Journal of Neuroscience

Genetic targeting of ERK1 suggests a predominant role for ERK2 in murine pain models.

Publication Date: 2010 Aug 25 PMID: 20739576
Authors: Alter, B. J. - Zhao, C. - Karim, F. - Landreth, G. E. - Gereau, R. W. 4th
Journal: J Neurosci

The extracellular signal-regulated kinase (ERK) isoforms, ERK1 and ERK2, are believed to be key signaling molecules in nociception and nociceptive sensitization. Studies using inhibitors targeting the shared ERK1/2 upstream activator, mitogen-activated protein kinase kinase (MEK), and transgenic mice expressing a dominant-negative form of MEK have established the importance of ERK1/2 signaling. However, these techniques do not discriminate between ERK1 and ERK2. To dissect the function of each isoform in pain, we used mice with a targeted genetic deletion of ERK1 [ERK1 knock-out (KO)] to test the hypothesis that ERK1 is required for behavioral sensitization in rodent pain models. Despite activation (phosphorylation) of ERK1 after acute noxious stimulation and in models of chronic pain, we found that ERK1 was not required for formalin-induced spontaneous behaviors, complete Freund's adjuvant-induced heat and mechanical hypersensitivity, and spared nerve injury-induced mechanical hypersensitivity. However, ERK1 deletion did delay formalin-induced long-term heat hypersensitivity, without affecting formalin-induced mechanical hypersensitivity, suggesting that ERK1 partially shapes long-term responses to formalin. Interestingly, ERK1 deletion resulted in elevated basal ERK2 phosphorylation. However, this did not appear to influence nociceptive processing, since inflammation-induced ERK2 phosphorylation and pERK1/2 immunoreactivity in spinal cord were not elevated in ERK1 KO mice. Additionally, systemic MEK inhibition with SL327 (alpha-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneace tonitrile) attenuated formalin-induced spontaneous behaviors similarly in wild-type and ERK1 KO mice, indicating that unrelated signaling pathways do not functionally compensate for the loss of ERK1. Together, these results suggest that ERK1 plays a limited role in nociceptive sensitization and support a predominant role for ERK2 in these processes.

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Movement-related cortical stimulation can induce human motor plasticity.

Publication Date: 2010 Aug 25 PMID: 20739575
Authors: Thabit, M. N. - Ueki, Y. - Koganemaru, S. - Fawi, G. - Fukuyama, H. - Mima, T.
Journal: J Neurosci

Repeated paired associative stimulation combining peripheral nerve stimulation and transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can produce human motor plasticity. However, previous studies used paired artificial stimuli, so that it is not known whether repetitive natural M1 activity associated with TMS can induce plasticity or not. To test this hypothesis, we developed a movement-related cortical stimulation (MRCS) protocol, in which the left M1 was stimulated by TMS at specific timing with respect to the mean expected reaction time (RT) of voluntary movement during a simple reaction time task using the right abductor pollicis brevis (APB) muscle. Seventeen normal volunteers were subjected to repeated MRCS intervention (0.2 Hz, 240 pairs). Motor function was assessed before and after MRCS. When TMS was given 50 ms before the RT of movement [MRCS(-50)], motor-evoked potential (MEP) amplitude of the right APB, but not other muscles, increased for up to 15 min post-MRCS. The RT of the right APB was also shortened. However, spinal excitability measured by F-wave did not change. When TMS was given 100 ms after the RT [MRCS(+100)], MEP amplitude was decreased. These findings show that this new MRCS protocol can produce timing-dependent motor associative plasticity, which may be clinically useful.

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Unexpected survival of neurons of origin of the pyramidal tract after spinal cord injury.

Publication Date: 2010 Aug 25 PMID: 20739574
Authors: Nielson, J. L. - Sears-Kraxberger, I. - Strong, M. K. - Wong, J. K. - Willenberg, R. - Steward, O.
Journal: J Neurosci

There is continuing controversy about whether the cells of origin of the corticospinal tract (CST) undergo retrograde cell death after spinal cord injury (SCI). All previous attempts to assess this have used imaging and/or histological techniques to assess upper motoneurons in the cerebral cortex. Here, we address the question in a novel way by assessing Wallerian degeneration and axon numbers in the medullary pyramid of Sprague Dawley rats after both acute SCI, either at cervical level 5 (C5) or thoracic level 9 (T9), and chronic SCI at T9. Our findings demonstrate that only a fraction of a percentage of the total axons in the medullary pyramid exhibit any sign of degeneration at any time after SCI--no more so than in uninjured control rats. Moreover, design-based counts of myelinated axons revealed no decrease in axon number in the medullary pyramid after SCI, regardless of injury level, severity, or time after injury. Spinal cord-injured rats had fewer myelinated axons in the medullary pyramid at 1 year after injury than aged matched controls, suggesting that injury may affect ongoing myelination of axons during aging. We conclude that SCI does not cause death of the CST cell bodies in the cortex; therefore, therapeutic strategies aimed at promoting axon regeneration of the CST in the spinal cord do not require a separate intervention to prevent retrograde degeneration of upper motoneurons in the cortex.

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Periodicity and evoked responses in motor cortex.

