells shapes visual signaling in the inner retina. Rod bipolar cells (RBCs), ON-sensitive cells that depolarize in response to light increments, receive reciprocal GABAergic feedback from A17 amacrine cells and additional GABAergic inputs from other amacrine cells located laterally in the inner plexiform layer. The circuitry and synaptic mechanisms underlying lateral GABAergic inhibition of RBCs are poorly understood. A-type and rho-subunit-containing (C-type) GABA receptors (GABA(A)Rs and GABA(C)Rs) mediate both forms of inhibition, but their relative activation during synaptic transmission is unclear, and potential interactions between adjacent reciprocal and lateral synapses have not been explored. Here, we recorded from RBCs in acute slices of rat retina and isolated lateral GABAergic inhibition by pharmacologically ablating A17 amacrine cells. We found that amacrine cells providing lateral GABAergic inhibition to RBCs receive excitatory synaptic input mostly from ON bipolar cells via activation of both Ca(2+)-impermeable and Ca(2+)-permeable AMPA receptors (CP-AMPARs) but not NMDA receptors (NMDARs). Voltage-gated Ca(2+) (Ca(v)) channels mediate the majority of Ca(2+) influx that triggers GABA release, although CP-AMPARs contribute a small component. The intracellular Ca(2+) signal contributing to transmitter release is amplified by Ca(2+)-induced Ca(2+) release from intracellular stores via activation of ryanodine receptors. Furthermore, lateral nonreciprocal feedback is mediated primarily by GABA(C)Rs that are activated independently from receptors mediating reciprocal feedback inhibition. These results illustrate numerous physiological differences that distinguish GABA release at reciprocal and lateral synapses, indicating complex, pathway-specific modulation of RBC signaling.

MeSH Categories: Amacrine Cells/metabolism, Animals, Calcium/metabolism, Calcium Channels/physiology, *Feedback, Physiological, Ion Channel Gating, Rats, Receptors, AMPA/biosynthesis, Receptors, GABA/physiology, Receptors, Kainic Acid/biosynthesis, Retinal Bipolar Cells/*physiology, Retinal Rod Photoreceptor Cells/*physiology, Sodium Channels/physiology, Synapses/physiology, gamma-Aminobutyric Acid/*physiology

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A genetic model of chronic rhinosinusitis-associated olfactory inflammation reveals reversible functional impairment and dramatic neuroepithelial reorganization.

Publication Date: 2010 Feb 10 PMID: 20147558
Authors: Lane, A. P. - Turner, J. - May, L. - Reed, R.
Journal: J Neurosci

Inflammatory sinus and nasal disease is a common cause of human olfactory loss. To explore the mechanisms underlying rhinosinusitis-associated olfactory loss, we have generated a transgenic mouse model of olfactory inflammation, in which tumor necrosis factor alpha (TNF-alpha) expression is induced in a temporally controlled manner specifically within the olfactory epithelium (OE). Like the human disease, TNF-alpha expression leads to a progressive infiltration of inflammatory cells into the OE. Using this model, we have defined specific phases of the pathologic process. An initial loss of sensation without significant disruption is observed, followed by a striking reorganization of the sensory neuroepithelium. An inflamed and disrupted state is sustained chronically by continued induction of cytokine expression. After prolonged maintenance in a deficient state, there is a dramatic recovery of function and a normal histologic appearance when TNF-alpha expression is extinguished. Although obstruction of airflow is also a contributing factor in human rhinosinusitis, this in vivo model demonstrates for the first time that direct effects of inflammation on OE structure and function are important mechanisms of olfactory dysfunction. These features mimic essential aspects of chronic rhinosinusitis-associated olfactory loss, and illuminate underlying cellular and molecular aspects of the disease. This manipulable model also serves as a platform for developing novel therapeutic interventions.

MeSH Categories: Animals, Aryl Hydrocarbon Hydroxylases/genetics, Cell Proliferation, Chronic Disease, *Disease Models, Animal, Mice, Mice, Transgenic, Neuroepithelial Cells/immunology/*pathology, Olfaction Disorders/genetics/immunology/*pathology/*physiopathology, Olfactory Mucosa/immunology/*metabolism/*pathology, Promoter Regions, Genetic, Rhinitis/immunology/*physiopathology, Sinusitis/immunology/*physiopathology, Steroid Hydroxylases/genetics, Tumor Necrosis Factor-alpha/biosynthesis/genetics

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Ca2+/calmodulin disrupts AKAP79/150 interactions with KCNQ (M-Type) K+ channels.

Publication Date: 2010 Feb 10 PMID: 20147557
Authors: Bal, M. - Zhang, J. - Hernandez, C. C. - Zaika, O. - Shapiro, M. S.
Journal: J Neurosci

M-type channels are localized to neuronal, cardiovascular, and epithelial tissues, where they play critical roles in control of excitability and K(+) transport, and are regulated by numerous receptors via G(q/11)-mediated signals. One pathway shown for KCNQ2 and muscarinic receptors uses PKC, recruited to the channels by A-kinase anchoring protein (AKAP)79/150. As M-type channels can be variously composed of KCNQ1-5 subunits, and M current is known to be regulated by Ca(2+)/calmodulin (CaM) and PIP(2), we probed the generality of AKAP79/150 actions among KCNQ1-5 channels, and the influence of Ca(2+)/CaM and PIP(2) on AKAP79/150 actions. We first examined which KCNQ subunits are targeted by AKAP79 in Chinese hamster ovary (CHO) cells heterologously expressing KCNQ1-5 subunits and AKAP79, using fluorescence resonance energy transfer (FRET) under total internal reflection fluorescence (TIRF) microscopy, and patch-clamp analysis. Donor-dequenching FRET between CFP-tagged KCNQ1-5 and YFP-tagged AKAP79 revealed association of KCNQ2-5, but not KCNQ1, with AKAP79. In parallel with these results, CHO cells stably expressing M(1) receptors studied under perforated patch-clamp showed cotransfection of AKAP79 to "sensitize" KCNQ2/3 heteromers and KCNQ2-5, but not KCNQ1, homomers to muscarinic inhibition, manifested by shifts in the dose-response relations to lower concentrations. The effect on KCNQ4 was abolished by the T553A mutation of the putative PKC phosphorylation site. We then probed the role of CaM and PIP(2) in these AKAP79 actions. TIRF/FRET experiments revealed cotransfection of wild-type, but not dominant-negative (DN), CaM that cannot bind Ca(2+), to disrupt the interaction of YFP-tagged AKAP79(1-153) with CFP-tagged KCNQ2-5. Tonic depletion of PIP(2) by cotransfection of a PIP(2) phosphatase had no effect, and sudden depletion of PIP(2) did not delocalize GFP-tagged AKAP79 from the membrane. Finally, patch-clamp experiments showed cotransfection of wild-type, but not DN, CaM to prevent the AKAP79-mediated sensitization of KCNQ2/3 heteromers to muscarinic inhibition. Thus, AKAP79 acts on KCNQ2-5, but not KCNQ1-containing channels, with effects disrupted by calcified CaM, but not by PIP(2) depletion.

MeSH Categories: A Kinase Anchor Proteins/genetics/*metabolism, Animals, CHO Cells, Calcium/*physiology, Calmodulin/*physiology, Cell Membrane/metabolism, Cricetinae, Cricetulus, Fluorescence Resonance Energy Transfer, Humans, KCNQ Potassium Channels/genetics/*metabolism, Microscopy, Fluorescence, Patch-Clamp Techniques, Phosphatidylinositol 4,5-Diphosphate/physiology, Protein Multimerization, Protein Subunits/genetics/metabolism, Transfection

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Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior.

Publication Date: 2010 Feb 10 PMID: 20147556
Authors: Plaza-Zabala, A. - Martin-Garcia, E. - de Lecea, L. - Maldonado, R. - Berrendero, F.
Journal: J Neurosci

Emerging evidence suggests that the hypocretinergic system is involved in addictive behavior. In this study, we investigated the role of these hypothalamic neuropeptides in anxiety-like responses of nicotine and stress-induced reinstatement of nicotine-seeking behavior. Acute nicotine (0.8 mg/kg, s.c.) induced anxiogenic-like effects in the elevated plus-maze and activated the paraventricular nucleus of the hypothalamus (PVN) as revealed by c-Fos expression. Pretreatment with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 or preprohypocretin gene deletion blocked both nicotine effects. In the PVN, SB334867 also prevented the activation of corticotrophin releasing factor (CRF) and arginine-vasopressin (AVP) neurons, which expressed Hcrtr-1. In addition, an increase of the percentage of c-Fos-positive hypocretin cells in the perifornical and dorsomedial hypothalamic (PFA/DMH) areas was found after nicotine (0.8 mg/kg, s.c.) administration. Intracerebroventricular infusion of hypocretin-1 (Hcrt-1) (0.75 nmol/1 mul) or footshock stress reinstated a previously extinguished nicotine-seeking behavior. The effects of Hcrt-1 were blocked by SB334867, but not by the CRF1 receptor antagonist antalarmin. Moreover, SB334867 did not block CRF-dependent footshock-induced reinstatement of nicotine-seeking while antalarmin was effective in preventing this nicotine motivational response. Therefore, the Hcrt system interacts with CRF and AVP neurons in the PVN and modulates the anxiogenic-like effects of nicotine whereas Hcrt and CRF play a different role in the reinstatement of nicotine-seeking. Indeed, Hcrt-1 reinstates nicotine-seeking through a mechanism independent of CRF activation whereas CRF mediates the reinstatement induced by stress.

