Journal of Neuroscience

The relationship between nature of social change, age, and position of new neurons and their survival in adult zebra finch brain.

Publication Date: 2008 May 14 PMID: 18480295
Authors: Adar, E. - Nottebohm, F. - Barnea, A.
Journal: J Neurosci

Some kinds of neurons are spontaneously recruited in the intact, healthy adult brain, but the variables that affect their survival are not always clear. We show that in caudal nidopallium of adult male zebra finches, the rostrocaudal position of newly recruited neurons, their age (1 vs 3 months), and the nature of social change (complex vs simple) after the neurons were born affect their survival. Greater social complexity promoted the survival of younger new neurons, and the demise of older ones; a less marked social change promoted the survival of older new neurons. These effects were position dependent. We suggest that functional correlations between new neuron recruitment/survival and its inferred benefit to the animal might be better perceived when taking into account the position of cells, their age at the time of life style changes, and the nature and magnitude of the life style change.

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Ketamine, but not phencyclidine, selectively modulates cerebellar GABA(A) receptors containing alpha6 and delta subunits.

Publication Date: 2008 May 14 PMID: 18480294
Authors: Hevers, W. - Hadley, S. H. - Luddens, H. - Amin, J.
Journal: J Neurosci

Phencyclidine (PCP) and ketamine are dissociative anesthetics capable of inducing analgesia, psychomimetic behavior, and a catatonic state of unconsciousness. Despite broad similarities, there are notable differences between the clinical actions of ketamine and PCP. Ketamine has a lower incidence of adverse effects and generally produces greater CNS depression than PCP. Both noncompetitively inhibit NMDA receptors, yet there is little evidence that these drugs affect GABA(A) receptors, the primary target of most anesthetics. alpha6beta2/3delta receptors are subtypes of the GABA(A) receptor family and are abundantly expressed in granular neurons within the adult cerebellum. Here, using an oocyte expression system, we show that at anesthetically relevant concentrations, ketamine, but not PCP, modulates alpha6beta2delta and alpha6beta3delta receptors. Additionally, at higher concentrations, ketamine directly activates these GABA(A) receptors. Comparatively, dizocilpine (MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]), a potent noncompetitive antagonist of NMDA receptors that is structurally unrelated to PCP, did not produce any effect on alpha6beta2delta receptors. Of the recombinant GABA(A) receptor subtypes examined (alpha1beta2, alpha1beta2gamma2, alpha1beta2delta, alpha4beta2gamma2, alpha4beta2delta, alpha6beta2gamma2, alpha6beta2delta, and alpha6beta3delta), the actions of ketamine were unique to alpha6beta2delta and alpha6beta3delta receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from alpha6-containing GABA(A) receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null alpha6(-/-) and delta(-/-)mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on alpha6beta2/3delta receptors.

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Phosphorylation of Homer3 by calcium/calmodulin-dependent kinase II regulates a coupling state of its target molecules in Purkinje cells.

Publication Date: 2008 May 14 PMID: 18480293
Authors: Mizutani, A. - Kuroda, Y. - Futatsugi, A. - Furuichi, T. - Mikoshiba, K.
Journal: J Neurosci

Homer proteins are components of postsynaptic density (PSD) and play a crucial role in coupling diverse target molecules. However, the regulatory aspect of Homer-mediated coupling has been addressed only about a dominant-negative effect of Homer1a, which requires de novo gene expression. Here, we present evidence that Homer-mediated coupling is regulated by its phosphorylation state. We found that Homer3, the predominant isoform in Purkinje cells, is phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) both in vitro and in vivo. Biochemical fractionation with phosphor-specific antibodies revealed the presence of phosphorylated Homer3 in the cytosolic fraction in contrast to high levels of nonphosphorylated Homer3 in PSD. In P/Q-type voltage-gated-Ca2+ channel knock-out mice, in which CaMKII activation was reduced, the levels of Homer3 phosphorylation and the soluble form of Homer 3 were markedly lower. Furthermore, both robust phosphorylation of Homer3 and its dissociation from metabotropic glutamate receptor 1alpha (mGluR1alpha) were triggered by depolarization in primary cultured Purkinje cells, and these events were inhibited by CaMKII inhibitor. An in vitro binding kinetic analysis revealed that these phosphorylation-dependent events were attributable to a decrease in the affinity of phosphorylated Homer3 for its ligand. In a heterologous system, the Ca2+ signaling pattern induced by mGluR1alpha activation was modulated by the Homer3 phosphorylation state. Together, these findings suggested that Homer3 in Purkinje cells might function as a reversible coupler regulated by CaMKII phosphorylation and that the phosphorylation is capable of regulating the postsynaptic molecular architecture in response to synaptic activity.

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High-frequency whisker vibration is encoded by phase-locked responses of neurons in the rat's barrel cortex.

Publication Date: 2008 May 14 PMID: 18480292
Authors: Ewert, T. A. - Vahle-Hinz, C. - Engel, A. K.
Journal: J Neurosci

Rats perform texture discrimination during tactile exploration with their whiskers with high spatial and temporal precision. Although the peripheral mechanoreceptors provide tactile information with exquisite temporal resolution, physiological studies have suggested that this information might be lost at the cortical level. To address this discrepancy, multiunit and single-unit recordings were performed in the barrel cortex of isoflurane-anesthetized rats using continuous sinusoidal vibration of single whiskers at 15-700 Hz. In multiunit recordings, sustained phase-locked responses occurred up to vibration frequencies of 700 Hz, and 1:1 stimulus locking was observed up to 320 Hz. Wide-band responses of multiunits showed frequency encoding between 20 and 320 Hz. The discharge rates were not different for stimuli in the low- and high-frequency ranges, but they were significantly lower for non-phase-locked responses to high-frequency vibration. Response adaptation was present in only 25% of the cases, whereas in the majority of cases, entrainment to the vibratory frequency remained constant or even increased with stimulus duration. Increased entrainment to high-frequency stimulation was accompanied by the emergence of induced activity in the gamma-band range. Analysis of single-unit activity revealed that phase locking to vibratory stimuli was more precise than that observed for the multiunit responses. The results show that whisker vibrations at frequencies above 100 Hz are faithfully encoded by sustained phase-locked responses of cortical neurons under isoflurane anesthesia. It is conceivable that the awake animal makes use of the tactile signals at even much higher frequencies, which can be provided by the peripheral mechanoreceptors during texture discrimination.

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Coactivation of M(1) muscarinic and alpha1 adrenergic receptors stimulates extracellular signal-regulated protein kinase and induces long-term depression at CA3-CA1 synapses in rat hippocampus.

Publication Date: 2008 May 14 PMID: 18480291
Authors: Scheiderer, C. L. - Smith, C. C. - McCutchen, E. - McCoy, P. A. - Thacker, E. E. - Kolasa, K. - Dobrunz, L. E. - McMahon, L. L.
Journal: J Neurosci

Intact cholinergic innervation from the medial septum and noradrenergic innervation from the locus ceruleus are required for hippocampal-dependent learning and memory. However, much remains unclear about the precise roles of acetylcholine (ACh) and norepinephrine (NE) in hippocampal function, particularly in terms of how interactions between these two transmitter systems might play an important role in synaptic plasticity. Previously, we reported that activation of either muscarinic M(1) or adrenergic alpha1 receptors induces activity- and NMDA receptor-dependent long-term depression (LTD) at CA3-CA1 synapses in acute hippocampal slices, referred to as muscarinic LTD (mLTD) and norepinephrine LTD (NE LTD), respectively. In this study, we tested the hypothesis that mLTD and NE LTD are independent forms of LTD, yet require activation of a common Galphaq-coupled signaling pathway for their induction, and investigated the net effect of coactivation of M(1) and alpha1 receptors on the magnitude of LTD induced. We find that neither mLTD nor NE LTD requires phospholipase C activation, but both plasticities are prevented by inhibiting the Src kinase family and extracellular signal-regulated protein kinase (ERK) activation. Interestingly, LTD can be induced when M(1) and alpha1 agonists are coapplied at concentrations too low to induce LTD when applied separately, via a summed increase in ERK activation. Thus, because ACh and NE levels in vivo covary, especially during periods of memory encoding and consolidation, cooperative signaling through M(1) and alpha1 receptors could function to induce long-term changes in synaptic function important for cognition.

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Temporal characteristics of audiovisual information processing.

Publication Date: 2008 May 14 PMID: 18480290
Authors: Alpert, G. F. - Hein, G. - Tsai, N. - Naumer, M. J. - Knight, R. T.
Journal: J Neurosci

In complex natural environments, auditory and visual information often have to be processed simultaneously. Previous functional magnetic resonance imaging (fMRI) studies focused on the spatial localization of brain areas involved in audiovisual (AV) information processing, but the temporal characteristics of AV information flow in these regions remained unclear. In this study, we used fMRI and a novel information-theoretic approach to study the flow of AV sensory information. Subjects passively perceived sounds and images of objects presented either alone or simultaneously. Applying the measure of mutual information, we computed for each voxel the latency in which the blood oxygenation level-dependent signal had the highest information content about the preceding stimulus. The results indicate that, after AV stimulation, the earliest informative activity occurs in right Heschl's gyrus, left primary visual cortex, and the posterior portion of the superior temporal gyrus, which is known as a region involved in object-related AV integration. Informative activity in the anterior portion of superior temporal gyrus, middle temporal gyrus, right occipital cortex, and inferior frontal cortex was found at a later latency. Moreover, AV presentation resulted in shorter latencies in multiple cortical areas compared with isolated auditory or visual presentation. The results provide evidence for bottom-up processing from primary sensory areas into higher association areas during AV integration in humans and suggest that AV presentation shortens processing time in early sensory cortices.

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Reward-dependent modulation of neuronal activity in the primate dorsal raphe nucleus.

Publication Date: 2008 May 14 PMID: 18480289
Authors: Nakamura, K. - Matsumoto, M. - Hikosaka, O.
Journal: J Neurosci

The dopamine system has been thought to play a central role in guiding behavior based on rewards. Recent pharmacological studies suggest that another monoamine neurotransmitter, serotonin, is also involved in reward processing. To elucidate the functional relationship between serotonin neurons and dopamine neurons, we performed single-unit recording in the dorsal raphe nucleus (DRN), a major source of serotonin, and the substantia nigra pars compacta, a major source of dopamine, while monkeys performed saccade tasks in which the position of the target indicated the size of an upcoming reward. After target onset, but before reward delivery, the activity of many DRN neurons was modulated tonically by the expected reward size with either large- or small-reward preference, whereas putative dopamine neurons had phasic responses and only preferred large rewards. After reward delivery, the activity of DRN neurons was modulated tonically by the received reward size with either large- or small-reward preference, whereas the activity of dopamine neurons was not modulated except after the unexpected reversal of the position-reward contingency. Thus, DRN neurons encode the expected and received rewards, whereas dopamine neurons encode the difference between the expected and received rewards. These results suggest that the DRN, probably including serotonin neurons, signals the reward value associated with the current behavior.