Publication Date: 2010 Aug 25 PMID: 20739573
Authors: Reimer, J. - Hatsopoulos, N. G.
Journal: J Neurosci

Spiking in primary motor cortex (MI) exhibits a characteristic beta frequency periodicity, but the functional relevance of this rhythmic firing is controversial. We simultaneously recorded multiple single units and local field potentials in MI in two monkeys (Macaca mulatta) during continuous, self-paced movements to serially presented targets. We find that the appearance of each new target evokes precisely timed spiking in MI at a characteristic latency but that the exact timing of this response varies depending on its relationship to the phase of the ongoing beta range oscillation. As a result of this interaction between evoked spiking and endogenous beta periodicity, we find that the amount of information about target location encoded in the spiking of MI neurons is not simply a function of elapsed time but depends also on oscillatory phase. Our results suggest that periodicity may be an important feature of the early stages of sensorimotor processing in the cortical motor system.

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Excitatory glycine responses of CNS myelin mediated by NR1/NR3 "NMDA" receptor subunits.

Publication Date: 2010 Aug 25 PMID: 20739572
Authors: Pina-Crespo, J. C. - Talantova, M. - Micu, I. - States, B. - Chen, H. S. - Tu, S. - Nakanishi, N. - Tong, G. - Zhang, D. - Heinemann, S. F. - Zamponi, G. W. - Stys, P. K. - Lipton, S. A.
Journal: J Neurosci

NMDA receptors are typically excited by a combination of glutamate and glycine. Here we describe excitatory responses in CNS myelin that are gated by a glycine agonist alone and mediated by NR1/NR3 "NMDA" receptor subunits. Response properties include activation by d-serine, inhibition by the glycine-site antagonist CNQX, and insensitivity to the glutamate-site antagonist d-APV. d-Serine responses were abrogated in NR3A-deficient mice. Our results suggest the presence of functional NR1/NR3 receptors in CNS myelin.

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Target-specific encoding of response inhibition: increased contribution of AMPA to NMDA receptors at excitatory synapses in the prefrontal cortex.

Publication Date: 2010 Aug 25 PMID: 20739571
Authors: Hayton, S. J. - Lovett-Barron, M. - Dumont, E. C. - Olmstead, M. C.
Journal: J Neurosci

Impulse control suppresses actions that are inappropriate in one context, but may be beneficial in others. The medial prefrontal cortex (mPFC) mediates this process by providing a top-down signal to inhibit competing responses, although the mechanism by which the mPFC acquires this ability is unknown. To that end, we examined synaptic changes in the mPFC associated with learning to inhibit an incorrect response. Rats were trained in a simple response inhibition task to withhold responding until a signal was presented. We then measured synaptic plasticity of excitatory synapses in the mPFC, using whole-cell patch-clamp recordings, in brain slices prepared from trained rats. Response inhibition training significantly increased the relative contribution of AMPA receptors to the overall EPSC in prelimbic, but not infralimbic, neurons of the mPFC. This potentiation of synaptic transmission closely paralleled the acquisition and extinction of response inhibition. Using a retrograde fluorescent tracer, we observed that these plastic changes were selective for efferents projecting to the ventral striatum, but not the dorsal striatum or amygdala. Therefore, we suggest that response inhibition is encoded by a selective strengthening of a subset of corticostriatal projections, uncovering a synaptic mechanism of impulse control. This information could be exploited in therapeutic interventions for disorders of impulse control, such as addiction, attention deficit-hyperactivity disorder, and schizophrenia.

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Hippocampal ripple-contingent training accelerates trace eyeblink conditioning and retards extinction in rabbits.

Publication Date: 2010 Aug 25 PMID: 20739570
Authors: Nokia, M. S. - Penttonen, M. - Wikgren, J.
Journal: J Neurosci

There are at least two distinct oscillatory states of the hippocampus that are related to distinct behavioral patterns. Theta (4-12 Hz) oscillation has been suggested to indicate selective attention during which the animal concentrates on some features of the environment while suppressing reactivity to others. In contrast, sharp-wave ripples ( approximately 200 Hz) can be seen in a state in which the hippocampus is at its most responsive to any kind of afferent stimulation. In addition, external stimulation tends to evoke and reset theta oscillation, the phase of which has been shown to modulate synaptic plasticity in the hippocampus. Theoretically, training on a hippocampus-dependent learning task contingent upon ripples could enhance learning rate due to elevated responsiveness and enhanced phase locking of the theta oscillation. We used a brain-computer interface to detect hippocampal ripples in rabbits to deliver trace eyeblink conditioning and extinction trials selectively contingent upon them. A yoked control group was trained regardless of their ongoing neural state. Ripple-contingent training expedited acquisition of the conditioned response early in training and evoked stronger theta-band phase locking to the conditioned stimulus. Surprisingly, ripple-contingent training also resulted in slower extinction in well trained animals. We suggest that the ongoing oscillatory activity in the hippocampus determines the extent to which a stimulus can induce a phase reset of the theta oscillation, which in turn is the determining factor of learning rate in trace eyeblink conditioning.

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Transcranial electric stimulation entrains cortical neuronal populations in rats.

Publication Date: 2010 Aug 25 PMID: 20739569
Authors: Ozen, S. - Sirota, A. - Belluscio, M. A. - Anastassiou, C. A. - Stark, E. - Koch, C. - Buzsaki, G.
Journal: J Neurosci

Low intensity electric fields have been suggested to affect the ongoing neuronal activity in vitro and in human studies. However, the physiological mechanism of how weak electrical fields affect and interact with intact brain activity is not well understood. We performed in vivo extracellular and intracellular recordings from the neocortex and hippocampus of anesthetized rats and extracellular recordings in behaving rats. Electric fields were generated by sinusoid patterns at slow frequency (0.8, 1.25 or 1.7 Hz) via electrodes placed on the surface of the skull or the dura. Transcranial electric stimulation (TES) reliably entrained neurons in widespread cortical areas, including the hippocampus. The percentage of TES phase-locked neurons increased with stimulus intensity and depended on the behavioral state of the animal. TES-induced voltage gradient, as low as 1 mV/mm at the recording sites, was sufficient to phase-bias neuronal spiking. Intracellular recordings showed that both spiking and subthreshold activity were under the combined influence of TES forced fields and network activity. We suggest that TES in chronic preparations may be used for experimental and therapeutic control of brain activity.