MeSH Categories: Animals, Anxiety/metabolism/physiopathology/*psychology, Arginine Vasopressin/metabolism, Behavior, Addictive/metabolism/physiopathology/*psychology, Benzoxazoles/pharmacology, Conditioning, Operant/drug effects, Corticotropin-Releasing Hormone/metabolism, Extinction, Psychological, Intracellular Signaling Peptides and Proteins/genetics/*physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons/metabolism, Neuropeptides/genetics/*physiology, Nicotine/administration & dosage/*pharmacology, Paraventricular Hypothalamic Nucleus/drug, effects/metabolism/physiopathology, Pyrimidines/pharmacology, Pyrroles/pharmacology, Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors, Receptors, G-Protein-Coupled/antagonists & inhibitors, Receptors, Neuropeptide/antagonists & inhibitors, Self Administration, Tobacco Use Disorder/metabolism/physiopathology/*psychology, Urea/analogs & derivatives/pharmacology

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Reduced laterality as a trait marker of schizophrenia--evidence from structural and functional neuroimaging.

Publication Date: 2010 Feb 10 PMID: 20147555
Authors: Oertel, V. - Knochel, C. - Rotarska-Jagiela, A. - Schonmeyer, R. - Lindner, M. - van de Ven, V. - Haenschel, C. - Uhlhaas, P. - Maurer, K. - Linden, D. E.
Journal: J Neurosci

Laterality is a characteristic principle of the organization of the brain systems for language, and reduced hemispheric asymmetry has been considered a risk factor for schizophrenia. Here we sought support for the risk factor hypothesis by investigating whether reduced asymmetry of temporal lobe structure and function is also present in unaffected relatives. Sixteen schizophrenia patients, 16 age-matched first-degree relatives, and 15 healthy controls underwent high-resolution three-dimensional anatomical imaging and functional magnetic resonance imaging during auditory stimulation. Both the overall auditory cortex and planum temporale volumes and the lateralization to the left hemisphere were markedly reduced in patients. The decrease of lateralization correlated with increased severity of symptoms. In addition, both the overall functional activation in response to auditory stimulation and its asymmetry were reduced in the patients. Relatives had intermediate values between patients and controls on both structural and functional measures. This study provides added support for the idea that reduced hemispheric asymmetry is a biological risk factor for schizophrenia.

MeSH Categories: Acoustic Stimulation, Adult, Antipsychotic Agents/therapeutic use, Auditory Cortex/pathology/physiopathology, Brain/*pathology/*physiopathology, Female, *Functional Laterality, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Schizophrenia/drug therapy/*pathology/*physiopathology

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Postnatal development of a segmental switch enables corticospinal tract transmission to spinal forelimb motor circuits.

Publication Date: 2010 Feb 10 PMID: 20147554
Authors: Chakrabarty, S. - Martin, J. H.
Journal: J Neurosci

Development of skilled movements and the corticospinal tract (CST) begin prenatally and continue postnatally. Because the CST is required for skilled movements in maturity, it is accepted that motor skills cannot occur until the CST develops a mature organization. We recently showed that the CST plays an essential role in postnatal development of interneurons comprising the spinal circuits it engages. We proposed that CST signals are more effectively transmitted to ventral motor circuits after interneuron maturation, thereby enabling expression of CST motor functions, suggesting development of a segmental switch promoting transmission. We tested this by recording CST-evoked focal synaptic potentials, extracellularly, in the cervical enlargement of cats before and after interneuron maturation [postnatal week 5 (PW5) to PW7]. We compared monosynaptic CST amplitude input to segmental circuits with oligosynaptic ventral horn responses, as a measure of CST-evoked segmental response transmission from input to output. The M1 primary motor cortex was unilaterally inactivated between PW5 and PW7 to determine activity dependence. CST interneuron contacts were identified using confocal microscopy. CST terminals contact diverse interneuron classes. CST stimulation strongly activated ventral motor circuits at the ages when both interneurons and CST spinal terminations have developed a mature phenotype, supporting development of segmental transmission of CST signals. CST activity blockade impeded development of effective segmental transmission by the inactivated CST and created a novel path for transmission from the ipsilateral, unaffected, CST. Our findings show that development of segmental CST signal transmission regulates nascent CST motor control functions and provide insight into systems-level mechanisms for protracted motor skill development.

MeSH Categories: Animals, Anterior Horn Cells/physiology, Axons/physiology, Calcium-Binding Proteins/metabolism, Cats, Choline O-Acetyltransferase/metabolism, Electric Stimulation, Evoked Potentials, Interneurons/physiology, Microscopy, Confocal, Motor Cortex/growth & development/*physiology, Motor Skills/physiology, Pyramidal Tracts/cytology/growth & development/*physiology, Synaptic Potentials, Time Factors

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A surface-based analysis of hemispheric asymmetries and folding of cerebral cortex in term-born human infants.

Publication Date: 2010 Feb 10 PMID: 20147553
Authors: Hill, J. - Dierker, D. - Neil, J. - Inder, T. - Knutsen, A. - Harwell, J. - Coalson, T. - Van Essen, D.
Journal: J Neurosci

We have established a population average surface-based atlas of human cerebral cortex at term gestation and used it to compare infant and adult cortical shape characteristics. Accurate cortical surface reconstructions for each hemisphere of 12 healthy term gestation infants were generated from structural magnetic resonance imaging data using a novel segmentation algorithm. Each surface was inflated, flattened, mapped to a standard spherical configuration, and registered to a target atlas sphere that reflected shape characteristics of all 24 contributing hemispheres using landmark constrained surface registration. Population average maps of sulcal depth, depth variability, three-dimensional positional variability, and hemispheric depth asymmetry were generated and compared with previously established maps of adult cortex. We found that cortical structure in term infants is similar to the adult in many respects, including the pattern of individual variability and the presence of statistically significant structural asymmetries in lateral temporal cortex, including the planum temporale and superior temporal sulcus. These results indicate that several features of cortical shape are minimally influenced by the postnatal environment.

MeSH Categories: Atlases as Topic, Cerebral Cortex/*anatomy & histology, Female, Humans, Image Processing, Computer-Assisted, Infant, Newborn, Magnetic Resonance Imaging, Male

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The guanine exchange factor vav controls axon growth and guidance during Drosophila development.

Publication Date: 2010 Feb 10 PMID: 20147552
Authors: Malartre, M. - Ayaz, D. - Amador, F. F. - Martin-Bermudo, M. D.
Journal: J Neurosci

The Vav proteins are guanine exchange factors (GEFs) that trigger the activation of the Rho GTPases in general and the Rac family in particular. While the role of the mammalian vav genes has been extensively studied in the hematopoietic system and the immune response, there is little information regarding the role of vav outside of these systems. Here, we report that the single Drosophila vav homolog is ubiquitously expressed during development, although it is enriched along the embryonic ventral midline and in the larval eye discs and brain. We have analyzed the role that vav plays during development by generating Drosophila null mutant alleles. Our results indicate that vav is required during embryogenesis to prevent longitudinal axons from crossing the midline. Later on, during larval development, vav is required within the axons to regulate photoreceptor axon targeting to the optic lobe. Finally, we demonstrate that adult vav mutant escapers, which exhibit coordination problems, display axon growth defects in the ellipsoid body, a brain area associated with locomotion control. In addition, we show that vav interacts with other GEFs known to act downstream of guidance receptors. Thus, we propose that vav acts in coordination with other GEFs to regulate axon growth and guidance during development by linking guidance signals to the cytoskeleton via the modulation of Rac activity.

MeSH Categories: Animals, Axons/*physiology, Body Patterning, Cell Differentiation, Cell Movement, Central Nervous System/embryology/growth &, development/metabolism/ultrastructure, Drosophila/embryology/growth & development/*ultrastructure, Larva/growth & development/metabolism/ultrastructure, Mutation, Neuroglia/cytology/metabolism, Photoreceptor Cells, Invertebrate/metabolism/ultrastructure, Proto-Oncogene Proteins c-vav/biosynthesis/genetics/*physiology

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Detection of low salience whisker stimuli requires synergy of tectal and thalamic sensory relays.