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Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present.

Publication Date: 2008 May 14 PMID: 18480288
Authors: Li, J. - Ramenaden, E. R. - Peng, J. - Koito, H. - Volpe, J. J. - Rosenberg, P. A.
Journal: J Neurosci

Reactive microglia and astrocytes are present in lesions of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, it is not clear whether they are actively involved in the pathogenesis of these disorders. Previous studies demonstrated that microglia, but not astrocytes, are required for lipopolysaccharide (LPS)-induced selective killing of developing oligodendrocytes (preOLs) and that the toxicity is mediated by microglia-derived peroxynitrite. Here we report that, when astrocytes are present, the LPS-induced, microglia-dependent toxicity to preOLs is no longer mediated by peroxynitrite but instead by a mechanism dependent on tumor necrosis factor-alpha (TNFalpha) signaling. Blocking peroxynitrite formation with nitric oxide synthase (NOS) inhibitors or a decomposition catalyst did not prevent LPS-induced loss of preOLs in mixed glial cultures. PreOLs were highly vulnerable to peroxynitrite; however, the presence of astrocytes prevented the toxicity. Whereas LPS failed to kill preOLs in cocultures of microglia and preOLs deficient in inducible NOS (iNOS) or gp91(phox), the catalytic subunit of the superoxide-generating NADPH oxidase, LPS caused a similar degree of preOL death in mixed glial cultures of wild-type, iNOS-/-, and gp91(phox-/-) mice. TNFalpha neutralizing antibody inhibited LPS toxicity, and addition of TNFalpha induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNFalpha or its receptors TNFR1/2 completely abolished the deleterious effect of LPS. Our results reveal that TNFalpha signaling, rather than peroxynitrite, is essential in LPS-triggered preOL death in an environment containing all major glial cell types and underscore the importance of intercellular communication in determining the mechanism underlying inflammatory preOL death.

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Human apolipoprotein E redistributes fibrillar amyloid deposition in Tg-SwDI mice.

Publication Date: 2008 May 14 PMID: 18480287
Authors: Xu, F. - Vitek, M. P. - Colton, C. A. - Previti, M. L. - Gharkholonarehe, N. - Davis, J. - Van Nostrand, W. E.
Journal: J Neurosci

Human apolipoprotein (ApoE) genotype influences the development of Alzheimer's disease and cerebral amyloid angiopathy (CAA). Specific mutations within the amyloid-beta protein (Abeta) peptide have been identified that cause familial forms of CAA. However, the effect of APOE genotype on accumulation of CAA mutant Abeta in brain is not well understood. In the present study, we determined how human ApoE3 or ApoE4 influence cerebral Abeta accumulation in transgenic mice (Tg-SwDI) that accumulate human Dutch/Iowa (E22Q/D23N) CAA mutant Abeta in brain, primarily in the form of fibrillar cerebral microvascular amyloid. Using Tg-SwDI mice bred onto a human APOE3/3 or human APOE4/4 background, we found that both human ApoE3 and ApoE4 proteins led to a strong reduction in the amount of cerebral microvascular amyloid with an unexpected concomitant appearance of extensive fibrillar parenchymal plaque amyloid. There was strong colocalization of all ApoE proteins with fibrillar amyloid deposits in the mice. In Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice, there was no change in the levels of total Abeta(40) and Abeta(42) or in the amounts of soluble and insoluble Abeta in brain compared with Tg-SwDI mice on the endogenous mouse APOE background. The shift from primarily cerebral microvascular amyloid to parenchymal plaque amyloid in Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice resulted in a parallel shift in the association of activated microglia. These findings indicate that human ApoE has a strong influence on the spatial development of human Dutch/Iowa CAA mutant amyloid accumulation in mouse brain and that microglial activation is in response to the spatial accumulation of fibrillar amyloid.

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Mechanisms of prolonged presynaptic Ca2+ signaling and glutamate release induced by TRPV1 activation in rat sensory neurons.

Publication Date: 2008 May 14 PMID: 18480286
Authors: Medvedeva, Y. V. - Kim, M. S. - Usachev, Y. M.
Journal: J Neurosci

Transient receptor potential vanilloid receptor 1 (TRPV1)-mediated release of neuroactive peptides and neurotransmitters from the peripheral and central terminals of primary sensory neurons can critically contribute to nociceptive processing at the periphery and in the CNS. However, the mechanisms that link TRPV1 activation with Ca2+ signaling at the release sites and neurosecretion are poorly understood. Here we demonstrate that a brief stimulation of the receptor using either capsaicin or the endogenous TRPV1 agonist N-arachidonoyl-dopamine induces a prolonged elevation of presynaptic [Ca2+](i) and a concomitant enhancement of glutamate release at sensory synapses. Initiation of this response required Ca2+ entry, primarily via TRPV1. The sustained phase of the response was independent of extracellular Ca2+ and was prevented by inhibitors of mitochondrial Ca2+ uptake and release mechanisms. Measurements using a mitochondria-targeted Ca2+ indicator, mtPericam, revealed that TRPV1 activation elicits a long-lasting Ca2+ elevation in presynaptic mitochondria. The concentration of TRPV1 agonist determined the duration of mitochondrial and cytosolic Ca2+ signals in presynaptic boutons and, consequently, the period of enhanced glutamate release and action potential firing by postsynaptic neurons. These data suggest that mitochondria control vanilloid-induced neurotransmission by translating the strength of presynaptic TRPV1 stimulation into duration of the postsynaptic response.

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The basolateral nucleus of the amygdala is necessary to induce the opposing effects of stressful experience on learning in males and females.

Publication Date: 2008 May 14 PMID: 18480285
Authors: Waddell, J. - Bangasser, D. A. - Shors, T. J.
Journal: J Neurosci

The basolateral nucleus of the amygdala (BLA) has been implicated in the modulation of learning after stress. Acute inescapable stress enhances classical eyeblink conditioning in male rats, whereas the same stressor impairs eyeblink conditioning in female rats. The experiments here directly assessed whether inactivation of the BLA during stress exposure would block both the stress-induced facilitation in males and the retardation of eyeblink conditioning in females. To this end, the BLA was temporarily inactivated by infusion of the GABA agonist muscimol before acute stressor exposure. All rats were trained in a different context 24 h later. Males infused with muscimol before the stressful event did not exhibit facilitated eyeblink conditioning, whereas those infused with the vehicle emitted more conditioned responses than unstressed males. Females infused with muscimol before stress did not express a deficit in conditioning, whereas those infused with vehicle and stressed emitted fewer conditioned responses than unstressed vehicle controls. These data demonstrate that neuronal activity within the BLA during stress exposure is necessary to modulate learning 24 h later in a new context. Thus, the BLA is necessary to induce the long-term effect of stressful experience on conditioning regardless of sex and direction of modulation.

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Spoken word memory traces within the human auditory cortex revealed by repetition priming and functional magnetic resonance imaging.

Publication Date: 2008 May 14 PMID: 18480284
Authors: Gagnepain, P. - Chetelat, G. - Landeau, B. - Dayan, J. - Eustache, F. - Lebreton, K.
Journal: J Neurosci

Previous neuroimaging studies in the visual domain have shown that neurons along the perceptual processing pathway retain the physical properties of written words, faces, and objects. The aim of this study was to reveal the existence of similar neuronal properties within the human auditory cortex. Brain activity was measured using functional magnetic resonance imaging during a repetition priming paradigm, with words and pseudowords heard in an acoustically degraded format. Both the amplitude and peak latency of the hemodynamic response (HR) were assessed to determine the nature of the neuronal signature of spoken word priming. A statistically significant stimulus type by repetition interaction was found in various bilateral auditory cortical areas, demonstrating either HR suppression and enhancement for repeated spoken words and pseudowords, respectively, or word-specific repetition suppression without any significant effects for pseudowords. Repetition latency shift only occurred with word-specific repetition suppression in the right middle/posterior superior temporal sulcus. In this region, both repetition suppression and latency shift were related to behavioral priming. Our findings highlight for the first time the existence of long-term spoken word memory traces within the human auditory cortex. The timescale of auditory information integration and the neuronal mechanisms underlying priming both appear to differ according to the level of representations coded by neurons. Repetition may "sharpen" word-nonspecific representations coding short temporal variations, whereas a complex interaction between the activation strength and temporal integration of neuronal activity may occur in neuronal populations coding word-specific representations within longer temporal windows.

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Conditions for propagating synchronous spiking and asynchronous firing rates in a cortical network model.

Publication Date: 2008 May 14 PMID: 18480283
Authors: Kumar, A. - Rotter, S. - Aertsen, A.
Journal: J Neurosci

Isolated feedforward networks (FFNs) of spiking neurons have been studied extensively for their ability to propagate transient synchrony and asynchronous firing rates, in the presence of activity independent synaptic background noise (Diesmann et al., 1999; van Rossum et al., 2002). In a biologically realistic scenario, however, the FFN should be embedded in a recurrent network, such that the activity in the FFN and the network activity may dynamically interact. Previously, transient synchrony propagating in an FFN was found to destabilize the dynamics of the embedding network (Mehring et al., 2003). Here, we show that by modeling synapses as conductance transients, rather than current sources, it is possible to embed and propagate transient synchrony in the FFN, without destabilizing the background network dynamics. However, the network activity has a strong impact on the type of activity that can be propagated in the embedded FFN. Global synchrony and high firing rates in the embedding network prohibit the propagation of both, synchronous and asynchronous spiking activity. In contrast, asynchronous low-rate network states support the propagation of both, synchronous spiking and asynchronous, but only low firing rates. In either case, spiking activity tends to synchronize as it propagates, challenging the feasibility to transmit information in asynchronous firing rates. Finally, asynchronous network activity allows to embed more than one FFN, with the amount of cross talk depending on the degree of overlap in the FFNs. This opens the possibility of computational mechanisms using transient synchrony among the activities in multiple FFNs.

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Attention to odor modulates thalamocortical connectivity in the human brain.