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Developmental mechanisms for suppressing the effects of delayed release at the endbulb of held.

Publication Date: 2010 Aug 25 PMID: 20739568
Authors: Yang, H. - Xu-Friedman, M. A.
Journal: J Neurosci

Delayed release of neurotransmitter, also called asynchronous release, is commonly observed at synapses, yet its influence on transmission of spike information is unknown. We examined this issue at endbulb of Held synapses, which are formed by auditory nerve fibers onto bushy cells in the cochlear nucleus. Endbulbs from CBA/CaJ mice aged P6-P49 showed prominent delayed release when driven at physiologically relevant rates. In bushy cells from mice before the onset of hearing (P6-P12), spikes were driven by delayed release up to 100 ms after presynaptic activity. However, no such spikes were observed in bushy cells from mice after the onset of hearing (>P14). Dynamic-clamp experiments indicated that delayed release can drive spikes in older bushy cells provided synchronous release is absent, suggesting that activity normally suppresses these spikes. Application of apamin or alpha-dendrotoxin revealed late spikes in older bushy cells, suggesting that postsynaptic activation of K(V)1.x and SK channels during spiking suppresses the subsequent effects of delayed release. The developmental upregulation of these potassium channels would be highly adaptive for temporally precise auditory processing. Furthermore, delayed release appeared to influence synchronous neurotransmitter release. Enhancement of delayed release using strontium was correlated with lower firing probability in current clamp and smaller synchronous EPSCs in voltage clamp. EGTA-AM had the opposite effects. These effects were consistent with delayed and synchronous release competing for a single vesicle pool. Thus delayed release apparently has negative presynaptic and postsynaptic consequences at the endbulb, which are partly mitigated by postsynaptic potassium channel expression.

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Neural predictors of within-subject fluctuations in attentional control.

Publication Date: 2010 Aug 25 PMID: 20739567
Authors: Leber, A. B.
Journal: J Neurosci

Whether salient objects automatically capture attention has long been the subject of considerable controversy. A possible resolution, investigated in this functional magnetic resonance imaging (fMRI) study, is that observers vacillate between periods when attention capture is robust and when it is minimal. Human observers searched static displays for a target circle among nontarget squares; an irrelevant color singleton distractor appeared on 50% of trials. Behavioral results showed a distraction effect in which response times to distractor-present trials were slower than for distractor-absent trials. fMRI results confirmed that this distraction effect not only fluctuated within experimental sessions, but the momentary degree of distraction could be predicted in advance by pretrial activity in middle frontal gyrus. A second experiment ruled out an alternative account by which participants achieved resistance to capture by trading off search efficiency. Together, these data reveal that observers frequently exert the capacity to resist attentional distraction, although they do not to sustain this capacity for long periods of time.

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Reward prediction error coding in dorsal striatal neurons.

Publication Date: 2010 Aug 25 PMID: 20739566
Authors: Oyama, K. - Hernadi, I. - Iijima, T. - Tsutsui, K.
Journal: J Neurosci

In the current theory of learning, the reward prediction error (RPE), the difference between expected and received reward, is thought to be a key factor in reward-based learning, working as a teaching signal. The activity of dopamine neurons is known to code RPE, and the release of dopamine is known to modify the strength of synaptic connectivity in the target neurons. A fundamental interest in current neuroscience concerns the origin of RPE signals in the brain. Here, we show that a group of rat striatal neurons show a clear parametric RPE coding similar to that of dopamine neurons when tested under probabilistic pavlovian conditioning. Together with the fact that striatum and dopamine neurons have strong direct and indirect fiber connections, the result suggests that the striatum plays an important role in coding RPE signal by cooperating with dopamine neurons.

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Alternative splicing of neuroligin regulates the rate of presynaptic differentiation.

Publication Date: 2010 Aug 25 PMID: 20739565
Authors: Lee, H. - Dean, C. - Isacoff, E.
Journal: J Neurosci

Neuroligins (NLGs) and Neurexins (NRXs) are important adhesion molecules that promote synapse formation. Multiple splice variants of NLG and NRX exist, but their specific functions are unclear. Here we report that a surrogate postsynaptic cell expressing full-length NLG-1 triggers slow presynaptic differentiation in a contacting axon. In contrast, a version of NLG-1, which lacks insert B (NLG-1DeltaB), induces rapid presynaptic differentiation, reaching the rate seen at native neuronal synapses. We show that this acceleration is attributed to the removal of the N-linked glycosylation site within insert B. NLG-1DeltaB also increases synaptic density at neuro-neuronal synapses more than does full-length NLG-1. Other postsynaptic adhesion proteins, such as N-cadherin, EphB2, and SynCAM-1, alone or in combination with full-length NLG-1, do not trigger fast differentiation, suggesting that rapid presynaptic differentiation depends on a unique interaction of NLG-1DeltaB with axonal proteins. Indeed, we find that NLG-1DeltaB recruits more axonal alpha-NRX. Our results suggest that the engagement of alpha-NRX is a key to rapid induction of synapses at new sites of axo-dendritic contact.