Publication Date: 2010 Feb 10 PMID: 20147551
Authors: Cohen, J. D. - Castro-Alamancos, M. A.
Journal: J Neurosci

Detection of a sensory stimulus depends on its psychophysical saliency; the higher the saliency, the easier the detection. But it is not known whether sensory relay nuclei differ in their ability to detect low salient whisker stimuli. We found that reversible lesions of either the somatosensory thalamus or superior colliculus blocked detection of a low salience whisker conditioned stimulus (WCS) in an active avoidance task, without affecting detection of a high salience WCS. Thus, thalamic and tectal sensory relays work synergistically to detect low salient stimuli during avoidance behavior, but are redundant during detection of highly salient stimuli. We also recorded electrophysiological responses evoked by high and low salience stimuli in the superior colliculus and barrel cortex of freely behaving animals during active exploration, awake immobility, and sensory detection in the active avoidance task. Field potential (FP) responses evoked in barrel cortex and superior colliculus by high intensity stimuli are larger and adapt more to frequency than those evoked by low-intensity stimuli. FP responses are also more suppressed and adapt less during active exploration, and become further suppressed in barrel cortex during successful detection of either high or low salient stimuli in the active avoidance task. In addition, unit recordings revealed that firing rate increases in superior colliculus during active exploration and especially during successful detection of either high or low salient stimuli in the active avoidance task. We conclude that detection of low salient stimuli is achieved by a sparse neural code distributed through multiple sensory relays.

MeSH Categories: Afferent Pathways, Animals, Avoidance Learning/physiology, Conditioning, Classical, Evoked Potentials, Male, Psychophysics, Rats, Rats, Sprague-Dawley, Somatosensory Cortex/*physiology, Superior Colliculi/*physiology, Thalamus/*physiology, Trigeminal Nuclei/*physiology, Vibrissae/*physiology

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Ecto-5'-nucleotidase (CD73) inhibits nociception by hydrolyzing AMP to adenosine in nociceptive circuits.

Publication Date: 2010 Feb 10 PMID: 20147550
Authors: Sowa, N. A. - Taylor-Blake, B. - Zylka, M. J.
Journal: J Neurosci

Ecto-5'-nucleotidase (NT5E, CD73) is a membrane-anchored protein that hydrolyzes extracellular adenosine 5'-monophosphate (AMP) to adenosine in diverse tissues but has not been directly studied in nociceptive neurons. We found that NT5E was located on peptidergic and nonpeptidergic nociceptive neurons in dorsal root ganglia (DRG) and on axon terminals in lamina II (the substantia gelatinosa) of spinal cord. NT5E was also located on epidermal keratinocytes, cells of the dermis, and on nociceptive axon terminals in the epidermis. Following nerve injury, NT5E protein and AMP histochemical staining were coordinately reduced in lamina II. In addition, AMP hydrolytic activity was reduced in DRG neurons and spinal cord of Nt5e(-/-) mice. The antinociceptive effects of AMP, when combined with the adenosine kinase inhibitor 5-iodotubericidin, were reduced by approximately 50% in Nt5e(-/-) mice and were eliminated in Adenosine A(1) receptor (A(1)R, Adora1) knock-out mice. Additionally, Nt5e(-/-) mice displayed enhanced sensitivity in the tail immersion assay, in the complete Freund's adjuvant model of inflammatory pain and in the spared nerve injury model of neuropathic pain. Collectively, our data indicate that the ectonucleotidase NT5E regulates nociception by hydrolyzing AMP to adenosine in nociceptive circuits and represents a new molecular target for the treatment of chronic pain. Moreover, our data suggest NT5E is well localized to regulate nucleotide signaling between skin cells and sensory axons.

MeSH Categories: 5'-Nucleotidase/genetics/*metabolism, Adenosine/*metabolism, Adenosine Monophosphate/*metabolism, Animals, Cell Membrane/enzymology, Ganglia, Spinal/enzymology, Hydrolysis, Hyperalgesia/physiopathology, Inflammation/physiopathology, Male, Mice, Mice, Knockout, Nerve Endings/enzymology, Nociceptors/metabolism, Pain/*metabolism/physiopathology, Presynaptic Terminals/enzymology, Receptor, Adenosine A1/genetics/physiology, Sciatic Nerve/injuries, Skin/enzymology/innervation

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Distinct roles of GABAergic interneurons in the regulation of striatal output pathways.

Publication Date: 2010 Feb 10 PMID: 20147549
Authors: Gittis, A. H. - Nelson, A. B. - Thwin, M. T. - Palop, J. J. - Kreitzer, A. C.
Journal: J Neurosci

Striatal GABAergic microcircuits are critical for motor function, yet their properties remain enigmatic due to difficulties in targeting striatal interneurons for electrophysiological analysis. Here, we use Lhx6-GFP transgenic mice to identify GABAergic interneurons and investigate their regulation of striatal direct- and indirect-pathway medium spiny neurons (MSNs). We find that the two major interneuron populations, persistent low-threshold spiking (PLTS) and fast spiking (FS) interneurons, differ substantially in their excitatory inputs and inhibitory outputs. Excitatory synaptic currents recorded from PLTS interneurons are characterized by a small, nonrectifying AMPA receptor-mediated component and a NMDA receptor-mediated component. In contrast, glutamatergic synaptic currents in FS interneurons have a large, strongly rectifying AMPA receptor-mediated component, but no detectable NMDA receptor-mediated responses. Consistent with their axonal morphology, the output of individual PLTS interneurons is relatively weak and sparse, whereas FS interneurons are robustly connected to MSNs and other FS interneurons and appear to mediate the bulk of feedforward inhibition. Synaptic depression of FS outputs is relatively insensitive to firing frequency, and dynamic-clamp experiments reveal that these short-term dynamics enable feedforward inhibition to remain efficacious across a broad frequency range. Surprisingly, we find that FS interneurons preferentially target direct-pathway MSNs over indirect-pathway MSNs, suggesting a potential mechanism for rapid pathway-specific regulation of striatal output pathways.

MeSH Categories: Action Potentials, Animals, Corpus Striatum/*physiology, Interneurons/*physiology, Mice, Mice, Transgenic, Neural Inhibition, Neural Pathways, Patch-Clamp Techniques, Receptors, AMPA/physiology, Receptors, N-Methyl-D-Aspartate/physiology, Synapses/physiology, gamma-Aminobutyric Acid/*metabolism

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Serotonin modulates fast-spiking interneuron and synchronous activity in the rat prefrontal cortex through 5-HT1A and 5-HT2A receptors.

Publication Date: 2010 Feb 10 PMID: 20147548
Authors: Puig, M. V. - Watakabe, A. - Ushimaru, M. - Yamamori, T. - Kawaguchi, Y.
Journal: J Neurosci

Alterations of the serotonergic system in the prefrontal cortex (PFC) are implicated in psychiatric disorders such as schizophrenia and depression. Although abnormal synchronous activity is observed in the PFC of these patients, little is known about the role of serotonin (5-HT) in cortical synchrony. We found that 5-HT, released by electrical stimulation of the dorsal raphe nucleus (DRN) in anesthetized rats, regulates the frequency and the amplitude of slow (<2 Hz) waves in the PFC via 5-HT(2A) receptors (5-HT(2A)Rs). 5-HT also modulates prefrontal gamma (30-80 Hz) rhythms through both 5-HT(1A)Rs and 5-HT(2A)Rs, but not 5-HT(2C)Rs, inducing an overall decrease in the amplitude of gamma oscillations. Because fast-spiking interneurons (FSi) are involved in the generation of gamma waves, we examined serotonergic modulation of FSi activity in vivo. Most FSi are inhibited by serotonin through 5-HT(1A)Rs, while a minority is activated by 5-HT(2A)Rs, and not 5-HT(2C)Rs. In situ hybridization histochemistry confirmed that distinct populations of FSi in the PFC express 5-HT(1A)Rs and 5-HT(2A)Rs, and that the number of FSi expressing 5-HT(2C)Rs is negligible. We conclude that 5-HT exerts a potent control on slow and gamma oscillations in the PFC. On the one hand, it shapes the frequency and amplitude of slow waves through 5-HT(2A)Rs. On the other hand, it finely tunes the amplitude of gamma oscillations through 5-HT(2A)R- and 5-HT(1A)R-expressing FSi, although it primarily downregulates gamma waves via the latter population. These results may provide insight into impaired serotonergic control of network activity in psychiatric illnesses such as schizophrenia and depression.