Publication Date: 2008 May 14 PMID: 18480282
Authors: Plailly, J. - Howard, J. D. - Gitelman, D. R. - Gottfried, J. A.
Journal: J Neurosci

It is widely assumed that the thalamus is functionally irrelevant for the sense of smell. Although animal studies suggest that the mediodorsal (MD) thalamus links primary olfactory (piriform) cortex to olfactory neocortical projection sites in orbitofrontal cortex (OFC), this transthalamic route is regarded to be inconsequential, particularly compared with a direct monosynaptic pathway linking piriform cortex and OFC. In this study, we combined functional magnetic resonance imaging with novel effective connectivity techniques to measure attention-dependent network coherence within direct (nonthalamic) and indirect (transthalamic) olfactory pathways. Human subjects were presented with (or without) an odor and with (or without) a tone, while selectively attending to either modality. Attention to odor significantly modulated neural coupling within the indirect pathway, strengthening MD thalamus-OFC connectivity. Critically, these effects were modality specific (odor > tone attention), directionally sensitive (forward > backward connections), and selective to route (indirect > direct pathway). Our findings support the idea that the human transthalamic pathway is an active modulatory target of olfactory attention. The results imply that olfaction, like all other sensory modalities, requires a thalamic relay, if only to consciously analyze a smell.

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Cytoskeletal requirements in axonal transport of slow component-b.

Publication Date: 2008 May 14 PMID: 18480281
Authors: Roy, S. - Winton, M. J. - Black, M. M. - Trojanowski, J. Q. - Lee, V. M.
Journal: J Neurosci

Slow component-b (SCb) translocates approximately 200 diverse proteins from the cell body to the axon and axon tip at average rates of approximately 2-8 mm/d. Several studies suggest that SCb proteins are cotransported as one or more macromolecular complexes, but the basis for this cotransport is unknown. The identification of actin and myosin in SCb led to the proposal that actin filaments function as a scaffold for the binding of other SCb proteins and that transport of these complexes is powered by myosin: the "microfilament-complex" model. Later, several SCb proteins were also found to bind F-actin, supporting the idea, but despite this, the model has never been directly tested. Here, we test this model by disrupting the cytoskeleton in a live-cell model system wherein we directly visualize transport of SCb cargoes. We focused on three SCb proteins that we previously showed were cotransported in our system: alpha-synuclein, synapsin-I, and glyceraldehyde-3-phosphate dehydrogenase. Disruption of actin filaments with latrunculin had no effect on the velocity or frequency of transport of these three proteins. Furthermore, cotransport of these three SCb proteins continued in actin-depleted axons. We conclude that actin filaments do not function as a scaffold to organize and transport these and possibly other SCb proteins. In contrast, depletion of microtubules led to a dramatic inhibition of vectorial transport of SCb cargoes. These findings do not support the microfilament-complex model, but instead indicate that the transport of protein complexes in SCb is powered by microtubule motors.

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Latent stem and progenitor cells in the hippocampus are activated by neural excitation.

Publication Date: 2008 May 14 PMID: 18480280
Authors: Walker, T. L. - White, A. - Black, D. M. - Wallace, R. H. - Sah, P. - Bartlett, P. F.
Journal: J Neurosci

The regulated production of neurons in the hippocampus throughout life underpins important brain functions such as learning and memory. Surprisingly, however, studies have so far failed to identify a resident hippocampal stem cell capable of providing the renewable source of these neurons. Here, we report that depolarizing levels of KCl produce a threefold increase in the number of neurospheres generated from the adult mouse hippocampus. Most interestingly, however, depolarizing levels of KCl led to the emergence of a small subpopulation of precursors (approximately eight per hippocampus) with the capacity to generate very large neurospheres (> 250 microm in diameter). Many of these contained cells that displayed the cardinal properties of stem cells: multipotentiality and self-renewal. In contrast, the same conditions led to the opposite effect in the other main neurogenic region of the brain, the subventricular zone, in which neurosphere numbers decreased by approximately 40% in response to depolarizing levels of KCl. Most importantly, we also show that the latent hippocampal progenitor population can be activated in vivo in response to prolonged neural activity found in status epilepticus. This work provides the first direct evidence of a latent precursor and stem cell population in the adult hippocampus, which is able to be activated by neural activity. Because the latent population is also demonstrated to reside in the aged animal, defining the precise mechanisms that underlie its activation may provide a means to combat the cognitive deficits associated with a decline in neurogenesis.

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Foxg1 is required for development of the vertebrate olfactory system.

Publication Date: 2008 May 14 PMID: 18480279
Authors: Duggan, C. D. - Demaria, S. - Baudhuin, A. - Stafford, D. - Ngai, J.
Journal: J Neurosci

Illuminating the molecular identity and regulation of early progenitor cells in the olfactory sensory epithelium represents an important challenge in the field of neural development. We show in both mouse and zebrafish that the winged helix transcription factor Foxg1 is expressed in an early progenitor population of the olfactory placode. In the mouse, Foxg1 is first expressed throughout the olfactory placode but later becomes restricted to the ventrolateral olfactory epithelium. The essential role of Foxg1 in olfactory development is demonstrated by the strikingly severe phenotype of Foxg1 knock-out mice: older embryos have no recognizable olfactory structures, including epithelium, bulb, or vomeronasal organs. Initially, a small number of olfactory progenitors are specified but show defects in both proliferation and differentiation. Similarly, antisense RNA knockdown of Foxg1 expression in the zebrafish shows a reduction in the number of neurons and mitotic cells in olfactory rosettes, mirroring the phenotype seen in the mouse Foxg1 null mutant. Using mosaic analysis in the zebrafish, we show that Foxg1 is required cell-autonomously for the production of mature olfactory receptor neurons. Therefore, we identified an evolutionarily conserved requirement for Foxg1 in the development of the vertebrate olfactory system.

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Neural ensemble decoding reveals a correlate of viewer- to object-centered spatial transformation in monkey parietal cortex.

Publication Date: 2008 May 14 PMID: 18480278
Authors: Crowe, D. A. - Averbeck, B. B. - Chafee, M. V.
Journal: J Neurosci

The parietal cortex contains representations of space in multiple coordinate systems including retina-, head-, body-, and world-based systems. Previously, we found that when monkeys are required to perform spatial computations on objects, many neurons in parietal area 7a represent position in an object-centered coordinate system as well. Because visual information enters the brain in a retina-centered reference frame, generation of an object-centered reference requires the brain to perform computation on the visual input. We provide evidence that area 7a contains a correlate of that computation. Specifically, area 7a contains neurons that code information in retina- and object-centered coordinate systems. The information in retina-centered coordinates emerges first, followed by the information in object-centered coordinates. We found that the strength and accuracy of these representations is correlated across trials. Finally, we found that retina-centered information could be used to predict subsequent object-centered signals, but not vice versa. These results are consistent with the hypothesis that either area 7a, or an area that precedes area 7a in the visual processing hierarchy, is performing the retina- to object-centered transformation.

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Gap junction-mediated astrocytic networks in the mouse barrel cortex.

Publication Date: 2008 May 14 PMID: 18480277
Authors: Houades, V. - Koulakoff, A. - Ezan, P. - Seif, I. - Giaume, C.
Journal: J Neurosci

The barrel field of the somatosensory cortex constitutes a well documented example of anatomofunctional compartmentalization and activity-dependent interaction between neurons and astrocytes. In astrocytes, intercellular communication through gap junction channels composed by connexin 43 and 30 underlies a network organization. Immunohistochemical and electrophysiological experiments were undertaken to determine the coupling properties of astrocyte networks in layer IV of the developing barrel cortex. The expression of both connexins was found to be enriched within barrels compared with septa and other cortical layers. Combination of dye-coupling experiments performed with biocytin and immunostaining with specific cell markers demonstrated that astrocytic networks do not involve neurons, oligodendrocytes or NG2 cells. The shape of dye coupling was oval in the barrel cortex whereas it was circular in layer IV outside the barrel field. Two-dimensional analysis of these coupling areas indicated that gap junctional communication was restricted from a barrel to its neighbor. Such enrichment of connexin expression and transversal restriction were not observed in a transgenic mouse lacking the barrel organization, whereas they were both observed in a double-transgenic mouse with restored barrels. Direct observation of sulforhodamine B spread indicated that astrocytes located between two barrels were either weakly or not coupled, whereas coupling within a barrel was oriented toward its center. These observations indicated a preferential orientation of coupling inside the barrels resulting from subpopulations of astrocytes with different coupling properties that contribute to shaping astrocytic networks. Such properties confine intercellular communication in astrocytes within a defined barrel as previously reported for excitatory neuronal circuits.

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Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination.

Publication Date: 2008 May 14 PMID: 18480276
Authors: Binder, M. D. - Cate, H. S. - Prieto, A. L. - Kemper, D. - Butzkueven, H. - Gresle, M. M. - Cipriani, T. - Jokubaitis, V. G. - Carmeliet, P. - Kilpatrick, T. J.
Journal: J Neurosci

The TAM family of receptor protein tyrosine kinases comprises three known members, namely Tyro3, Axl, and Mer. These receptors are widely expressed in the nervous system, including by oligodendrocytes, the cell type responsible for myelinating the CNS. We examined the potential role of the TAM family and of their principle cognate ligand, Gas6 (growth arrest gene 6), in modulating the phenotype of the cuprizone model of demyelination. We found that the expression profiles of Axl, Mer, and Gas6 mRNA were increased in the corpus callosum in a temporal profile correlating with the increased migration and proliferation of microglia/macrophages in this model. In contrast, expression of Tyro3 decreased, correlating with the loss of oligodendrocytes. Gas6 both promoted in vitro survival of oligodendrocytes (39.3 +/- 3.1 vs 11.8 +/- 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor alpha mRNA expression was reduced approximately 48%). In Gas6-/- mice subjected to cuprizone-challenge, demyelination was greater than in control mice, within the rostral region of the corpus callosum, as assessed by luxol fast blue staining (myelination reduced by 36%) and by ultrastructural analysis. An increased loss of Gst-pi (glutathione S-transferase-pi)-positive oligodendrocytes was also identified throughout the corpus callosum of Gas6-/- mice. Microglial marker expression (ionized calcium-binding adapter molecule 1) was increased in Gas6-/- mice but was restricted to the rostral corpus callosum. Therefore, TAM receptor activation and regulation can independently influence both oligodendrocyte survival and the microglial response after CNS damage.

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Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord.