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Id gene regulation and function in the Prosensory domains of the chicken inner ear: a link between Bmp signaling and Atoh1.

Publication Date: 2010 Aug 25 PMID: 20739564
Authors: Kamaid, A. - Neves, J. - Giraldez, F.
Journal: J Neurosci

Bone morphogenetic proteins (Bmps) regulate the expression of the proneural gene Atoh1 and the generation of hair cells in the developing inner ear. The present work explored the role of Inhibitor of Differentiation genes (Id1-3) in this process. The results show that Id genes are expressed in the prosensory domains of the otic vesicle, along with Bmp4 and Bmp7. Those domains exhibit high levels of the phosphorylated form of Bmp-responding R-Smads (P-Smad1,5,8), and of Bmp-dependent Smad transcriptional activity as shown by the BRE-tk-EGFP reporter. Increased Bmp signaling induces the expression of Id1-3 along with the inhibition of Atoh1. Conversely, the Bmp antagonist Noggin or the Bmp-receptor inhibitor Dorsomorphin elicit opposite effects, indicating that Bmp signaling is necessary for Id expression and Atoh1 regulation in the otocyst. The forced expression of Id3 is sufficient to reduce Atoh1 expression and to prevent the expression of hair cell differentiation markers. Together, these results suggest that Ids are part of the machinery that mediates the regulation of hair cell differentiation exerted by Bmps. In agreement with that, during hair cell differentiation Bmp4 expression, P-Smad1,5,8 levels and Id expression are downregulated from hair cells. However, Ids are also downregulated from the supporting cells which contrarily to hair cells exhibit high levels of Bmp4 expression, P-Smad1,5,8, and BRE-tk-EGFP activity, suggesting that in these cells Ids escape from Bmp/Smad signaling. The differential regulation of Ids in time and space may underlie the multiple functions of Bmp signaling during sensory organ development.

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Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex.

Publication Date: 2010 Aug 25 PMID: 20739563
Authors: Origlia, N. - Bonadonna, C. - Rosellini, A. - Leznik, E. - Arancio, O. - Yan, S. S. - Domenici, L.
Journal: J Neurosci

Overproduction of beta-amyloid (Abeta) is a pathologic feature of Alzheimer's disease, leading to cognitive impairment. Here, we investigated the impact of cell-specific receptor for advanced glycation end products (RAGE) on Abeta-induced entorhinal cortex (EC) synaptic dysfunction. We found both a transient depression of basal synaptic transmission and inhibition of long-term depression (LTD) after the application of Abeta in EC slices. Synaptic depression and LTD impairment induced by Abeta were rescued by functional suppression of RAGE. Remarkably, the rescue was only observed in slices from mice expressing a defective form of RAGE targeted to microglia, but not in slices from mice expressing defective RAGE targeted to neurons. Moreover, we found that the inflammatory cytokine IL-1beta (interleukin-1beta) and stress-activated kinases [p38 MAPK (p38 mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase)] were significantly altered and involved in RAGE signaling pathways depending on RAGE expression in neuron or microglia. These findings suggest a prominent role of microglial RAGE signaling in Abeta-induced EC synaptic dysfunction.

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Characterization of the intracellular localization, processing, and secretion of two glial cell line-derived neurotrophic factor splice isoforms.

Publication Date: 2010 Aug 25 PMID: 20739562
Authors: Lonka-Nevalaita, L. - Lume, M. - Leppanen, S. - Jokitalo, E. - Peranen, J. - Saarma, M.
Journal: J Neurosci

Endocrine and neuronal cells have highly developed secretion mechanisms, and the secretion can be either constitutive or regulated by physiological stimuli. In the constitutive pathway, intracellular transport vesicles undergo immediate fusion reactions after arrival at the target. In regulated secretion, vesicles accumulate near the target membrane until triggered to fuse, typically by a local rise in free Ca(2+). In the present study, we characterize the processing and secretion mechanisms of the glial cell line-derived neurotrophic factor (GDNF). Although the function of GDNF has been extensively studied, very little is known about the basic cell biology of GDNF and its precursor forms (alpha)pro-GDNF and (beta)pro-GDNF that have different pro-regions. Our results show that both (alpha)pro-GDNF and (beta)pro-GDNF are secreted. We demonstrate that KCl-induced depolarization increases the secretion of (beta)pro-GDNF and corresponding mature GDNF, but not (alpha)pro-GDNF and corresponding mature GDNF, to the cell medium in a Ca(2+)-dependent manner. In parallel with this, immunofluorescence analysis of cells show that (alpha)pro-GDNF/GDNF is localized mostly in the Golgi complex, whereas (beta)pro-GDNF/GDNF is localized primarily in secretogranin II and Rab3A-positive vesicles of the regulated secretory pathway. In addition, we find that matrix metalloproteinases and plasmin that cleave pro-BDNF and pro-NGF are not responsible for the cleavage of pro-GDNF, whereas furin endoproteinase, PACE4, and proprotein convertases PC5A, PC5B, and PC7 can cleave pro-GDNF into mature GDNF. Thus, the processing and secretion mechanisms of GDNF are different from those of BDNF and NGF.

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Microstructural brain differences predict functional hemodynamic responses in a reward processing task.