MeSH Categories: Action Potentials, Animals, Electric Stimulation, In Situ Hybridization, Interneurons/*physiology, Male, Periodicity, Prefrontal Cortex/drug effects/metabolism/*physiology, Raphe Nuclei/physiology, Rats, Rats, Wistar, Receptor, Serotonin, 5-HT1A/antagonists &, inhibitors/biosynthesis/*physiology, Receptor, Serotonin, 5-HT2A/antagonists &, inhibitors/biosynthesis/*physiology, Receptor, Serotonin, 5-HT2C/antagonists & inhibitors/biosynthesis, Serotonin/*physiology

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VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety.

Publication Date: 2010 Feb 10 PMID: 20147547
Authors: Amilhon, B. - Lepicard, E. - Renoir, T. - Mongeau, R. - Popa, D. - Poirel, O. - Miot, S. - Gras, C. - Gardier, A. M. - Gallego, J. - Hamon, M. - Lanfumey, L. - Gasnier, B. - Giros, B. - El Mestikawy, S.
Journal: J Neurosci

Three different subtypes of H(+)-dependent carriers (named VGLUT1-3) concentrate glutamate into synaptic vesicles before its exocytotic release. Neurons using other neurotransmitter than glutamate (such as cholinergic striatal interneurons and 5-HT neurons) express VGLUT3. It was recently reported that VGLUT3 increases acetylcholine vesicular filling, thereby, stimulating cholinergic transmission. This new regulatory mechanism is herein designated as vesicular-filling synergy (or vesicular synergy). In the present report, we found that deletion of VGLUT3 increased several anxiety-related behaviors in adult and in newborn mice as early as 8 d after birth. This precocious involvement of a vesicular glutamate transporter in anxiety led us to examine the underlying functional implications of VGLUT3 in 5-HT neurons. On one hand, VGLUT3 deletion caused a significant decrease of 5-HT(1A)-mediated neurotransmission in raphe nuclei. On the other hand, VGLUT3 positively modulated 5-HT transmission of a specific subset of 5-HT terminals from the hippocampus and the cerebral cortex. VGLUT3- and VMAT2-positive serotonergic fibers show little or no 5-HT reuptake transporter. These results unravel the existence of a novel subset of 5-HT terminals in limbic areas that might play a crucial role in anxiety-like behaviors. In summary, VGLUT3 accelerates 5-HT transmission at the level of specific 5-HT terminals and can exert an inhibitory control at the raphe level. Furthermore, our results suggest that the loss of VGLUT3 expression leads to anxiety-associated behaviors and should be considered as a potential new target for the treatment of this disorder.

MeSH Categories: Amino Acid Transport Systems, Acidic/genetics/*physiology, Animals, Anxiety/metabolism/*physiopathology, Autoreceptors/physiology, Cerebral Cortex/physiopathology, Hippocampus/physiopathology, Mice, Mice, Knockout, Presynaptic Terminals/metabolism, Raphe Nuclei/physiopathology, Receptor, Serotonin, 5-HT1A/physiology, Serotonin/*physiology, Serotonin Plasma Membrane Transport Proteins/metabolism, Synaptic Transmission, Vesicular Monoamine Transport Proteins/metabolism

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Attention differentially modulates similar neuronal responses evoked by varying contrast and direction stimuli in area MT.

Publication Date: 2010 Feb 10 PMID: 20147546
Authors: Khayat, P. S. - Niebergall, R. - Martinez-Trujillo, J. C.
Journal: J Neurosci

The effects of attention on the responses of visual neurons have been described as a scaling or additive modulation independent of stimulus features and contrast, or as a contrast-dependent modulation. We explored these alternatives by recording neuronal responses in macaque area MT to moving stimuli that evoked similar firing rates but varied in contrast and direction. We presented two identical pairs of stimuli, one inside the neurons' receptive field and the other outside, in the opposite hemifield. One stimulus of each pair always had high contrast and moved in the recorded cell's antipreferred direction (AP pattern), while the other (test pattern) could either move in the cell's preferred direction and vary in contrast, or have the same contrast as the AP pattern and vary in direction. For different stimulus pairs evoking similar responses, switching attention between the two AP patterns, or directing attention from a fixation spot to the AP pattern inside or outside the receptive field, produced a stronger suppression of responses to varying contrast pairs, reaching a maximum ( approximately 20%) at intermediate contrast. For invariable contrast pairs, switching attention from the fixation spot to the AP pattern produced a modulation that ranged from 10% suppression when the test pattern moved in the cells preferred direction to 14% enhancement when it moved in a direction 90 degrees away from that direction. Our results are incompatible with a scaling or additive modulation of MT neurons' response by attention, but support models where spatial and feature-based attention modulate input signals into the area normalization circuit.

MeSH Categories: Action Potentials, Animals, *Attention, *Contrast Sensitivity, Macaca, Male, *Motion Perception, Neurons/*physiology, Photic Stimulation, Temporal Lobe/*physiology

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Reevaluation of neurodegeneration in lurcher mice: constitutive ion fluxes cause cell death with, not by, autophagy.

Publication Date: 2010 Feb 10 PMID: 20147545
Authors: Nishiyama, J. - Matsuda, K. - Kakegawa, W. - Yamada, N. - Motohashi, J. - Mizushima, N. - Yuzaki, M.
Journal: J Neurosci

The lurcher (Lc) mice have served as a valuable model for neurodegeneration for decades. Although the responsible mutation was identified in genes encoding delta2 glutamate receptors (GluD2s), which are predominantly expressed in cerebellar Purkinje cells, how the mutant receptor (GluD2(Lc)) triggers cell death has remained elusive. Here, taking advantage of recent knowledge about the domain structure of GluD2, we reinvestigated Lc-mediated cell death, focusing on the "autophagic cell death" hypothesis. Although autophagy and cell death were induced by the expression of GluD2(Lc) in heterologous cells and cultured neurons, they were blocked by the introduction of mutations in the channel pore domain of GluD2(Lc) or by removal of extracellular Na(+). In addition, although GluD2(Lc) is reported to directly activate autophagy, mutant channels that are not associated with n-PIST (neuronal isoform of protein-interacting specifically with TC10)-Beclin1 still caused autophagy and cell death. Furthermore, cells expressing GluD2(Lc) showed decreased ATP levels and increased AMP-activated protein kinase (AMPK) activities in a manner dependent on extracellular Na(+). Thus, constitutive currents were likely necessary and sufficient to induce autophagy via AMPK activation, regardless of the n-PIST-Beclin1 pathway in vitro. Interestingly, the expression of dominant-negative AMPK suppressed GluD2(Lc)-induced autophagy but did not prevent cell death in heterologous cells. Similarly, the disruption of Atg5, a gene crucial for autophagy, did not prevent but rather aggravated Purkinje-cell death in Lc mice. Furthermore, calpains were specifically activated in Lc Purkinje cells. Together, these results suggest that Lc-mediated cell death was not caused by autophagy but necrosis with autophagic features both in vivo and in vitro.

MeSH Categories: AMP-Activated Protein Kinases/metabolism, Adenosine Triphosphate/metabolism, Animals, Apoptosis Regulatory Proteins/physiology, *Autophagy, Calcium/*metabolism, Calpain/metabolism, Carrier Proteins/physiology, Cations, Cell Death, Cells, Cultured, Enzyme Activation, Humans, Mice, Mice, Neurologic Mutants, Microtubule-Associated Proteins/genetics, Nerve Degeneration/metabolism/*pathology, Neurons/metabolism/*pathology, Purkinje Cells/cytology/metabolism, Receptors, Glutamate/biosynthesis/genetics, Sodium/*metabolism

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Common origins of hippocampal Ivy and nitric oxide synthase expressing neurogliaform cells.

Publication Date: 2010 Feb 10 PMID: 20147544
Authors: Tricoire, L. - Pelkey, K. A. - Daw, M. I. - Sousa, V. H. - Miyoshi, G. - Jeffries, B. - Cauli, B. - Fishell, G. - McBain, C. J.
Journal: J Neurosci

GABAergic interneurons critically regulate cortical computation through exquisite spatiotemporal control over excitatory networks. Precision of this inhibitory control requires a remarkable diversity within interneuron populations that is largely specified during embryogenesis. Although interneurons expressing the neuronal isoform of nitric oxide synthase (nNOS) constitute the largest hippocampal interneuron cohort their origin and specification remain unknown. Thus, as neurogliaform cells (NGC) and Ivy cells (IvC) represent the main nNOS(+) interneurons, we investigated their developmental origins. Although considered distinct interneuron subtypes, NGCs and IvCs exhibited similar neurochemical and electrophysiological signatures, including NPY expression and late spiking. Moreover, lineage analyses, including loss-of-function experiments and inducible fate-mapping, indicated that nNOS(+) IvCs and NGCs are both derived from medial ganglionic eminence (MGE) progenitors under control of the transcription factor Nkx2-1. Surprisingly, a subset of NGCs lacking nNOS arises from caudal ganglionic eminence (CGE) progenitors. Thus, while nNOS(+) NGCs and IvCs arise from MGE progenitors, a CGE origin distinguishes a discrete population of nNOS(-) NGCs.