Publication Date: 2008 May 14 PMID: 18480275
Authors: Kawasaki, Y. - Zhang, L. - Cheng, J. K. - Ji, R. R.
Journal: J Neurosci

Central sensitization, increased sensitivity in spinal cord dorsal horn neurons after injuries, plays an essential role in the induction and maintenance of chronic pain. However, synaptic mechanisms underlying central sensitization are incompletely known. Growing evidence suggests that proinflammatory cytokines (PICs), such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha), are induced in the spinal cord under various injury conditions and contribute to pain hypersensitivity. Using patch-clamp recordings in lamina II neurons of isolated spinal cord slices, we compared the effects of IL-1beta, IL-6, and TNFalpha on excitatory and inhibitory synaptic transmission. Whereas TNFalpha enhanced the frequency of spontaneous EPSCs (sEPSCs), IL-6 reduced the frequency of spontaneous IPSCs (sIPSCs). Notably, IL-1beta both enhanced the frequency and amplitude of sEPSCs and reduced the frequency and amplitude of sIPSCs. Consistently, TNFalpha and IL-1beta enhanced AMPA- or NMDA-induced currents, and IL-1beta and IL-6 suppressed GABA- and glycine-induced currents. Furthermore, all the PICs increased cAMP response element-binding protein (CREB) phosphorylation in superficial dorsal horn neurons and produced heat hyperalgesia after spinal injection. Surprisingly, soluble IL-6 receptor (sIL-6R) produced initial decrease of sEPSCs, followed by increase of sEPSCs and CREB phosphorylation. Spinal injection of sIL-6R also induced heat hyperalgesia that was potentiated by coadministration with IL-6. Together, our data have demonstrated that PICs induce central sensitization and hyperalgesia via distinct and overlapping synaptic mechanisms in superficial dorsal horn neurons either by increasing excitatory synaptic transmission or by decreasing inhibitory synaptic transmission. PICs may further induce long-term synaptic plasticity through CREB-mediated gene transcription. Blockade of PIC signaling could be an effective way to suppress central sensitization and alleviate chronic pain.

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Circuit and plasticity defects in the developing somatosensory cortex of FMR1 knock-out mice.

Publication Date: 2008 May 14 PMID: 18480274
Authors: Bureau, I. - Shepherd, G. M. - Svoboda, K.
Journal: J Neurosci

Silencing of the Fmr1 gene causes fragile X syndrome. Although defects in synaptic plasticity in the cerebral cortex have been linked to cognitive impairments in Fmr1 knock-out (ko) mice, the specific cortical circuits affected in the syndrome are unknown. Here, we investigated the development of excitatory projections in the barrel cortex of Fmr1 ko mice. In 2-week-old Fmr1 ko mice, a major ascending projection connecting layer 4 (L4) to L3 (L4-->L3), was defective in multiple and independent ways: its strength was reduced, caused by a lower connection probability; the axonal arbors of L4 cells were spatially diffuse in L2/3; the L4-->L3 projection did not show experience-dependent plasticity. By 3 weeks, the strength of the L4-->L3 projection was similar to that of wild type. Our data indicate that Fmr1 shapes sensory cortical circuits during a developmental critical period.

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Vibrissal responses of thalamic cells that project to the septal columns of the barrel cortex and to the second somatosensory area.

Publication Date: 2008 May 14 PMID: 18480273
Authors: Bokor, H. - Acsady, L. - Deschenes, M.
Journal: J Neurosci

The rodent somatosensory cortex contains barrel-related and septa-related circuits representing two separate streams of vibrissa information processing that differ in their response patterns and anatomical connections. Whereas barrel-related circuits process lemniscal inputs that transit through the thalamic barreloids, septa-related circuits process paralemniscal inputs and inputs that are relayed through the ventral lateral part of the ventral posterior medial nucleus (VPMvl). Septa-projecting thalamic afferents also target the secondary somatosensory cortical area. Although a number of studies have examined response properties in the lemniscal pathway, and demonstrated that barreloids receive feedback from specific sets of corticothalamic and reticular thalamic neurons, such information is currently lacking for the VPMvl. In the present study, we show that in sharp contrast to the relay cells of the barreloids VPMvl neurons exhibit large multiwhisker receptive fields that are independent of input from the principal trigeminal nucleus. Results also suggest that the topography of receptive fields and response properties in VPMvl rely on converging input from neurons of the interpolaris trigeminal nucleus. Tracer injection and single-cell labeling further reveal that the VPMvl receives input from specific populations of reticular thalamic and corticothalamic neurons. Together, these results confirm the status of the VPMvl as a thalamic relay of an independent parallel pathway of vibrissa information processing. They further indicate that a sensory pathway does not merely consist on a three-neuron chain that links the vibrissae to the cerebral cortex, but that it also involves specific sets of topographically related corticothalamic and reticular thalamic projections.

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A specific role for Ca2+-dependent adenylyl cyclases in recovery from adaptive presynaptic silencing.

Publication Date: 2008 May 14 PMID: 18480272
Authors: Moulder, K. L. - Jiang, X. - Chang, C. - Taylor, A. A. - Benz, A. M. - Conti, A. C. - Muglia, L. J. - Mennerick, S.
Journal: J Neurosci

Glutamate generates fast postsynaptic depolarization throughout the CNS. The positive-feedback nature of glutamate signaling likely necessitates flexible adaptive mechanisms that help prevent runaway excitation. We have previously explored presynaptic adaptive silencing, a form of synaptic plasticity produced by ongoing neuronal activity and by strong depolarization. Unsilencing mechanisms that maintain active synapses and restore normal function after adaptation are also important, but mechanisms underlying such presynaptic reactivation remain unexplored. Here we investigate the involvement of the cAMP pathway in the basal balance between silenced and active synapses, as well as the recovery of baseline function after depolarization-induced presynaptic silencing. Activation of the cAMP pathway activates synapses that are silent at rest, and pharmacological inhibition of cAMP signaling silences basally active synapses. Adenylyl cyclase (AC) 1 and AC8, the major Ca2+-sensitive AC isoforms, are not crucial for the baseline balance between silent and active synapses. In cells from mice doubly deficient in AC1 and AC8, the baseline percentage of active synapses was only modestly reduced compared with wild-type synapses, and forskolin unsilencing was similar in the two genotypes. Nevertheless, after strong presynaptic silencing, recovery of normal function was strongly inhibited in AC1/AC8-deficient synapses. The entire recovery phenotype of the double null was reproduced in AC8-deficient but not AC1-deficient cells. We conclude that, under normal conditions, redundant cyclase activity maintains the balance between presynaptically silent and active synapses, but AC8 plays a particularly important role in rapidly resetting the balance of active to silent synapses after adaptation to strong activity.

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Site-specific blockade of RAGE-Vd prevents amyloid-beta oligomer neurotoxicity.

Publication Date: 2008 May 14 PMID: 18480271
Authors: Sturchler, E. - Galichet, A. - Weibel, M. - Leclerc, E. - Heizmann, C. W.
Journal: J Neurosci

In the genesis of Alzheimer's disease (AD), converging lines of evidence suggest that amyloid-beta peptide (Abeta) triggers a pathogenic cascade leading to neuronal loss. It was long assumed that Abeta had to be assembled into extracellular amyloid fibrils or aggregates to exert its cytotoxic effects. Over the past decade, characterization of soluble oligomeric Abeta species in the brains of AD patients and in transgenic models has raised the possibility that different conformations of Abeta may contribute to AD pathology via different mechanisms. The receptor for advanced glycation end products (RAGE), a member of the Ig superfamily, is a cellular binding site for Abeta. Here, we investigate the role of RAGE in apoptosis induced by distinct well characterized Abeta conformations: Abeta oligomers (AbetaOs), Abeta fibrils (AbetaFs), and Abeta aggregates (AbetaAs). In our in vitro system, treatment with polyclonal anti-RAGE antibodies significantly improves SHSY-5Y cell and neuronal survival exposed to either AbetaOs or AbetaAs but does not affect AbetaF toxicity. Interestingly, using site-specific antibodies, we demonstrate that targeting of the V(d) domain of RAGE attenuates AbetaO-induced toxicity in both SHSY-5Y cells and rat cortical neurons, whereas inhibition of AbetaA-induced apoptosis requires the neutralization of the C(1d) domain of the receptor. Thus, our data indicate that distinct regions of RAGE are involved in Abeta-induced cellular and neuronal toxicity with respect to the Abeta aggregation state, and they suggest the blockage of particular sites of the receptor as a potential therapeutic strategy to attenuate neuronal death.

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Visual Motion Area MT+/V5 Responds to Auditory Motion in Human Sight-Recovery Subjects.

Publication Date: 2008 May 14 PMID: 18480270
Authors: Saenz, M. - Lewis, L. B. - Huth, A. G. - Fine, I. - Koch, C.
Journal: J Neurosci

Using functional magnetic resonance imaging, we found that cortical visual motion area MT+/V5 responded to auditory motion in two rare subjects who had been blind since early childhood and whose vision was partially recovered in adulthood. Visually normal control subjects did not show similar auditory responses. These auditory responses in MT+ were specific to motion compared with other complex auditory stimuli including frequency sweeps and speech. Thus, MT+ developed motion-specific responses to nonvisual input, suggesting that cross-modal plasticity can be influenced by the normal functional specialization of a cortical region. Regarding sight recovery after early blindness, our results further demonstrate that cross-modal responses coexist with regained visual responses within the visual cortex.

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BDNF signaling during olfactory bulb neurogenesis.

Publication Date: 2008 May 14 PMID: 18480269
Authors: Yuan, T. F.
Journal: J Neurosci

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Rat orbitofrontal cortex separately encodes response and outcome information during performance of goal-directed behavior.

Publication Date: 2008 May 7 PMID: 18463266
Authors: Furuyashiki, T. - Holland, P. C. - Gallagher, M.
Journal: J Neurosci

Orbitofrontal cortex (OFC) neurons encode rewards and the cues that predict them, providing a neural substrate for outcome expectancy, an important component of goal-directed behavior in animals and humans. Here, we recorded and analyzed single units from rat lateral OFC during performance of a task in which the encoding of an expected rewarding outcome could be isolated from the response made in obtaining it. We found concurrent encoding of the expected outcome and the behavioral response in mostly separate populations of OFC units, in each phase of task performance: odor sampling, behavioral response, and waiting during the delay before reward delivery. Population analyses showed that outcome encoding broadly spanned across each behavioral phase, whereas response-selective firings were time-locked to the behavioral events, especially the completion of the behavioral response. A significant subset of outcome-selective units maintained selective firings from either odor sampling or response initiation until reward delivery. In contrast, response-selective units typically showed transient activation time locked to the behavioral events and were less likely to maintain selective firings across behavioral phases than outcome-selective units. These data demonstrate a broader role of OFC information processing in goal-directed behavior, beyond its widely recognized role in outcome expectancy.

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Spatial summation can explain the attentional modulation of neuronal responses to multiple stimuli in area V4.