Publication Date: 2010 Aug 25 PMID: 20739561
Authors: Camara, E. - Rodriguez-Fornells, A. - Munte, T. F.
Journal: J Neurosci

Many aspects of human behavior are driven by rewards, yet different people are differentially sensitive to rewards and punishment. In this study, we show that white matter microstructure in the uncinate/inferior fronto-occipital fasciculus, defined by fractional anisotropy values derived from diffusion tensor magnetic resonance images, correlates with both short-term (indexed by the fMRI blood oxygenation level-dependent response to reward in the nucleus accumbens) and long-term (indexed by the trait measure sensitivity to punishment) reactivity to rewards. Moreover, trait measures of reward processing were also correlated with reward-related functional activation in the nucleus accumbens. The white matter tract revealed by the correlational analysis connects the anterior temporal lobe with the medial and lateral orbitofrontal cortex and also supplies the ventral striatum. The pattern of strong correlations suggests an intimate relationship between white matter structure and reward-related behavior that may also play a role in a number of pathological conditions, such as addiction and pathological gambling.

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Rapamycin activates autophagy and improves myelination in explant cultures from neuropathic mice.

Publication Date: 2010 Aug 25 PMID: 20739560
Authors: Rangaraju, S. - Verrier, J. D. - Madorsky, I. - Nicks, J. - Dunn, W. A. Jr - Notterpek, L.
Journal: J Neurosci

Misexpression and cytosolic retention of peripheral myelin protein 22 (PMP22) within Schwann cells (SCs) is associated with a genetically heterogeneous group of demyelinating peripheral neuropathies. PMP22 overproducer C22 and spontaneous mutant Trembler J (TrJ) mice display neuropathic phenotypes and affected nerves contain abnormally localized PMP22. Nutrient deprivation-induced autophagy is able to suppress the formation of PMP22 aggregates in a toxin-induced cellular model, and improve locomotor performance and myelination in TrJ mice. As a step toward therapies, we assessed whether pharmacological activation of autophagy by rapamycin (RM) could facilitate the processing of PMP22 within neuropathic SCs and enhance their capacity to myelinate peripheral axons. Exposure of mouse SCs to RM induced autophagy in a dose- and time-dependent manner and decreased the accumulation of poly-ubiquitinated substrates. The treatment of myelinating dorsal root ganglion (DRG) explant cultures from neuropathic mice with RM (25 nm) improved the processing of PMP22 and increased the abundance and length of myelin internodes, as well as the expression of myelin proteins. Notably, RM is similarly effective in both the C22 and TrJ model, signifying that the benefit overlaps among distinct genetic models of PMP22 neuropathies. Furthermore, lentivirus-mediated shRNA knockdown of the autophagy-related gene 12 (Atg12) abolished the activation of autophagy and the increase in myelin proteins, demonstrating that autophagy is critical for the observed improvement. Together, these results support the potential use of RM and other autophagy-enhancing compounds as therapeutic agents for PMP22-associated demyelinating neuropathies.

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Development of a large-scale functional brain network during human non-rapid eye movement sleep.

Publication Date: 2010 Aug 25 PMID: 20739559
Authors: Spoormaker, V. I. - Schroter, M. S. - Gleiser, P. M. - Andrade, K. C. - Dresler, M. - Wehrle, R. - Samann, P. G. - Czisch, M.
Journal: J Neurosci

Graph theoretical analysis of functional magnetic resonance imaging (fMRI) time series has revealed a small-world organization of slow-frequency blood oxygen level-dependent (BOLD) signal fluctuations during wakeful resting. In this study, we used graph theoretical measures to explore how physiological changes during sleep are reflected in functional connectivity and small-world network properties of a large-scale, low-frequency functional brain network. Twenty-five young and healthy participants fell asleep during a 26.7 min fMRI scan with simultaneous polysomnography. A maximum overlap discrete wavelet transformation was applied to fMRI time series extracted from 90 cortical and subcortical regions in normalized space after residualization of the raw signal against unspecific sources of signal fluctuations; functional connectivity analysis focused on the slow-frequency BOLD signal fluctuations between 0.03 and 0.06 Hz. We observed that in the transition from wakefulness to light sleep, thalamocortical connectivity was sharply reduced, whereas corticocortical connectivity increased; corticocortical connectivity subsequently broke down in slow-wave sleep. Local clustering values were closest to random values in light sleep, whereas slow-wave sleep was characterized by the highest clustering ratio (gamma). Our findings support the hypothesis that changes in consciousness in the descent to sleep are subserved by reduced thalamocortical connectivity at sleep onset and a breakdown of general connectivity in slow-wave sleep, with both processes limiting the capacity of the brain to integrate information across functional modules.

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Defects in mitochondrial axonal transport and membrane potential without increased reactive oxygen species production in a Drosophila model of Friedreich ataxia.

Publication Date: 2010 Aug 25 PMID: 20739558
Authors: Shidara, Y. - Hollenbeck, P. J.
Journal: J Neurosci

Friedreich ataxia, a neurodegenerative disorder resulting from frataxin deficiency, is thought to involve progressive cellular damage from oxidative stress. In Drosophila larvae with reduced frataxin expression (DfhIR), we evaluated possible mechanisms of cellular neuropathology by quantifying mitochondrial axonal transport, membrane potential (MMP), and reactive oxygen species (ROS) production in the DfhIR versus wild-type nervous system throughout development. Although dying-back neuropathy in DfhIR larvae did not occur until late third instar, reduced MMP was already apparent at second instar in the cell bodies, axons and neuromuscular junctions (NMJs) of segmental nerves. Defects in axonal transport of mitochondria appeared late in development in distal nerve of DfhIR larvae, with retrograde movement preferentially affected. As a result, by late third instar the neuromuscular junctions (NMJs) of DfhIR larvae accumulated a higher density of mitochondria, many of which were depolarized. Notably, increased ROS production was not detected in any neuronal region or developmental stage in DfhIR larvae. However, when challenged with antimycin A, neurons did respond with a larger increase in ROS. We propose that pathology in the frataxin-deficient nervous system involves decreased MMP and ATP production followed by failures of mitochondrial transport and NMJ function.