MeSH Categories: Action Potentials, Animals, Cell Lineage, Cell Polarity, Hippocampus/*cytology/enzymology, Immunohistochemistry, Interneurons/*cytology/enzymology/*physiology, Male, Mice, Mice, Transgenic, Neuropeptide Y/biosynthesis, Nitric Oxide Synthase Type I/*biosynthesis, Nuclear Proteins/physiology, Patch-Clamp Techniques, Reverse Transcriptase Polymerase Chain Reaction, Stem Cells/cytology/physiology, Telencephalon/cytology, Transcription Factors/physiology, Vasoactive Intestinal Peptide/biosynthesis

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Endocannabinoid signaling mediates psychomotor activation by adenosine A2A antagonists.

Publication Date: 2010 Feb 10 PMID: 20147543
Authors: Lerner, T. N. - Horne, E. A. - Stella, N. - Kreitzer, A. C.
Journal: J Neurosci

Adenosine A(2A) receptor antagonists are psychomotor stimulants that also hold therapeutic promise for movement disorders. However, the molecular mechanisms underlying their stimulant properties are not well understood. Here, we show that the robust increase in locomotor activity induced by an A(2A) antagonist in vivo is greatly attenuated by antagonizing cannabinoid CB(1) receptor signaling or by administration to CB(1)(-/-) mice. To determine the locus of increased endocannabinoid signaling, we measured the amount of anandamide [AEA (N-arachidonoylethanolamine)] and 2-arachidonoylglycerol (2-AG) in brain tissue from striatum and cortex. We find that 2-AG is selectively increased in striatum after acute blockade of A(2A) receptors, which are highly expressed by striatal indirect-pathway medium spiny neurons (MSNs). Using targeted whole-cell recordings from direct- and indirect-pathway MSNs, we demonstrate that A(2A) receptor antagonists potentiate 2-AG release and induction of long-term depression at indirect-pathway MSNs, but not direct-pathway MSNs. Together, these data outline a molecular mechanism by which A(2A) antagonists reduce excitatory synaptic drive on the indirect pathway through CB(1) receptor signaling, thus leading to increased psychomotor activation.

MeSH Categories: Afferent Pathways/metabolism, Animals, Arachidonic Acids/metabolism, Central Nervous System Stimulants/*pharmacology, Cerebral Cortex/drug effects/metabolism, Corpus Striatum/drug effects/metabolism, Endocannabinoids/*metabolism, Glutamic Acid/metabolism, Glycerides/metabolism, Long-Term Synaptic Depression, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity/*drug effects, Neurons/metabolism, Piperidines/pharmacology, Polyunsaturated Alkamides/metabolism, Pyrazoles/pharmacology, Pyrimidines/pharmacology, Receptor, Adenosine A2A/*antagonists & inhibitors, Receptor, Cannabinoid, CB1/antagonists & inhibitors/genetics/physiology, Signal Transduction

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Cell type-specific control of neuronal responsiveness by gamma-band oscillatory inhibition.

Publication Date: 2010 Feb 10 PMID: 20147542
Authors: Otte, S. - Hasenstaub, A. - Callaway, E. M.
Journal: J Neurosci

Neocortical networks are composed of diverse populations of cells that differ in their chemical content, electrophysiological characteristics, and connectivity. Gamma-frequency oscillatory activity of inhibitory subnetworks has been hypothesized to regulate information processing in the cortex as a whole. Inhibitory neurons in these subnetworks synchronize their firing and selectively innervate the perisomatic compartments of their target neurons, generating both tonic and rapidly fluctuating inhibition. How do different types of cortical neurons respond to changes in the level and structure of perisomatic inhibition? What accounts for response heterogeneity between cell types, and are these response properties fixed or flexible? To answer these questions, we use in vitro whole-cell recording and dynamic-clamp somatic current injection to study six distinct types of cortical neurons. We demonstrate that different types of neurons systematically vary in their receptiveness to fast changes in the structure of inhibition and the range over which changes in inhibitory tone affect their output. Using simple neuron models and model neuron hybrids (dynamic clamp), we determine which intrinsic differences between cell types lead to these variations in receptiveness. These results suggest important differences in the way cell types are affected by gamma-frequency inhibition, which may have important circuit level implications. Although intrinsic differences observed in vitro are useful for the elucidation of basic cellular properties and differences between cell types, we also investigate how the integrative properties of neurons are likely to be rapidly modulated in the context of active networks in vivo.

MeSH Categories: Action Potentials, Animals, Cell Membrane/physiology, Cerebral Cortex/cytology/physiology, Interneurons/physiology, Mice, Mice, Transgenic, Models, Neurological, Nerve Net/physiology, Neurons/*physiology, Patch-Clamp Techniques, Periodicity, Pyramidal Cells/physiology

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GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain.

Publication Date: 2010 Feb 10 PMID: 20147541
Authors: Eijkelkamp, N. - Heijnen, C. J. - Willemen, H. L. - Deumens, R. - Joosten, E. A. - Kleibeuker, W. - den Hartog, I. J. - van Velthoven, C. T. - Nijboer, C. - Nassar, M. A. - Dorn, G. W. 2nd - Wood, J. N. - Kavelaars, A.
Journal: J Neurosci

Chronic pain associated with inflammation is a common clinical problem, and the underlying mechanisms have only begun to be unraveled. GRK2 regulates cellular signaling by promoting G-protein-coupled receptor (GPCR) desensitization and direct interaction with downstream kinases including p38. The aim of this study was to determine the contribution of GRK2 to regulation of inflammatory pain and to unravel the underlying mechanism. GRK2(+/-) mice with an approximately 50% reduction in GRK2 developed increased and markedly prolonged thermal hyperalgesia and mechanical allodynia after carrageenan-induced paw inflammation or after intraplantar injection of the GPCR-binding chemokine CCL3. The effect of reduced GRK2 in specific cells was investigated using Cre-Lox technology. Carrageenan- or CCL3-induced hyperalgesia was increased but not prolonged in mice with decreased GRK2 only in Na(v)1.8 nociceptors. In vitro, reduced neuronal GRK2 enhanced CCL3-induced TRPV1 sensitization. In vivo, CCL3-induced acute hyperalgesia in GRK2(+/-) mice was mediated via TRPV1. Reduced GRK2 in microglia/monocytes only was required and sufficient to transform acute carrageenan- or CCL3-induced hyperalgesia into chronic hyperalgesia. Chronic hyperalgesia in GRK2(+/-) mice was associated with ongoing microglial activation and increased phospho-p38 and tumor necrosis factor alpha (TNF-alpha) in the spinal cord. Inhibition of spinal cord microglial, p38, or TNF-alpha activity by intrathecal administration of specific inhibitors reversed ongoing hyperalgesia in GRK2(+/-) mice. Microglia/macrophage GRK2 expression was reduced in the lumbar ipsilateral spinal cord during neuropathic pain, underlining the pathophysiological relevance of microglial GRK2. Thus, we identified completely novel cell-specific roles of GRK2 in regulating acute and chronic inflammatory hyperalgesia.

MeSH Categories: Animals, Astrocytes/metabolism, Cells, Cultured, Chemokine CCL3/pharmacology/physiology, Female, G-Protein-Coupled Receptor Kinase 2/genetics/*physiology, Hyperalgesia/enzymology/physiopathology, Inflammation/enzymology/physiopathology, Macrophages/enzymology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia/enzymology, Pain/*enzymology/immunology/*physiopathology, Peripheral Nervous System Diseases/enzymology/immunology/physiopathology, Rats, Rats, Sprague-Dawley, Sensory Receptor Cells/enzymology, Spinal Cord/enzymology, TRPV Cation Channels/physiology, Tumor Necrosis Factor-alpha/physiology, p38 Mitogen-Activated Protein Kinases/physiology

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Mental hoop diaries: emotional memories of a college basketball game in rival fans.