Publication Date: 2008 May 7 PMID: 18463265
Authors: Ghose, G. M. - Maunsell, J. H.
Journal: J Neurosci

Although many studies have shown that the activity of individual neurons in a variety of visual areas is modulated by attention, a fundamental question remains unresolved: can attention alter the visual representations of individual neurons? One set of studies, primarily relying on the attentional modulations observed when a single stimulus is presented within the receptive field of a neuron, suggests that neuronal selectivities, such as orientation or direction tuning, are not fundamentally altered by attention (Salinas and Abbott, 1997; McAdams and Maunsell, 1999; Treue and Martinez Trujillo, 1999). Another set of studies, relying on modulations observed when multiple stimuli are presented within a receptive field, suggests that attention can alter the weighting of sensory inputs (Moran and Desimone, 1985; Luck et al., 1997; Reynolds et al., 1999; Chelazzi et al., 2001). In these studies, when preferred and nonpreferred stimuli are simultaneously presented, responses are much stronger when attention is directed to the preferred stimulus than when it is directed to the nonpreferred stimulus. In this study, we recorded neuronal responses from individual neurons in visual cortical area V4 to both single and paired stimuli with a variety of attentional allocations and stimulus combinations. For each neuron studied, we constructed a quantitative model of input summation and then tested various models of attention. In many neurons, we are able to explain neuronal responses across the entire range of stimuli and attentional allocations tested. Specifically, we are able to reconcile seemingly inconsistent observations of single and paired stimuli attentional modulation with a new model in which attention can facilitate or suppress specific inputs to a neuron but does not fundamentally alter the integration of these inputs.

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The dystrophin Dp186 isoform regulates neurotransmitter release at a central synapse in Drosophila.

Publication Date: 2008 May 7 PMID: 18463264
Authors: Fradkin, L. G. - Baines, R. A. - van der Plas, M. C. - Noordermeer, J. N.
Journal: J Neurosci

The Dystrophin protein is encoded by a gene that, when mutated in humans, can cause Duchenne muscular dystrophy, a disease characterized by progressive muscle wasting. A number of Duchenne patients also exhibit poorly understood mental retardation, likely associated with loss of a brain-specific isoform. Furthermore, although Dystrophin isoforms and the related Utrophin protein have long been known to localize at synapses, their functions remain essentially unknown. In Drosophila, we find that the CNS-specific Dp186 isoform localizes to the embryonic and larval neuropiles, regions rich in synaptic contacts. In the absence of Dp186, evoked but not spontaneous presynaptic release is significantly enhanced. Increased presynaptic release can be fully rescued to wild-type levels by expression of a Dp186 transgene in the postsynaptic motoneuron, indicating that Dp186 likely regulates a retrograde signaling pathway. Potentiation of synaptic currents in the mutant also occurs when cholinergic transmission is inhibited or in the absence of Glass Bottom Boat (Gbb) or Wishful Thinking (Wit), a TGF-beta ligand and receptor, respectively, both previously implicated in synaptic retrograde signaling. These results are consistent with the possibility that Dp186 modulates other non-Gbb/Wit-dependent retrograde signaling pathways required to maintain normal synaptic physiology.

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Brain monoamine oxidase A activity predicts trait aggression.

Publication Date: 2008 May 7 PMID: 18463263
Authors: Alia-Klein, N. - Goldstein, R. Z. - Kriplani, A. - Logan, J. - Tomasi, D. - Williams, B. - Telang, F. - Shumay, E. - Biegon, A. - Craig, I. W. - Henn, F. - Wang, G. J. - Volkow, N. D. - Fowler, J. S.
Journal: J Neurosci

The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression.

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Dorsomedial prefrontal cortex contribution to behavioral and nucleus accumbens neuronal responses to incentive cues.

Publication Date: 2008 May 7 PMID: 18463262
Authors: Ishikawa, A. - Ambroggi, F. - Nicola, S. M. - Fields, H. L.
Journal: J Neurosci

Cue-elicited phasic changes in firing of nucleus accumbens (NAc) neurons can facilitate reward-seeking behavior. Here, we test the hypothesis that the medial prefrontal cortex (mPFC), which sends a dense glutamatergic projection to the NAc core, contributes to NAc neuronal firing responses to reward-predictive cues. Rats trained to perform an operant response to a cue for sucrose were implanted with recording electrodes in the core of the NAc and microinjection cannulas in the dorsal mPFC (dmPFC). The cue-evoked firing of NAc neurons was reduced by bilateral injection of GABA(A) and GABA(B) agonists into the dmPFC concomitant with loss of behavioral responding to the cue. In addition, unilateral dmPFC inactivation reduced ipsilateral cue excitations and contralateral cue inhibitions. These findings indicate that cue-evoked excitations and inhibitions of NAc core neurons depend on dmPFC projections to the NAc and that these phasic changes contribute to the behavioral response to reward-predictive cues.

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Neural correlates of forward and inverse models for eye movements: evidence from three-dimensional kinematics.

Publication Date: 2008 May 7 PMID: 18463261
Authors: Ghasia, F. F. - Meng, H. - Angelaki, D. E.
Journal: J Neurosci

Inverse and forward dynamic models have been conceptually important in computational motor control. In particular, inverse models are thought to convert desired action into appropriate motor commands. In parallel, forward models predict the consequences of the motor command on behavior by constructing an efference copy of the actual movement. Despite theoretical appeal, their neural representation has remained elusive. Here, we provide evidence supporting the notion that a group of premotor neurons called burst-tonic (BT) cells represent the output of the inverse model for eye movements. We show that BT neurons, like extraocular motoneurons but different from the evoked eye movement, do not carry signals appropriate for the half-angle rule of ocular kinematics during smooth-pursuit eye movements from eccentric positions. Along with findings of identical response dynamics as motoneurons, these results strongly suggest that BT cells carry a replica of the motor command. In contrast, eye-head (EH) neurons, a premotor cell type that is the target of Purkinje cell inhibition from the cerebellar flocculus/ventral paraflocculus, exhibit properties that could be consistent with the half-angle rule. Therefore, EH cells may be functionally related to the output of a forward internal model thought to construct an efference copy of the actual eye movement.

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Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model.

Publication Date: 2008 May 7 PMID: 18463260
Authors: Constantin, C. E. - Mair, N. - Sailer, C. A. - Andratsch, M. - Xu, Z. Z. - Blumer, M. J. - Scherbakov, N. - Davis, J. B. - Bluethmann, H. - Ji, R. R. - Kress, M.
Journal: J Neurosci

To provide a tool to investigate the mechanisms inducing and maintaining cancer-related pain and hyperalgesia, a soft tissue tumor/metastasis model was developed that is applicable in C57BL/6J wild-type and transgenic mice. We show that the experimental tumor-induced heat hyperalgesia and nociceptor sensitization were prevented by systemic treatment with the tumor necrosis factor alpha (TNFalpha) antagonist etanercept. In naive mice, exogenous TNFalpha evoked heat hyperalgesia in vivo and sensitized nociceptive nerve fibers to heat in vitro. TNFalpha enhanced the expression of the nociceptor-specific heat transducer ion channel transient receptor potential vanilloid 1 (TRPV1) and increased the amplitudes of capsaicin and heat-activated ionic currents via p38/MAP (mitogen-activated protein) kinase and PKC (protein kinase C). Deletion of the tumor necrosis factor receptor type 2 (TNFR2) gene attenuated heat hyperalgesia and prevented TRPV1 upregulation in tumor-bearing mice, whereas TNFR1 gene deletion played a minor role. We propose endogenous TNFalpha as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2.

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Molecular determinants of species-specific activation or blockade of TRPA1 channels.

Publication Date: 2008 May 7 PMID: 18463259
Authors: Chen, J. - Zhang, X. F. - Kort, M. E. - Huth, J. R. - Sun, C. - Miesbauer, L. J. - Cassar, S. C. - Neelands, T. - Scott, V. E. - Moreland, R. B. - Reilly, R. M. - Hajduk, P. J. - Kym, P. R. - Hutchins, C. W. - Faltynek, C. R.
Journal: J Neurosci

TRPA1 is an excitatory, nonselective cation channel implicated in somatosensory function, pain, and neurogenic inflammation. Through covalent modification of cysteine and lysine residues, TRPA1 can be activated by electrophilic compounds, including active ingredients of pungent natural products (e.g., allyl isothiocyanate), environmental irritants (e.g., acrolein), and endogenous ligands (4-hydroxynonenal). However, how covalent modification leads to channel opening is not understood. Here, we report that electrophilic, thioaminal-containing compounds [e.g., CMP1 (4-methyl-N-[2,2,2-trichloro-1-(4-nitro-phenylsulfanyl)-ethyl]-benzamide)] covalently modify cysteine residues but produce striking species-specific effects [i.e., activation of rat TRPA1 (rTRPA1) and blockade of human TRPA1 (hTRPA1) activation by reactive and nonreactive agonists]. Through characterizing rTRPA1 and hTRPA1 chimeric channels and point mutations, we identified several residues in the upper portion of the S6 transmembrane domains as critical determinants of the opposite channel gating: Ala-946 and Met-949 of rTRPA1 determine channel activation, whereas equivalent residues of hTRPA1 (Ser-943 and Ile-946) determine channel block. Furthermore, side-chain replacements at these critical residues profoundly affect channel function. Therefore, our findings reveal a molecular basis of species-specific channel gating and provide novel insights into how TRPA1 respond to stimuli.

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Altered phase precession and compression of temporal sequences by place cells in epileptic rats.

Publication Date: 2008 May 7 PMID: 18463258
Authors: Lenck-Santini, P. P. - Holmes, G. L.
Journal: J Neurosci

In the hippocampus, pyramidal cells encode information in two major ways: rate coding and temporal coding. Rate coding, in which information is coded through firing frequency, is exemplarily illustrated by place cells, characterized by their location-specific firing. In addition, the precise temporal organization of firing of multiple place cells provides information, in a compressed time window, about the temporal sequence of the locations visited by the animal. This encoding is accomplished through phase precession, a phenomenon whereby unit firing is linked to theta rhythm, one of the major hippocampal EEG oscillations. Although it is likely that this type of processing is critical for normal brain function, its involvement in pathologies associated with cognitive disorders is unknown. In this experiment, we determined whether the temporal organization of place cell firing is affected in an animal model of mesial temporal lobe epilepsy (MTLE), a disease accompanied with cognitive impairment. We investigated hippocampal coding and its relationship to theta rhythm in rats after status epilepticus (SE), a condition that leads to MTLE. We found a great proportion of SE place cells had aberrant phase/precession pattern and temporal organization of firing among pairs of neurons, which constitutes the compression of temporal sequences, was altered in SE rats. The same animals were also markedly impaired in the water maze task, a measure of spatial memory. We propose that the synaptic and cellular alterations observed in MTLE induce aberrant temporal coding in the hippocampus, contributing in turn to cognitive dysfunction.

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Spikes and bursts in two types of thalamic projection neurons differentially shape sleep patterns and auditory responses in a songbird.