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Insular cortex activity is associated with effects of negative expectation on nociceptive long-term habituation.

Publication Date: 2010 Aug 25 PMID: 20739557
Authors: Rodriguez-Raecke, R. - Doganci, B. - Breimhorst, M. - Stankewitz, A. - Buchel, C. - Birklein, F. - May, A.
Journal: J Neurosci

It is generally accepted that acute painful experience is influenced by context information shaping expectation and modulating attention, arousal, stress, and mood. However, little is known about the nature, duration, and extent of this effect, particularly regarding the negative expectation. We used a standardized longitudinal pain paradigm and painful heat test stimuli in healthy participants over a time course of 8 consecutive days, inducing nociceptive habituation over time. Thirty-eight healthy volunteers were randomly assigned to two different groups. One group received the information that the investigators expected the pain intensity to increase over time (context group). The other group was not given any information (control group). All participants rated the pain intensity of the daily standardized pain paradigm on a visual analog scale. In agreement with previous studies the pain ratings in the control group habituated over time. However, the context group reported no change of pain ratings over time. Functional imaging data showed a difference between the two groups in the right parietal operculum. These data suggest that a negative context not only has an effect on immediate pain but can modulate perception of pain in the future even without experience/conditioning. Neuronally, this process is mediated by the right opercular region.

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Theta oscillations reflect the dynamics of interference in episodic memory retrieval.

Publication Date: 2010 Aug 25 PMID: 20739556
Authors: Staudigl, T. - Hanslmayr, S. - Bauml, K. H.
Journal: J Neurosci

Selectively retrieving episodic information from a cue often induces interference from related episodes. To promote successful retrieval of the target episode, such interference is resolved by inhibition, causing retrieval-induced forgetting of the related but irrelevant information. Passively studying the episodic information again (reexposure) does not show this effect. This study examined the hypothesis that brain oscillations in the theta band (5-9 Hz) reflect the dynamics of interference in selective memory retrieval, analyzing EEG data from 24 healthy human subjects (21 women, 3 men). High versus low levels of interference were investigated by comparing the effects of selective retrieval with the effects of reexposure of material, with the former, but not the latter, inducing interference. Moreover, we analyzed repeated cycles of selective retrieval and reexposure, assuming that interference is reduced by inhibition across retrieval cycles, but not across reexposure cycles. We found greater theta band activity in selective retrieval than in reexposure, and a reduction in theta amplitude from the first to the second cycle of retrieval predicting the amount of retrieval-induced forgetting; the sources of theta amplitude reduction across retrieval cycles were located in the anterior cingulate cortex. No difference in theta activity was found across repeated cycles of reexposure. The results suggest that higher levels of interference in episodic memory are indexed by more theta band activity, and that successful interference resolution via inhibition causes a reduction in theta amplitude. Thus, theta band activity can serve as a neural marker of the dynamics of interference in selective episodic retrieval.

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Rats markedly escalate their intake and show a persistent susceptibility to reinstatement only when cocaine is injected rapidly.

Publication Date: 2010 Aug 25 PMID: 20739555
Authors: Wakabayashi, K. T. - Weiss, M. J. - Pickup, K. N. - Robinson, T. E.
Journal: J Neurosci

When drugs enter the brain rapidly, liability for addiction is increased, but why this is the case is not well understood. Here we examined the influence of varying the speed of intravenous cocaine delivery on self-administration behavior in rats given limited or extended opportunity to take drug. The speed of cocaine delivery had no effect on self-administration behavior when rats were given only 1 h each day to take cocaine. When given sixfold more time to take cocaine, rats that received cocaine rapidly (5-45 s) increased their total intake eightfold. However, rats that received cocaine more slowly (>90 s) did not avail themselves of the opportunity to take much more drug: they increased their intake only twofold. Furthermore, when tested 45 d after the last self-administration session, a drug-priming injection reinstated drug-seeking behavior only in rats that in the past had cocaine injected rapidly (5 s), and this was associated with a persistent suppression in the ability of cocaine to induce immediate early gene expression. Cocaine may be potentially more addictive when it reaches the brain rapidly because (1) this promotes a marked escalation in intake and (2) it renders individuals more susceptible to relapse long after the discontinuation of drug use. This is presumably because the rapid uptake of drug to the brain preferentially promotes persistent changes in brain systems that regulate motivation for drug, and continuing exposure to large amounts of drug produces a vicious cycle of additional maladaptive changes in brain and behavior.

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Dependence on a retinophilin/myosin complex for stability of PKC and INAD and termination of phototransduction.