Publication Date: 2010 Feb 10 PMID: 20147540
Authors: Botzung, A. - Rubin, D. C. - Miles, A. - Cabeza, R. - Labar, K. S.
Journal: J Neurosci

The rivalry between the men's basketball teams of Duke University and the University of North Carolina-Chapel Hill (UNC) is one of the most storied traditions in college sports. A subculture of students at each university form social bonds with fellow fans, develop expertise in college basketball rules, team statistics, and individual players, and self-identify as a member of a fan group. The present study capitalized on the high personal investment of these fans and the strong affective tenor of a Duke-UNC basketball game to examine the neural correlates of emotional memory retrieval for a complex sporting event. Male fans watched a competitive, archived game in a social setting. During a subsequent functional magnetic resonance imaging session, participants viewed video clips depicting individual plays of the game that ended with the ball being released toward the basket. For each play, participants recalled whether or not the shot went into the basket. Hemodynamic signal changes time locked to correct memory decisions were analyzed as a function of emotional intensity and valence, according to the fan's perspective. Results showed intensity-modulated retrieval activity in midline cortical structures, sensorimotor cortex, the striatum, and the medial temporal lobe, including the amygdala. Positively valent memories specifically recruited processing in dorsal frontoparietal regions, and additional activity in the insula and medial temporal lobe for positively valent shots recalled with high confidence. This novel paradigm reveals how brain regions implicated in emotion, memory retrieval, visuomotor imagery, and social cognition contribute to the recollection of specific plays in the mind of a sports fan.

MeSH Categories: Basketball/*psychology, Cerebral Cortex/physiology, *Emotions, Humans, Imagination, Magnetic Resonance Imaging, Male, *Mental Recall, Young Adult

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Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior.

Publication Date: 2010 Feb 10 PMID: 20147539
Authors: Blundell, J. - Blaiss, C. A. - Etherton, M. R. - Espinosa, F. - Tabuchi, K. - Walz, C. - Bolliger, M. F. - Sudhof, T. C. - Powell, C. M.
Journal: J Neurosci

Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding partners have been linked to cases of human autism and mental retardation. We have now characterized NL1-deficient mice in autism- and mental retardation-relevant behavioral tasks. NL1 knock-out (KO) mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at corticostriatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial coagonist d-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and NL1 in particular, in autism and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.

MeSH Categories: Animals, Cerebral Cortex/physiology, Corpus Striatum/physiology, Cycloserine/pharmacology, Drug Partial Agonism, Excitatory Postsynaptic Potentials, *Grooming, Hippocampus/physiology, Long-Term Potentiation, Maze Learning, Membrane Proteins/*genetics/physiology, *Memory, Mice, Mice, Knockout, Nerve Tissue Proteins/*genetics/physiology, Neural Cell Adhesion Molecules/metabolism, Patch-Clamp Techniques, Receptors, AMPA/metabolism, Receptors, N-Methyl-D-Aspartate/agonists/metabolism, Social Behavior, *Spatial Behavior, *Stereotyped Behavior, Synapses/physiology

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Neural representation of natural images in visual area V2.

Publication Date: 2010 Feb 10 PMID: 20147538
Authors: Willmore, B. D. - Prenger, R. J. - Gallant, J. L.
Journal: J Neurosci

Area V2 is a major visual processing stage in mammalian visual cortex, but little is currently known about how V2 encodes information during natural vision. To determine how V2 represents natural images, we used a novel nonlinear system identification approach to obtain quantitative estimates of spatial tuning across a large sample of V2 neurons. We compared these tuning estimates with those obtained in area V1, in which the neural code is relatively well understood. We find two subpopulations of neurons in V2. Approximately one-half of the V2 neurons have tuning that is similar to V1. The other half of the V2 neurons are selective for complex features such as those that occur in natural scenes. These neurons are distinguished from V1 neurons mainly by the presence of stronger suppressive tuning. Selectivity in these neurons therefore reflects a balance between excitatory and suppressive tuning for specific features. These results provide a new perspective on how complex shape selectivity arises, emphasizing the role of suppressive tuning in determining stimulus selectivity in higher visual cortex.

MeSH Categories: Animals, Cluster Analysis, Electrophysiology, Macaca mulatta, Male, Models, Neurological, Neurons/*physiology, Visual Cortex/*physiology, *Visual Perception

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CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment and Alzheimer's disease.

Publication Date: 2010 Feb 10 PMID: 20147537
Authors: Fjell, A. M. - Walhovd, K. B. - Fennema-Notestine, C. - McEvoy, L. K. - Hagler, D. J. - Holland, D. - Brewer, J. B. - Dale, A. M.
Journal: J Neurosci

Brain atrophy and altered CSF levels of amyloid beta (Abeta(42)) and the microtubule-associated protein tau are potent biomarkers of Alzheimer's disease (AD)-related pathology. However, the relationship between CSF biomarkers and brain morphometry is poorly understood. Thus, we addressed the following questions. (1) Can CSF biomarker levels explain the morphometric differences between normal controls (NC) and patients with mild cognitive impairment (MCI) or AD? (2) How are CSF biomarkers related to atrophy across the brain? (3) How closely are CSF biomarkers and morphometry related to clinical change [clinical dementia rating sum of boxes (CDR-sb)]? Three hundred seventy participants (105 NC, 175 MCI, 90 AD) from the Alzheimer's Disease Neuroimaging Initiative were studied, of whom 309 were followed for 1 year and 176 for 2 years. Analyses were performed across the entire cortical surface, as well as for 30 cortical and subcortical regions of interest. Results showed that CSF biomarker levels could not account for group differences in brain morphometry at baseline but that CSF biomarker levels showed moderate relationships to longitudinal atrophy rates in numerous brain areas, not restricted to medial temporal structures. Baseline morphometry was at least as predictive of atrophy as were CSF biomarkers. Even MCI patients with levels of Abeta(42) comparable with controls and of p-tau lower than controls showed more atrophy than the controls. Morphometry predicted change in CDR-sb better than did CSF biomarkers. These results indicate that morphometric changes in MCI and AD are not secondary to CSF biomarker changes and that the two types of biomarkers yield complementary information.

MeSH Categories: Aged, Aged, 80 and over, Alzheimer Disease/*cerebrospinal fluid/diagnosis/*pathology, Amyloid beta-Protein/cerebrospinal fluid, Atrophy, Biological Markers/cerebrospinal fluid, Brain/*pathology, Cognition Disorders/*cerebrospinal fluid/diagnosis/*pathology, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Peptide Fragments/cerebrospinal fluid, Predictive Value of Tests, Prognosis, tau Proteins/cerebrospinal fluid

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Complement component c1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury.

Publication Date: 2010 Feb 10 PMID: 20147536
Authors: Ten, V. S. - Yao, J. - Ratner, V. - Sosunov, S. - Fraser, D. A. - Botto, M. - Sivasankar, B. - Morgan, B. P. - Silverstein, S. - Stark, R. - Polin, R. - Vannucci, S. J. - Pinsky, D. - Starkov, A. A.
Journal: J Neurosci

Hypoxic-ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia-ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia-ischemia. Only C1q(-/-) mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q(-/-) brain mitochondria and preserved activity of the respiratory chain. Compared with C1q(+/+) neurons, cortical C1q(-/-) neurons exhibited resistance to oxygen-glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q(-/-) neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation.

MeSH Categories: Animals, Animals, Newborn, Antigens, CD59/pharmacology, Brain Infarction/metabolism/pathology, Cells, Cultured, Complement Activation, Complement C1q/genetics/*physiology, Cytosol/metabolism, Female, Glucose/deficiency, Hypoxia-Ischemia, Brain/*metabolism/pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria/*physiology, Neurons/metabolism, *Oxidative Stress, Oxygen/metabolism, Reactive Oxygen Species/metabolism

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Cortical mechanisms for the segregation and representation of acoustic textures.

Publication Date: 2010 Feb 10 PMID: 20147535
Authors: Overath, T. - Kumar, S. - Stewart, L. - von Kriegstein, K. - Cusack, R. - Rees, A. - Griffiths, T. D.
Journal: J Neurosci

Auditory object analysis requires two fundamental perceptual processes: the definition of the boundaries between objects, and the abstraction and maintenance of an object's characteristic features. Although it is intuitive to assume that the detection of the discontinuities at an object's boundaries precedes the subsequent precise representation of the object, the specific underlying cortical mechanisms for segregating and representing auditory objects within the auditory scene are unknown. We investigated the cortical bases of these two processes for one type of auditory object, an "acoustic texture," composed of multiple frequency-modulated ramps. In these stimuli, we independently manipulated the statistical rules governing (1) the frequency-time space within individual textures (comprising ramps with a given spectrotemporal coherence) and (2) the boundaries between textures (adjacent textures with different spectrotemporal coherences). Using functional magnetic resonance imaging, we show mechanisms defining boundaries between textures with different coherences in primary and association auditory cortices, whereas texture coherence is represented only in association cortex. Furthermore, participants' superior detection of boundaries across which texture coherence increased (as opposed to decreased) was reflected in a greater neural response in auditory association cortex at these boundaries. The results suggest a hierarchical mechanism for processing acoustic textures that is relevant to auditory object analysis: boundaries between objects are first detected as a change in statistical rules over frequency-time space, before a representation that corresponds to the characteristics of the perceived object is formed.