Publication Date: 2008 May 7 PMID: 18463257
Authors: Hahnloser, R. H. - Wang, C. Z. - Nager, A. - Naie, K.
Journal: J Neurosci

In mammals, the thalamus plays important roles for cortical processing, such as relay of sensory information and induction of rhythmical firing during sleep. In neurons of the avian cerebrum, in analogy with cortical up and down states, complex patterns of regular-spiking and dense-bursting modes are frequently observed during sleep. However, the roles of thalamic inputs for shaping these firing modes are largely unknown. A suspected key player is the avian thalamic nucleus uvaeformis (Uva). Uva is innervated by polysensory input, receives indirect cerebral feedback via the midbrain, and projects to the cerebrum via two distinct pathways. Using pharmacological manipulation, electrical stimulation, and extracellular recordings of Uva projection neurons, we study the involvement of Uva in zebra finches for the generation of spontaneous activity and auditory responses in premotor area HVC (used as a proper name) and the downstream robust nucleus of the arcopallium (RA). In awake and sleeping birds, we find that single Uva spikes suppress and spike bursts enhance spontaneous and auditory-evoked bursts in HVC and RA neurons. Strong burst suppression is mediated mainly via tonically firing HVC-projecting Uva neurons, whereas a fast burst drive is mediated indirectly via Uva neurons projecting to the nucleus interface of the nidopallium. Our results reveal that cerebral sleep-burst epochs and arousal-related burst suppression are both shaped by sophisticated polysynaptic thalamic mechanisms.

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Localized loss of Ca2+ homeostasis in neuronal dendrites is a downstream consequence of metabolic compromise during extended NMDA exposures.

Publication Date: 2008 May 7 PMID: 18463256
Authors: Vander Jagt, T. A. - Connor, J. A. - Shuttleworth, C. W.
Journal: J Neurosci

Excessive Ca(2+) loading is central to most hypotheses of excitotoxic neuronal damage. We examined dendritic Ca(2+) signals in single CA1 neurons, injected with fluorescent indicators, after extended exposures to a low concentration of NMDA (5 microM). As shown previously, NMDA produces an initial transient Ca(2+) elevation of several micromolar, followed by recovery to submicromolar levels. Then after a delay of approximately 20-40 min, a large Ca(2+) elevation appears in apical dendrites and propagates to the soma. We show here that this large delayed Ca(2+) increase is required for ultimate loss of membrane integrity. However, transient removal of extracellular Ca(2+) for varying epochs before and after NMDA exposure does not delay the propagation of these events. In contrast to compound Ca(2+) elevations, intracellular Na(+) elevations are monophasic and were promptly reversed by the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]. MK-801 applied after the transient Ca(2+) elevations blocked the delayed propagating Ca(2+) increase. Even if applied after the propagating response was visualized, MK-801 restored resting Ca(2+) levels. Propagating Ca(2+) increases in dendrites were delayed or prevented by (1) reducing extracellular Na(+), (2) injecting ATP together with the Ca(2+) indicator, or (3) provision of exogenous pyruvate. These results show that extended NMDA exposure initiates degenerative signaling generally in apical dendrites. Although very high Ca(2+) levels can report the progression of these responses, Ca(2+) itself may not be required for the propagation of degenerative signaling along dendrites. In contrast, metabolic consequences of sustained Na(+) elevations may lead to failure of ionic homeostasis in dendrites and precede Ca(2+)-dependent cellular compromise.

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The impact of an LGNd impulse on the awake visual cortex: synaptic dynamics and the sustained/transient distinction.

Publication Date: 2008 May 7 PMID: 18463255
Authors: Stoelzel, C. R. - Bereshpolova, Y. - Gusev, A. G. - Swadlow, H. A.
Journal: J Neurosci

We used spike-triggered current source-density analysis to examine axonal and postsynaptic currents generated in the visual cortex of awake rabbits by spontaneous spikes of individual sustained and transient dorsal lateral geniculate nucleus (LGNd) neurons. Using these data, we asked whether sustained/transient sensory responses are related to short-term synaptic dynamics at the thalamocortical synapse. Most sustained (34 of 40) and transient (24 of 25) neurons generated axonal and monosynaptic responses in layer 4 and/or 6 of the aligned cortical domain, with input from transient neurons arriving approximately 0.3 ms earlier and 100-200 microm deeper. Postsynaptic cortical responses generated by both thalamic cell classes were reduced in amplitude after a preceding impulse and slowly recovered over a period of >750 ms. We interpret this to reflect interval-dependent recovery from chronic depression at the thalamocortical synapse, caused by significant spontaneous firing of LGNd cells (approximately 8 Hz). Surprisingly, postsynaptic cortical responses generated by spontaneous spikes of sustained thalamic neurons were more depressed than those of transient neurons. This difference was seen both in layers 4 and 6. The depression saturated rapidly with multiple preceding impulses, and postsynaptic responses generated by sustained neurons during maintained visual stimulation remained sufficiently robust to allow a sustained flow of information to the cortex. Our results indicate a relationship between the sensory response properties of thalamic neurons and the short-term dynamics of their synapses, and suggest that cortical recipients of sustained and transient thalamic inputs will differ considerably in their response modulation by prior impulse activity.

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Enkephalin elevations contribute to neuronal and behavioral impairments in a transgenic mouse model of Alzheimer's disease.

Publication Date: 2008 May 7 PMID: 18463254
Authors: Meilandt, W. J. - Yu, G. Q. - Chin, J. - Roberson, E. D. - Palop, J. J. - Wu, T. - Scearce-Levie, K. - Mucke, L.
Journal: J Neurosci

The enkephalin signaling pathway regulates various neural functions and can be altered by neurodegenerative disorders. In Alzheimer's disease (AD), elevated enkephalin levels may reflect compensatory processes or contribute to cognitive impairments. To differentiate between these possibilities, we studied transgenic mice that express human amyloid precursor protein (hAPP) and amyloid-beta (Abeta) peptides in neurons and exhibit key aspects of AD. Met-enkephalin levels in neuronal projections from the entorhinal cortex and dentate gyrus (brain regions important for memory that are affected in early stages of AD) were increased in hAPP mice, as were preproenkephalin mRNA levels. Genetic manipulations that exacerbate or prevent excitotoxicity also exacerbated or prevented the enkephalin alterations. In human AD brains, enkephalin levels in the dentate gyrus were also increased. In hAPP mice, enkephalin elevations correlated with the extent of Abeta-dependent neuronal and behavioral alterations, and memory deficits were reduced by irreversible blockade of mu-opioid receptors with the antagonist beta-funaltrexamine. We conclude that enkephalin elevations may contribute to cognitive impairments in hAPP mice and possibly in humans with AD. The therapeutic potential of reducing enkephalin production or signaling merits further exploration.

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Glutamate transporters regulate lesion-induced plasticity in the developing somatosensory cortex.

Publication Date: 2008 May 7 PMID: 18463253
Authors: Takasaki, C. - Okada, R. - Mitani, A. - Fukaya, M. - Yamasaki, M. - Fujihara, Y. - Shirakawa, T. - Tanaka, K. - Watanabe, M.
Journal: J Neurosci

Glutamate transporters are involved in neural differentiation, neuronal survival, and synaptic transmission. In the present study, we examined glutamate transporter 1 (GLT1) expression in the neonatal somatosensory cortex of C57BL/6 mice, and pursued its role in somatosensory development by comparing barrel development between GLT1 knock-out and control mice. During the first few neonatal days, a critical period for barrels, GLT1 expression is strikingly upregulated in cortical astrocytes, whereas it was downregulated in neuronal elements to below the detection threshold. GLT1 knock-out neonates developed normally in terms of body growth, cortical histoarchitecture, barrel formation, and critical period termination. However, when row C whiskers were lesioned during the critical period, reduction of lesioned row C barrels and reciprocal expansion of intact row B/D barrels were both milder in GLT1 knock-out mice than in control littermates. Accordingly, the map plasticity index, calculated as (B + D)/2C, was significantly lowered in GLT1 knock-out mice. We also found that extracellular glutamate levels in the neonatal somatosensory cortex were significantly elevated in GLT1 knock-out mice. Diminished lesion-induced plasticity was further found in mutant mice lacking glutamate-aspartate transporter (GLAST), an astrocyte-specific glutamate transporter throughout development. Therefore, glutamate transporters regulate critical period plasticity by enhancing expansion of active barrels and shrinkage of inactive barrels. Because cortical contents of glutamate receptors and GLAST were unaltered in GLT1 knock-out mice, this action appears to be mediated, at least partly, by keeping the ambient glutamate level low. Considering an essential role of glutamate receptors in the formation of whisker-related thalamocortical synapse patterning, glutamate transporters thus facilitate their activity-dependent remodeling.

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Interdomain cytoplasmic interactions govern the intracellular trafficking, gating, and modulation of the Kv2.1 channel.

Publication Date: 2008 May 7 PMID: 18463252
Authors: Mohapatra, D. P. - Siino, D. F. - Trimmer, J. S.
Journal: J Neurosci

Voltage-gated potassium (Kv) channels comprise four transmembrane alpha subunits, often associated with cytoplasmic beta subunits that impact channel expression and function. Here, we show that cell surface expression, voltage-dependent activation gating, and phosphorylation-dependent modulation of Kv2.1 are regulated by cytoplasmic N/C interaction within the alpha subunit. Kv2.1 surface expression is greatly reduced by C-terminal truncation. Tailless Kv2.1 channels exhibit altered voltage-dependent gating properties and lack the bulk of the phosphorylation-dependent modulation of channel gating. Remarkably, the soluble C terminus of Kv2.1 associates with tailless channels and rescues their expression, function, and phosphorylation-dependent modulation. Soluble N and C termini of Kv2.1 can also interact directly. We also show that the N/C-terminal interaction in Kv2.1 is governed by a 34 aa motif in the juxtamembrane cytoplasmic C terminus, and a 17 aa motif located in the N terminus at a position equivalent to the beta subunit binding site in other Kv channels. Deletion of either motif disrupts N/C-terminal interaction and surface expression, function, and phosphorylation-dependent modulation of Kv2.1 channels. These findings provide novel insights into intrinsic mechanisms for the regulation of Kv2.1 trafficking, gating, and phosphorylation-dependent modulation through cytoplasmic N/C-terminal interaction, which resembles alpha/beta subunit interaction in other Kv channels.

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Functional magnetic resonance imaging of delay and trace eyeblink conditioning in the primary visual cortex of the rabbit.