Publication Date: 2010 Aug 25 PMID: 20739554
Authors: Venkatachalam, K. - Wasserman, D. - Wang, X. - Li, R. - Mills, E. - Elsaesser, R. - Li, H. S. - Montell, C.
Journal: J Neurosci

Normal termination of signaling is essential to reset signaling cascades, especially those such as phototransduction that are turned on and off with great rapidity. Genetic approaches in Drosophila led to the identification of several proteins required for termination, including protein kinase C (PKC), NINAC (neither inactivation nor afterpotential C) p174, which consists of fused protein kinase and myosin domains, and a PDZ (postsynaptic density-95/Discs Large/zona occludens-1) scaffold protein, INAD (inactivation no afterpotential D). Here, we describe a mutation affecting a poorly characterized but evolutionarily conserved protein, Retinophilin (Retin), which is expressed primarily in the phototransducing compartment of photoreceptor cells, the rhabdomeres. Retin and NINAC formed a complex and were mutually dependent on each other for expression. Loss of retin resulted in an age-dependent impairment in termination of phototransduction. Mutations that affect termination of the photoresponse typically lead to a reduction in levels of the major rhodopsin (Rh1) to attenuate signaling. Consistent with the slower termination in retin(1), the mutant photoreceptor cells exhibited increased endocytosis of Rh1 and a decline in Rh1 protein. The slower termination in retin(1) was a consequence of a cascade of defects, which began with the reduction in NINAC p174 levels. The diminished p174 concentration caused a decrease in INAD. Because PKC requires interaction with INAD for protein stability, this leads to reduction in PKC levels. The decline in PKC was age dependent and paralleled the onset of the termination phenotype in retin(1) mutant flies. We conclude that the slower termination of the photoresponse in retin(1) resulted from a requirement for the Retin/NINAC complex for stability of INAD and PKC.

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Dynamics of the Parkinsonian striatal microcircuit: entrainment into a dominant network state.

Publication Date: 2010 Aug 25 PMID: 20739553
Authors: Jaidar, O. - Carrillo-Reid, L. - Hernandez, A. - Drucker-Colin, R. - Bargas, J. - Hernandez-Cruz, A.
Journal: J Neurosci

Neuronal synchronization in basal ganglia circuits plays a key role in the encoding of movement, procedural memory storage and habit formation. Striatal dopamine (DA) depletion during Parkinsonism causes abnormal synchronization in corticobasal ganglia loops resulting in motor dysfunction. However, the dynamics of the striatal microcircuit underlying abnormal synchronization in Parkinsonism is poorly understood. Here we used targeted whole-cell recordings, calcium imaging allowing the recording from dozens of cells simultaneously and analytical approaches, to describe the striking alterations in network dynamics that the striatal microcircuit undergoes following DA depletion in a rat model of Parkinson disease (PD): In addition to a significant enhancement of basal neuronal activity frequent periods of spontaneous synchronization were observed. Multidimensional reduction techniques of vectorized network dynamics revealed that increased synchronization resulted from a dominant network state that absorbed most spontaneously active cells. Abnormal synchronous activity can be virtually abolished by glutamatergic antagonists, while blockade of GABAergic transmission facilitates the engagement of striatal cell assemblies in the dominant state. Finally, a dopaminergic receptor agonist was capable of uncoupling neurons from the dominant state. Abnormal synchronization and "locking" into a dominant state may represent the basic neuronal mechanism that underlies movement disorders at the microcircuit level.

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The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis-like ketamine responses.

Publication Date: 2010 Aug 25 PMID: 20739552
Authors: Sorce, S. - Schiavone, S. - Tucci, P. - Colaianna, M. - Jaquet, V. - Cuomo, V. - Dubois-Dauphin, M. - Trabace, L. - Krause, K. H.
Journal: J Neurosci

Subanesthetic doses of NMDA receptor antagonist ketamine induce schizophrenia-like symptoms in humans and behavioral changes in rodents. Subchronic administration of ketamine leads to loss of parvalbumin-positive interneurons through reactive oxygen species (ROS), generated by the NADPH oxidase NOX2. However, ketamine induces very rapid alterations, in both mice and humans. Thus, we have investigated the role of NOX2 in acute responses to subanesthetic doses of ketamine. In wild-type mice, ketamine caused rapid (30 min) behavioral alterations, release of neurotransmitters, and brain oxidative stress, whereas NOX2-deficient mice did not display such alterations. Decreased expression of the subunit 2A of the NMDA receptor after repetitive ketamine exposure was also precluded by NOX2 deficiency. However, neurotransmitter release and behavioral changes in response to amphetamine were not altered in NOX2-deficient mice. Our results suggest that NOX2 is a major source of ROS production in the prefrontal cortex controlling glutamate release and associated behavioral alterations after acute ketamine exposure. Prolonged NOX2-dependent glutamate release may lead to neuroadaptative downregulation of NMDA receptor subunits.

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Insulin reveals Akt signaling as a novel regulator of norepinephrine transporter trafficking and norepinephrine homeostasis.

Publication Date: 2010 Aug 25 PMID: 20739551
Authors: Robertson, S. D. - Matthies, H. J. - Owens, W. A. - Sathananthan, V. - Christianson, N. S. - Kennedy, J. P. - Lindsley, C. W. - Daws, L. C. - Galli, A.
Journal: J Neurosci

Noradrenergic signaling in the CNS plays an essential role in circuits involving attention, mood, memory, and stress as well as providing pivotal support for autonomic function in the peripheral nervous system. The high-affinity norepinephrine (NE) transporter (NET) is the primary mechanism by which noradrenergic synaptic transmission is terminated. Data indicate that NET function is regulated by insulin, a hormone critical for the regulation of metabolism. Given the high comorbidity of metabolic disorders such as diabetes and obesity with mental disorders such as depression and schizophrenia, we sought to determine how insulin signaling regulates NET function and thus noradrenergic homeostasis. Here, we show that acute insulin treatment, through the downstream kinase protein kinase B (Akt), significantly decreases NET surface expression in mouse hippocampal slices and superior cervical ganglion neuron boutons (sites of synaptic NE release). In vivo manipulation of insulin/Akt signaling, with streptozotocin, a drug that induces a type 1-like diabetic state in mice, also results in aberrant NET function and NE homeostasis. Notably, we also demonstrate that Akt inhibition or stimulation, independent of insulin, is capable of altering NET surface availability. These data suggest that aberrant states of Akt signaling such as in diabetes and obesity have the potential to alter NET function and noradrenergic tone in the brain. Furthermore, they provide one potential molecular mechanism by which Akt, a candidate gene for mood disorders such as schizophrenia and depression, can impact brain monoamine homeostasis.