MeSH Categories: Acoustic Stimulation, Adolescent, Adult, Auditory Cortex/*physiology, Echo-Planar Imaging, Female, Humans, Male, Pitch Perception/*physiology, Stochastic Processes, Young Adult

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Integration of vibrotactile signals for whisker-related perception in rats is governed by short time constants: comparison of neurometric and psychometric detection performance.

Publication Date: 2010 Feb 10 PMID: 20147534
Authors: Stuttgen, M. C. - Schwarz, C.
Journal: J Neurosci

Rats explore environments by sweeping their whiskers across objects and surfaces. Both sensor movement and repetitive sweeping typical for this behavior require that vibrotactile signals are integrated over time. While temporal integration properties of neurons along the whisker somatosensory pathway have been studied extensively, the consequences for behavior are unknown. Here, we investigate the ability of head-fixed rats to integrate information over time for the detection of near-threshold pulsatile deflection sequences applied to a single whisker. Psychometric detection performance was assessed with whisker stimuli composed of different numbers of pulses (1-31) delivered at varying frequencies (10, 20, 100 Hz). Detection performance indeed improved with increasing number and frequency of pulses, albeit this improvement was much lower than predicted by probabilistic combination, suggesting highly sublinear integration of pulses. This behavioral observation was reflected in the firing properties of concomitantly recorded barrel cortex neurons, which showed substantial response adaptation to repetitive whisker deflection. To estimate the integration time with which barrel cortex neuronal activity must be read out to match behavior, we constructed a model monitoring spiking activity of simulated neuronal pools, where spike trains were channeled through a leaky integrator with exponential decay. Detection was accomplished by simple threshold crossings. This simple model gave an excellent match of neurometric and psychometric data at surprisingly small time constants tau of 5-8 ms, thus limiting integration largely to <25 ms. This result carries important implications regarding sensory processing for whisker-mediated perception.

MeSH Categories: Action Potentials, Animals, Behavior, Animal, Female, Models, Neurological, Monte Carlo Method, Neurons/physiology, Perception/*physiology, Psychometrics, Rats, Rats, Sprague-Dawley, Reaction Time, Somatosensory Cortex/*physiology, Time Factors, *Touch, Vibration, Vibrissae/*physiology

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The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity.

Publication Date: 2010 Feb 10 PMID: 20147533
Authors: Kron, M. M. - Zhang, H. - Parent, J. M.
Journal: J Neurosci

Dentate granule cell (DGC) neurogenesis persists throughout life in the hippocampal dentate gyrus. In rodent temporal lobe epilepsy models, status epilepticus (SE) stimulates neurogenesis, but many newborn DGCs integrate aberrantly and are hyperexcitable, whereas others may integrate normally and restore inhibition. The overall influence of altered neurogenesis on epileptogenesis is therefore unclear. To better understand the role DGC neurogenesis plays in seizure-induced plasticity, we injected retroviral (RV) reporters to label dividing DGC progenitors at specific times before or after SE, or used x-irradiation to suppress neurogenesis. RV injections 7 weeks before SE to mark DGCs that had matured by the time of SE labeled cells with normal placement and morphology 4 weeks after SE. RV injections 2 or 4 weeks before seizure induction to label cells still developing during SE revealed normally located DGCs exhibiting hilar basal dendrites and mossy fiber sprouting (MFS) when observed 4 weeks after SE. Cells labeled by injecting RV after SE displayed hilar basal dendrites and ectopic migration, but not sprouting, at 28 d after SE; when examined 10 weeks after SE, however, these cells showed robust MFS. Eliminating cohorts of newborn DGCs by focal brain irradiation at specific times before or after SE decreased MFS or hilar ectopic DGCs, supporting the RV labeling results. These findings indicate that developing DGCs exhibit maturation-dependent vulnerability to SE, indicating that abnormal DGC plasticity derives exclusively from aberrantly developing DGCs. Treatments that restore normal DGC development after epileptogenic insults may therefore ameliorate epileptogenic network dysfunction and associated morbidities.

MeSH Categories: Animals, Cell Division, Cell Movement, Dendrites/physiology, Dentate Gyrus/growth & development/*pathology/physiopathology, Epilepsy, Temporal Lobe/*pathology/physiopathology, Male, Mossy Fibers, Hippocampal/physiology, Neurogenesis, Neuronal Plasticity, Rats, Rats, Sprague-Dawley, Seizures/*pathology/physiopathology, Status Epilepticus/pathology/physiopathology, Stem Cells/pathology/physiology

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Perisomatic voltage-gated sodium channels actively maintain linear synaptic integration in principal neurons of the medial superior olive.

Publication Date: 2010 Feb 10 PMID: 20147532
Authors: Scott, L. L. - Mathews, P. J. - Golding, N. L.
Journal: J Neurosci

Principal neurons of the medial superior olive (MSO) compute azimuthal sound location by integrating phase-locked inputs from each ear. While previous experimental and modeling studies have proposed that voltage-gated sodium channels (VGSCs) play an important role in synaptic integration in the MSO, these studies appear at odds with the unusually weak active backpropagation of action potentials into the soma and dendrites. To understand the spatial localization and biophysical properties of VGSCs, we isolated sodium currents in MSO principal neurons in gerbil brainstem slices. Nucleated and cell-attached patches revealed that VGSC density at the soma is comparable to that of many other neuron types, but channel expression is largely absent from the dendrites. Further, while somatic VGSCs activated with conventional voltage dependence (V(1/2) = -30 mV), they exhibited an unusually negative range of steady-state inactivation (V(1/2) = -77 mV), leaving approximately 92% of VGSCs inactivated at the resting potential (approximately -58 mV). In current-clamp experiments, non-inactivated VGSCs were sufficient to amplify subthreshold EPSPs near action potential threshold, counterbalancing the suppression of EPSP peaks by low voltage-activated potassium channels. EPSP amplification was restricted to the perisomatic region of the neuron, and relatively insensitive to preceding inhibition. Finally, computational modeling showed that the exclusion of VGSCs from the dendrites equalizes somatic EPSP amplification across synaptic locations and lowered the threshold for bilateral versus unilateral excitatory synaptic inputs. Together, these findings suggest that the pattern of sodium channel expression in MSO neurons contributes to these neurons' selectivity for coincident binaural inputs.

MeSH Categories: Action Potentials, Animals, Dendrites/physiology, Gerbillinae, Ion Channel Gating, Neurons/*physiology, Olivary Nucleus/*physiology, Patch-Clamp Techniques, Sodium Channels/*physiology, Synapses/*physiology, Synaptic Potentials

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CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.

Publication Date: 2010 Feb 10 PMID: 20147531
Authors: Liu, Y. - Bando, Y. - Vargas-Lowy, D. - Elyaman, W. - Khoury, S. J. - Huang, T. - Reif, K. - Chitnis, T.
Journal: J Neurosci

To assess the effects and mechanisms of a CD200R1 agonist administered during the progressive stage of a multiple sclerosis model, we administered CD200R1 agonist (CD200Fc) or control IgG2a during the chronic phase of disease (days 10-30) in mice with experimental autoimmune encephalomyelitis (EAE), induced using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) peptide. We found that administration of CD200Fc during the chronic stages of EAE reduced disease severity, demyelination, and axonal damage, through the modulation of several key disease mechanisms. CD200Fc treatment suppressed macrophage and microglial accumulation within the CNS, in part through downregulation of adhesion molecules VLA-4 and LFA-1, which are necessary for macrophage migration. Additionally, expression of activation markers MHC-II and CD80 and production of proinflammatory cytokines IL-6, tumor necrosis factor-alpha, and nitric oxide by CD11b(+) cells were decreased in both the spleen and CNS in CD200Fc-treated animals. Antigen-presenting cell function in the spleen and CNS was suppressed in CD200Fc-treated mice, but there were no significant alterations on T cell activation or phenotype. CD200Fc increased apoptosis of CD11b(+) cells but not astrocytes. In contrast, addition of CD200Fc treatment protected oligodendrocytes from apoptosis in vitro and in vivo. Our results demonstrate that CD200R1 agonists modulate both myeloid- and non-myeloid-related mechanisms of chronic disease in the EAE model and may be effective in the treatment of progressive multiple sclerosis and other neurodegenerative diseases.