Publication Date: 2008 May 7 PMID: 18463251
Authors: Miller, M. J. - Weiss, C. - Song, X. - Iordanescu, G. - Disterhoft, J. F. - Wyrwicz, A. M.
Journal: J Neurosci

The primary sensory cortices have been shown in recent years to undergo experience- and learning-related plasticity under a variety of experimental circumstances. In this study, we used functional magnetic resonance imaging (fMRI) in parallel with both delay and trace eyeblink conditioning to image the learning-related functional activation within the primary visual cortex (V1) of awake, behaving rabbits. We expected that the differing level of forebrain dependence between these two conditioning paradigms should produce a differential blood oxygenation level-dependent (BOLD) functional response in V1. Our results showed a significant expansion of activated volume within V1, particularly early in learning, after training with the more cognitively demanding trace paradigm. In contrast, the simpler delay paradigm produced an increase in the magnitude of the BOLD response in activated voxels, but no significant change in activated volume. No accompanying learning-related changes were observed in the primary somatosensory cortex, which mediates the unconditioned stimulus. These results suggest that the recruitment of additional neurons within V1 is necessary to support the more demanding memory imposed by the trace interval. To our knowledge, this work is the first functional imaging study to compare directly trace and delay eyeblink conditioning in an animal model.

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Loss of IP3 receptor-dependent Ca2+ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity.

Publication Date: 2008 May 7 PMID: 18463250
Authors: Petravicz, J. - Fiacco, T. A. - McCarthy, K. D.
Journal: J Neurosci

Astrocytes in the hippocampus release calcium (Ca(2+)) from intracellular stores intrinsically and in response to activation of G(q)-linked G-protein-coupled receptors (GPCRs) through the binding of inositol 1,4,5-trisphosphate (IP(3)) to its receptor (IP(3)R). Astrocyte Ca(2+) has been deemed necessary and sufficient to trigger the release of gliotransmitters, such as ATP and glutamate, from astrocytes to modulate neuronal activity. Several lines of evidence suggest that IP(3)R type 2 (IP(3)R2) is the primary IP(3)R expressed by astrocytes. To determine whether IP(3)R2 is the primary functional IP(3)R responsible for astrocytic Ca(2+) increases, we conducted experiments using an IP(3)R2 knock-out mouse model (IP(3)R2 KO). We show, for the first time, that lack of IP(3)R2 blocks both spontaneous and G(q)-linked GPCR-mediated increases in astrocyte Ca(2+). Furthermore, neuronal G(q)-linked GPCR Ca(2+) increases remain intact, suggesting that IP(3)R2 does not play a major functional role in neuronal calcium store release or may not be expressed in neurons. Additionally, we show that lack of IP(3)R2 in the hippocampus does not affect baseline excitatory neuronal synaptic activity as measured by spontaneous EPSC recordings from CA1 pyramidal neurons. Whole-cell recordings of the tonic NMDA receptor-mediated current indicates that ambient glutamate levels are also unaffected in the IP(3)R2 KO. These data show that IP(3)R2 is the key functional IP(3)R driving G(q)-linked GPCR-mediated Ca(2+) increases in hippocampal astrocytes and that removal of astrocyte Ca(2+) increases does not significantly affect excitatory neuronal synaptic activity or ambient glutamate levels.

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Presynaptic melanocortin-4 receptors on vagal afferent fibers modulate the excitability of rat nucleus tractus solitarius neurons.

Publication Date: 2008 May 7 PMID: 18463249
Authors: Wan, S. - Browning, K. N. - Coleman, F. H. - Sutton, G. - Zheng, H. - Butler, A. - Berthoud, H. R. - Travagli, R. A.
Journal: J Neurosci

The nucleus tractus solitarius (NTS) integrates visceral sensory signals with information from the forebrain to control homeostatic functions, including food intake. Melanocortin 3/4 receptor (MC3/4R) ligands administered directly to the caudal brainstem powerfully modulate meal size but not frequency, suggesting the enhancement of visceral satiety signals. Using whole-cell recordings from rat brainstem slices, we examined the effects of melanocortin ligands, alpha-melanocyte-stimulating hormone (alphaMSH) and melanotan II (MTII), on EPSC in NTS neurons. Thirty-two percent of NTS neurons responded to perfusion with MTII or alphaMSH with either an increase (24%) or a decrease (8%) in the frequency, but not amplitude, of spontaneous EPSCs; the effects of MTII were abolished by pretreatment with SHU9119. After surgical vagal deafferentation, only four of 34 (9%) NTS neurons responded to MTII with an increase in EPSC frequency. When EPSCs were evoked by electrical stimulation of the tractus solitarius in Krebs' solution with 2.4 mm Ca(2+)(e), alphaMSH and MTII increased the amplitude in six of the 28 neurons tested, decreased amplitude in 14 with no effect in the remaining eight neurons. In four of six neurons unresponsive to MTII, decreasing Ca(2+)(e) levels to 1.5 mM uncovered an excitatory effect of MTII on EPSC amplitude. Reverse transcription-PCR analysis revealed the presence of MC4R, but not MC3R, in nodose ganglia. These results show that MC4R signaling leads mainly to presynaptic modulation of glutamatergic synaptic transmission and suggest that melanocortinergic-induced decrease of food intake may occur via enhancement of vagal afferent satiation signals from the gastrointestinal tract.

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P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury.

Publication Date: 2008 May 7 PMID: 18463248
Authors: Tozaki-Saitoh, H. - Tsuda, M. - Miyata, H. - Ueda, K. - Kohsaka, S. - Inoue, K.
Journal: J Neurosci

Extracellular nucleotides have been implicated as signaling molecules used by microglia to sense adverse physiological conditions, such as neuronal damage. They act through purinoceptors, especially the G-protein-coupled P2Y receptor P2Y(12)R. Emerging evidence has indicated that activated spinal microglia responding to nerve injury are key cellular intermediaries in the resulting highly debilitating chronic pain state, namely neuropathic pain. However, the role of microglial P2Y(12)Rs in neuropathic pain remains unknown. Here, we show that the level of P2Y(12)R mRNA expression was markedly increased in the spinal cord ipsilateral to the nerve injury and that this expression was highly restricted to ionized binding calcium adapter molecule 1-positive microglia. An increase in the immunofluorescence of P2Y(12)R protein in the ipsilateral spinal cord was also observed after nerve injury, and P2Y(12)R-positive cells were double labeled with the microglial marker OX-42. Blocking spinal P2Y(12)R by the intrathecal administration of its antagonist AR-C69931MX prevented the development of tactile allodynia (pain hypersensitivity to innocuous stimuli), a hallmark of neuropathic pain syndrome. Furthermore, mice lacking P2ry(12) (P2ry(12)(-/-)) displayed impaired tactile allodynia after nerve injury without any change in basal mechanical sensitivity. Moreover, a single intrathecal administration of AR-C69931MX or oral administration of clopidogrel (a P2Y(12)R blocker clinically in use) to nerve-injured rats produced a striking alleviation of existing tactile allodynia. Together, our findings indicate that activation of P2Y(12)Rs in spinal microglia may be a critical event in the pathogenesis of neuropathic pain and suggest that blocking microglial P2Y(12)R might be a viable therapeutic strategy for treating neuropathic pain.

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Loss of apoptosis-inducing factor results in cell-type-specific neurogenesis defects.

Publication Date: 2008 May 7 PMID: 18463247
Authors: Ishimura, R. - Martin, G. R. - Ackerman, S. L.
Journal: J Neurosci

Mitochondrial dysfunction is commonly associated with neurodegeneration in the aging brain. In addition, the importance of mitochondrial function during brain development is illustrated by the neurological deficits observed in infants with mitochondrial complex deficiencies. However, the extent to which abnormalities in mitochondrial function might impact neurogenesis during brain development is not well understood. Previously, we demonstrated that adult harlequin (Hq) mutant mice, which have an 80% reduction in the mitochondrial protein apoptosis-inducing factor (AIF), exhibited signs of oxidative stress and progressive loss of adult cerebellar and retinal neurons. To assess whether in addition to its role in postmitotic neuron survival Aif is also necessary for cerebellar development, we analyzed embryos in which Aif was deleted in the prospective midbrain and cerebellum at a very early stage of development using an En1 (engrailed 1) promoter-driven cre recombinase gene. These mutant mice, which died at birth, had midbrain defects and dramatic deficits in cerebellar Purkinje and granule cell precursors. Additional analysis revealed that Aif-null Purkinje cell precursors prematurely entered S-phase, but most failed to undergo mitosis and ultimately died via apoptosis. In contrast, proliferation of mutant granule cell precursors was blocked before S-phase. Mice in which Aif was deleted later in embryogenesis using a nestin promoter-driven cre gene survive for several days after birth, and postnatal granule cell precursors in these mice also failed to enter S-phase. Our results indicate that the loss of Aif results in cell cycle abnormalities in a neuron-specific manner during cerebellar development.

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Neural correlates of perceptual learning in the auditory brainstem: efferent activity predicts and reflects improvement at a speech-in-noise discrimination task.

Publication Date: 2008 May 7 PMID: 18463246
Authors: de Boer, J. - Thornton, A. R.
Journal: J Neurosci

An extensive corticofugal system extends from the auditory cortex toward subcortical nuclei along the auditory pathway. Corticofugal influences reach even into the inner ear via the efferents of the olivocochlear bundle, the medial branch of which modulates preneural sound amplification gain. This corticofugal system is thought to contribute to neuroplasticity underlying auditory perceptual learning. In the present study, we investigated the involvement of the medial olivocochlear bundle (MOCB) in perceptual learning as a result of auditory training. MOCB activity was monitored in normal-hearing adult listeners during a 5 d training regimen on a consonant-vowel phoneme-in-noise discrimination task. The results show significant group learning, with great inter-individual variability in initial performance and improvement. As observed in previous auditory training studies, poor initial performers tended to show greater learning. Strikingly, MOCB activity measured on the first training day strongly predicted the subsequent amount of improvement, such that weaker initial MOCB activity was associated with greater improvement. Moreover, in listeners that improved significantly, an increase in MOCB activity was observed after training. Thus, as discrimination thresholds of listeners converged over the course of training, differences in MOCB activity between listeners decreased. Additional analysis showed that MOCB activity did not explain variation in performance between listeners on any training day but rather reflected an individual listener's performance relative to their personal optimal range. The findings suggest an MOCB-mediated listening strategy that facilitates speech-in-noise perception. The operation of this strategy is flexible and susceptible to training, presumably because of task-related adaptation of descending control from the cortex.

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Damage-induced activation of ERK1/2 in cochlear supporting cells is a hair cell death-promoting signal that depends on extracellular ATP and calcium.