MeSH Categories: Animals, Antigens, Surface/biosynthesis/*genetics, Apoptosis/drug effects, Cells, Cultured, Chronic Disease, Encephalomyelitis, Autoimmune, Experimental/*drug, therapy/immunology/pathology, Humans, Immunoglobulin Fc Fragments/*genetics, Immunoglobulin G/*genetics, Macrophages/drug effects/physiology, Mice, Mice, Inbred C57BL, Microglia/drug effects/physiology, Multiple Sclerosis/*drug therapy/immunology/pathology, Receptors, Cell Surface/*agonists/biosynthesis/*genetics, Recombinant Fusion Proteins/*therapeutic use, Spinal Cord/drug effects/metabolism/pathology, Spleen/immunology/pathology, T-Lymphocytes/drug effects/physiology

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Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice.

Publication Date: 2010 Feb 10 PMID: 20147530
Authors: Gao, Y. - Vasilyev, D. V. - Goncalves, M. B. - Howell, F. V. - Hobbs, C. - Reisenberg, M. - Shen, R. - Zhang, M. Y. - Strassle, B. W. - Lu, P. - Mark, L. - Piesla, M. J. - Deng, K. - Kouranova, E. V. - Ring, R. H. - Whiteside, G. T. - Bates, B. - Walsh, F. S. - Williams, G. - Pangalos, M. N. - Samad, T. A. - Doherty, P.
Journal: J Neurosci

Endocannabinoids (eCBs) function as retrograde signaling molecules at synapses throughout the brain, regulate axonal growth and guidance during development, and drive adult neurogenesis. There remains a lack of genetic evidence as to the identity of the enzyme(s) responsible for the synthesis of eCBs in the brain. Diacylglycerol lipase-alpha (DAGLalpha) and -beta (DAGLbeta) synthesize 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain. However, their respective contribution to this and to eCB signaling has not been tested. In the present study, we show approximately 80% reductions in 2-AG levels in the brain and spinal cord in DAGLalpha(-/-) mice and a 50% reduction in the brain in DAGLbeta(-/-) mice. In contrast, DAGLbeta plays a more important role than DAGLalpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGLbeta(-/-) mice. Levels of arachidonic acid decrease in parallel with 2-AG, suggesting that DAGL activity controls the steady-state levels of both lipids. In the hippocampus, the postsynaptic release of an eCB results in the transient suppression of GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGLalpha(-/-) animals and relatively unaffected in DAGLbeta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGLalpha(-/-) and/or DAGLbeta(-/-) mice. These findings provide the first evidence that DAGLalpha is the major biosynthetic enzyme for 2-AG in the nervous system and reveal an essential role for this enzyme in regulating retrograde synaptic plasticity and adult neurogenesis.

MeSH Categories: Animals, Arachidonic Acids/metabolism, Brain/cytology/*metabolism, Endocannabinoids/*physiology, Glycerides/metabolism, Hippocampus/cytology/metabolism, Lipoprotein Lipase/*genetics, Liver/metabolism, Mice, Mice, Knockout, Neurogenesis, Neuronal Plasticity, Signal Transduction, Spinal Cord/metabolism, Synapses/physiology

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Interaction between facilitation and depression at a large CNS synapse reveals mechanisms of short-term plasticity.

Publication Date: 2010 Feb 10 PMID: 20147529
Authors: Muller, M. - Goutman, J. D. - Kochubey, O. - Schneggenburger, R.
Journal: J Neurosci

The two fundamental forms of short-term plasticity, short-term depression and facilitation, coexist at most synapses, but little is known about their interaction. Here, we studied the interplay between short-term depression and facilitation at calyx of Held synapses. Stimulation at a "low" frequency of 10 or 20 Hz, which is in the range of the spontaneous activity of these auditory neurons in vivo, induced synaptic depression. Surprisingly, an instantaneous increase of the stimulation frequency to 100 or 200 Hz following the low-frequency train uncovered a robust facilitation of EPSCs relative to the predepressed amplitude level. This facilitation decayed rapidly ( approximately 30 ms) and depended on presynaptic residual Ca(2+), but it was not caused by Ca(2+) current facilitation. To probe the release probability of the remaining readily releasable vesicles following the low-frequency train we made presynaptic Ca(2+) uncaging experiments in the predepressed state of the synapse. We found that low-frequency stimulation depletes the fast-releasable vesicle pool (FRP) down to approximately 40% of control and that the remaining FRP vesicles are released with approximately 2-fold slower release kinetics, indicating a hitherto unknown intrinsic heterogeneity among FRP vesicles. Thus, vesicles with an intrinsically lower release probability predominate after low frequency stimulation and undergo facilitation during the onset of subsequent high-frequency trains. Facilitation in the predepressed state of the synapse might help to stabilize the amount of transmitter release at the onset of high-frequency firing at these auditory synapses.

MeSH Categories: Acoustic Stimulation, Action Potentials, Animals, Auditory Pathways/*physiology, Brain Stem/*physiology, Calcium/physiology, Excitatory Postsynaptic Potentials, Neuronal Plasticity, Neurotransmitter Agents/metabolism, Patch-Clamp Techniques, Rats, Rats, Wistar, Synapses/*physiology, Synaptic Vesicles/physiology

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Temporally diverse firing patterns in olfactory receptor neurons underlie spatiotemporal neural codes for odors.

Publication Date: 2010 Feb 10 PMID: 20147528
Authors: Raman, B. - Joseph, J. - Tang, J. - Stopfer, M.
Journal: J Neurosci

Odorants are represented as spatiotemporal patterns of spikes in neurons of the antennal lobe (AL; insects) and olfactory bulb (OB; vertebrates). These response patterns have been thought to arise primarily from interactions within the AL/OB, an idea supported, in part, by the assumption that olfactory receptor neurons (ORNs) respond to odorants with simple firing patterns. However, activating the AL directly with simple pulses of current evoked responses in AL neurons that were much less diverse, complex, and enduring than responses elicited by odorants. Similarly, models of the AL driven by simplistic inputs generated relatively simple output. How then are dynamic neural codes for odors generated? Consistent with recent results from several other species, our recordings from locust ORNs showed a great diversity of temporal structure. Furthermore, we found that, viewed as a population, many response features of ORNs were remarkably similar to those observed within the AL. Using a set of computational models constrained by our electrophysiological recordings, we found that the temporal heterogeneity of responses of ORNs critically underlies the generation of spatiotemporal odor codes in the AL. A test then performed in vivo confirmed that, given temporally homogeneous input, the AL cannot create diverse spatiotemporal patterns on its own; however, given temporally heterogeneous input, the AL generated realistic firing patterns. Finally, given the temporally structured input provided by ORNs, we clarified several separate, additional contributions of the AL to olfactory information processing. Thus, our results demonstrate the origin and subsequent reformatting of spatiotemporal neural codes for odors.

MeSH Categories: Action Potentials, Animals, Computer Simulation, Female, Grasshoppers, Male, Models, Neurological, Odors, Olfactory Pathways/physiology, Olfactory Perception/*physiology, Olfactory Receptor Neurons/*physiology, Time Factors

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Subcortical representation of non-Fourier image features.

Publication Date: 2010 Feb 10 PMID: 20147527
Authors: Rosenberg, A. - Husson, T. R. - Issa, N. P.
Journal: J Neurosci

A fundamental goal of visual neuroscience is to identify the neural pathways representing different image features. It is widely argued that the early stages of these pathways represent linear features of the visual scene and that the nonlinearities necessary to represent complex visual patterns are introduced later in cortex. We tested this by comparing the responses of subcortical and cortical neurons to interference patterns constructed by summing sinusoidal gratings. Although a linear mechanism can detect the component gratings, a nonlinear mechanism is required to detect an interference pattern resulting from their sum. Consistent with in vitro retinal ganglion cell recordings, we found that interference patterns are represented subcortically by cat LGN Y-cells, but not X-cells. Linear and nonlinear tuning properties of LGN Y-cells were then characterized and compared quantitatively with those of cortical area 18 neurons responsive to interference patterns. This comparison revealed a high degree of similarity between the two neural populations, including the following: (1) the representation of similar spatial frequencies in both their linear and nonlinear responses, (2) comparable orientation selectivity for the high spatial frequency carrier of interference patterns, and (3) the same difference in their temporal frequency selectivity for drifting gratings versus the envelope of interference patterns. The present findings demonstrate that the nonlinear subcortical Y-cell pathway represents complex visual patterns and likely underlies cortical responses to interference patterns. We suggest that linear and nonlinear mechanisms important for encoding visual scenes emerge in parallel through distinct pathways originating at the retina.

MeSH Categories: Action Potentials, Animals, Cats, Fourier Analysis, Geniculate Bodies/physiology, Neural Pathways, Neurons/*physiology, Photic Stimulation, Retinal Ganglion Cells/physiology, Visual Cortex/*physiology, Visual Perception/*physiology

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