Publication Date: 2008 May 7 PMID: 18463245
Authors: Lahne, M. - Gale, J. E.
Journal: J Neurosci

Acoustic overstimulation and ototoxic drugs can cause permanent hearing loss as a result of the damage and death of cochlear hair cells. Relatively little is known about the signaling pathways triggered by such trauma, although a significant role has been described for the c-Jun N-terminal kinase [one of the mitogen-activated protein kinases (MAPKs)] pathway. We investigated the role of another MAPK family, the extracellularly regulated kinases 1 and 2 (ERK1/2) during hair cell damage in neonatal cochlear explants. Within minutes of subjecting explants to mechanical damage, ERK1/2 were transiently activated in Deiters' and phalangeal cells but not in hair cells. The activation of ERK1/2 spread along the length of the cochlea, reaching its peak 5-10 min after damage onset. Release of extracellular ATP and the presence of functional connexin proteins were critical for the activation and spread of ERK1/2. Damage elicited an intercellular Ca(2+) wave in the hair cell region in the first seconds after damage. In the absence of Ca(2+) influx, the intercellular Ca(2+) wave and the magnitude and spread of ERK1/2 activation were reduced. Treatment with the aminoglycoside neomycin produced a similar pattern of ERK1/2 activation in supporting cells surrounding pyknotic hair cells. When ERK1/2 activation was prevented, there was a reduction in the number of pyknotic hair cells. Thus, activation of ERK1/2 in cochlear supporting cells in vitro is a common damage signaling mechanism that acts to promote hair cell death, indicating a direct role for supporting cells in regulating hair cell death.

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Protein kinase A anchoring via AKAP150 is essential for TRPV1 modulation by forskolin and prostaglandin E2 in mouse sensory neurons.

Publication Date: 2008 May 7 PMID: 18463244
Authors: Schnizler, K. - Shutov, L. P. - Van Kanegan, M. J. - Merrill, M. A. - Nichols, B. - McKnight, G. S. - Strack, S. - Hell, J. W. - Usachev, Y. M.
Journal: J Neurosci

Phosphorylation-dependent modulation of the vanilloid receptor TRPV1 is one of the key mechanisms mediating the hyperalgesic effects of inflammatory mediators, such as prostaglandin E(2) (PGE(2)). However, little is known about the molecular organization of the TRPV1 phosphorylation complex and specifically about scaffolding proteins that position the protein kinase A (PKA) holoenzyme proximal to TRPV1 for effective and selective regulation of the receptor. Here, we demonstrate the critical role of the A-kinase anchoring protein AKAP150 in PKA-dependent modulation of TRPV1 function in adult mouse dorsal root ganglion (DRG) neurons. We found that AKAP150 is expressed in approximately 80% of TRPV1-positive DRG neurons and is coimmunoprecipitated with the capsaicin receptor. In functional studies, PKA stimulation with forskolin markedly reduced desensitization of TRPV1. This effect was blocked by the PKA selective inhibitors KT5720 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epox y-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-ca rboxylicacid hexyl ester] and H89 (N-[2-(p-bromo-cinnamylamino)-ethyl]-5-isoquinoline-sulfon-amide 2HCl), as well as by the AKAP inhibitory peptide Ht31. Similarly, PGE(2) decreased TRPV1 desensitization in a manner sensitive to the PKA inhibitor KT5720. Both the forskolin and PGE(2) effects were strongly impaired in DRG neurons from knock-in mice that express a mutant AKAP150 lacking the PKA-binding domain (Delta36 mice). Protein kinase C-dependent sensitization of TRPV1 remained intact in Delta36 mice. The PGE(2)/PKA signaling defect in DRG neurons from Delta36 mice was rescued by overexpressing the full-length human ortholog of AKAP150 in these cells. In behavioral testing, PGE(2)-induced thermal hyperalgesia was significantly diminished in Delta36 mice. Together, these data suggest that PKA anchoring by AKAP150 is essential for the enhancement of TRPV1 function by activation of the PGE(2)/PKA signaling pathway.

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Abnormal neural oscillatory activity to speech sounds in schizophrenia: a magnetoencephalography study.

Publication Date: 2008 May 7 PMID: 18463243
Authors: Hirano, S. - Hirano, Y. - Maekawa, T. - Obayashi, C. - Oribe, N. - Kuroki, T. - Kanba, S. - Onitsuka, T.
Journal: J Neurosci

Schizophrenia impairs many cognitive functions, and abnormalities in language processing have been proposed as one of the bases for this disorder. Previously, it was reported that different magnetoencephalography (MEG) patterns of the evoked oscillatory activity (eOA) of 20-45 Hz to speech and nonspeech sounds were evidence of a fast mechanism for the representation and identification of speech sounds in humans. The current study tested the hypothesis that the schizophrenics would show abnormal neural oscillatory activity, as measured by eOA, to speech and nonspeech sounds. Twenty patients and 23 control subjects participated in this study. MEG responses to speech and nonspeech sounds were recorded and eOA power and phase locking at 20-45 Hz were analyzed. Patients showed significantly delayed peak latencies of the eOA power and phase locking to speech sounds in the left hemisphere and to nonspeech sounds in the right hemisphere. Patients also showed a significantly reduced eOA power to speech sounds in the left hemisphere in 0-50 ms and a significantly larger eOA power to speech sounds in the left hemisphere in 100-150 ms. In addition, the analyses of the lateralization index revealed the pattern of hemispheric lateralization to be the opposite in patients. These results indicated that patients showed different characteristics of eOA compared with normal controls, probably related to deficits in a fast mechanism for identifying speech sounds. Moreover, the present study suggests that schizophrenia might be characterized by an opposite pattern of hemispheric lateralization in auditory evoked oscillations.

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Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats: a test of the astrocyte-neuron lactate-shuttle hypothesis.

Publication Date: 2008 May 7 PMID: 18463242
Authors: Erlichman, J. S. - Hewitt, A. - Damon, T. L. - Hart, M. - Kurascz, J. - Li, A. - Leiter, J. C.
Journal: J Neurosci

The astrocyte-neuronal lactate-shuttle hypothesis posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 microM alpha-cyano-4-hydroxy-cinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT) 2 but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 microM 4-CIN significantly reduced the magnitude of the acidosis in neurons but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-D-glucose analog in neurons but did not alter the uptake rate of this 2-deoxy-D-glucose analog in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Therefore, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates.

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Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina.

Publication Date: 2008 May 7 PMID: 18463241
Authors: Damiani, D. - Alexander, J. J. - O'Rourke, J. R. - McManus, M. - Jadhav, A. P. - Cepko, C. L. - Hauswirth, W. W. - Harfe, B. D. - Strettoi, E.
Journal: J Neurosci

MicroRNAs (miRNAs) are small, highly conserved molecules that have been shown to regulate the expression of genes by binding to specific target mRNAs. Dicer, an RNase III endonuclease, is essential for the production and function of mature miRNAs, and removal of Dicer has been shown to disrupt many developmental processes. In this study, Dicer was removed specifically from the retina using a floxed Dicer conditional allele and the retinal Chx10Cre transgene. Retinal Dicer knock-out mice displayed a reproducible inability to respond to light. In addition, morphological defects were observed with the formation of photoreceptor rosettes at postnatal day 16, which progressed to more general cellular disorganization and widespread degeneration of retinal cell types as the animals aged. This was accompanied by concomitant decrease in both scotopic and photopic electroretinogram (ERG) responses. Interestingly, removing a single allele of Dicer resulted in ERG deficits throughout life but not to morphological abnormalities. Northern blot analysis of Dicer-depleted retinas showed a decrease in several miRNAs. The observation that progressive retinal degeneration occurred after removal of Dicer raises the possibility that miRNAs are involved in retinal neurodegenerative disorders.

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Cyclin-dependent kinase 5 supports neuronal survival through phosphorylation of Bcl-2.

Publication Date: 2008 May 7 PMID: 18463240
Authors: Cheung, Z. H. - Gong, K. - Ip, N. Y.
Journal: J Neurosci

Accumulating evidence indicates that deregulation of cyclin-dependent kinase 5 (Cdk5) activity is associated with apoptosis in various neurodegenerative disease models. Interestingly, recent studies suggest that Cdk5 may also favor neuronal survival. Nonetheless, whether Cdk5 is directly required for neuronal survival during development remains enigmatic. In the current study, we established the pivotal role of Cdk5 in neuronal survival during development by demonstrating that reduction or absence of Cdk5 activity markedly exacerbated neuronal death in cultures and in vivo. Interestingly, the antiapoptotic protein Bcl-2 (B-cell lymphoma protein 2) was identified as a novel substrate of Cdk5. We found that Cdk5-mediated phosphorylation of Bcl-2 at Ser70 was required for the neuroprotective effect of Bcl-2. Intriguingly, inhibition of this phosphorylation conferred proapoptotic property to Bcl-2. Furthermore, overexpression of a Bcl-2 mutant lacking the Cdk5 phosphorylation site abolished the protective effect of Cdk5 re-expression in Cdk5(-/-) neurons, suggesting that Ser70 phosphorylation of Bcl-2 contributed to Cdk5-mediated neuronal survival. Our observations revealed that Cdk5-mediated Bcl-2 phosphorylation is pivotal for the antiapoptotic effect of Bcl-2 and contributes to the maintenance of neuronal survival by Cdk5. Our study has also identified Cdk5 as a regulator of Bcl-2 function in neuronal apoptosis.

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Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress.

Publication Date: 2008 May 7 PMID: 18463239
Authors: Press, C. - Milbrandt, J.
Journal: J Neurosci

Axonal degeneration is a prominent feature of many neurological disorders that are associated with mitochondrial dysfunction, including Parkinson's disease, motor neuron disease, and inherited peripheral neuropathies. Studies of the Wld(s) mutant mouse, which undergoes delayed Wallerian degeneration in response to axonal injury, suggest that axonal degeneration is an active process. Wld(s) mice also have slower axonal degeneration and disease progression in numerous models of neurodegenerative disease. The Wld(s) mutation results in the production of a chimeric protein that contains the full-length coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), which alone is sufficient for axonal protection in vitro. To test the effects of increased Nmnat expression on axonal degeneration induced by mitochondrial dysfunction, we examined dorsal root ganglion (DRG) neurons treated with rotenone. Rotenone induced profound axonal degeneration in DRG neurons; however, this degeneration was delayed by expression of Nmnat. Nmnat-mediated protection resulted in decreased axonal accumulation and sensitivity to reactive oxygen species (ROS) but did not affect the change in the rate of rotenone-induced loss in neuronal ATP. Nmnat also prevented axonal degeneration caused by exposure to exogenous oxidants and reduced the level of axonal ROS after treatment with vincristine, further supporting the idea that Nmnat promotes axonal protection by mitigating the effects of ROS.

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