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Direction opponency, not quadrature, is key to the 1/4 cycle preference for apparent motion in the motion energy model.

Publication Date: 2010 Aug 25 PMID: 20739550
Authors: Heess, N. - Bair, W.
Journal: J Neurosci

Sensitivity to visual motion is a fundamental property of neurons in the visual cortex and has received wide attention in terms of mathematical models. A key feature of many popular models for cortical motion sensors is the use of pairs of functions that are related by a 90 degrees phase shift. This phase relationship, known as quadrature, is the hallmark of the motion energy model and played an important role in the development of a class of model dubbed elaborated Reichardt detectors. For decades, the literature has supported a link between quadrature and the observation that motion detectors and human observers often prefer a 1/4 cycle displacement of an apparent motion stimulus that consists of a pair of sinusoidal gratings. We show that there is essentially no link between quadrature and this preference. Quadrature is neither necessary nor sufficient for a motion sensor to prefer 1/4 cycle displacement, and motion energy is not maximized for a 1/4 cycle step. Other properties of motion sensors are the key: the opponent subtraction of two oppositely tuned stages that individually have sinusoidal displacement tuning curves. Thus, psychophysical and neurophysiological data revealing a preference at or near 1/4 cycle displacement do not offer specific support for common quadrature or energy-based motion models. Instead, they point to a broader class of model.

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In vivo NMDA receptor activation accelerates motor unit maturation, protects spinal motor neurons, and enhances SMN2 gene expression in severe spinal muscular atrophy mice.

Publication Date: 2010 Aug 25 PMID: 20739549
Authors: Biondi, O. - Branchu, J. - Sanchez, G. - Lancelin, C. - Deforges, S. - Lopes, P. - Pariset, C. - Lecolle, S. - Cote, J. - Chanoine, C. - Charbonnier, F.
Journal: J Neurosci

Spinal muscular atrophy (SMA), a lethal neurodegenerative disease that occurs in childhood, is caused by the misexpression of the survival of motor neuron (SMN) protein in motor neurons. It is still unclear whether activating motor units in SMA corrects the delay in the postnatal maturation of the motor unit resulting in an enhanced neuroprotection. In the present work, we demonstrate that an adequate NMDA receptor activation in a type 2 SMA mouse model significantly accelerated motor unit postnatal maturation, counteracted apoptosis in the spinal cord, and induced a marked increase of SMN expression resulting from a modification of SMN2 gene transcription pattern. These beneficial effects were dependent on the level of NMDA receptor activation since a treatment with high doses of NMDA led to an acceleration of the motor unit maturation but favored the apoptotic process and decreased SMN expression. In addition, these results suggest that the NMDA-induced acceleration of motor unit postnatal maturation occurred independently of SMN. The NMDA receptor activating treatment strongly extended the life span in two different mouse models of severe SMA. The analysis of the intracellular signaling cascade that lay downstream the activated NMDA receptor revealed an unexpected reactivation of the CaMKII/AKT/CREB (cAMP response element-binding protein) pathway that induced an enhanced SMN expression. Therefore, pharmacological activation of spinal NMDA receptors could constitute a useful strategy for both increasing SMN expression and limiting motor neuron death in SMA spinal cord.

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Direct innervation and modulation of orexin neurons by lateral hypothalamic LepRb neurons.

Publication Date: 2010 Aug 25 PMID: 20739548
Authors: Louis, G. W. - Leinninger, G. M. - Rhodes, C. J. - Myers, M. G. Jr
Journal: J Neurosci

Leptin, the adipose-derived hormonal signal of body energy stores, acts via the leptin receptor (LepRb) on neurons in multiple brain regions. We previously identified LepRb neurons in the lateral hypothalamic area (LHA), which are distinct from neighboring leptin-regulated melanin-concentrating hormone (MCH)- or orexin (OX)-expressing cells. Neither the direct synaptic targets of LHA LepRb neurons nor their potential role in the regulation of other LHA neurons has been determined, however. We thus generated several adenoviral and transgenic systems in which cre recombinase promotes the expression of the tracer, WGA (wheat germ agglutinin), and used these in combination with LepRb(cre) mice to determine the neuronal targets of LHA LepRb neurons. This analysis revealed that, although some LHA LepRb neurons project to dopamine neurons in the ventral tegmental area, LHA LepRb neurons also densely innervate the LHA where they directly synapse with OX, but not MCH, neurons. Indeed, few other LepRb neurons in the brain project to the OX-containing region of the mouse LHA, and direct leptin action via LHA LepRb neurons regulates gene expression in OX neurons. These findings thus reveal a major role for LHA leptin action in the modulation of OX neurons, suggesting the importance of LHA LepRb neurons in the regulation of OX signaling that is crucial to leptin action and metabolic control.

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Beta-band activity during motor planning reflects response uncertainty.

Publication Date: 2010 Aug 25 PMID: 20739547
Authors: Tzagarakis, C. - Ince, N. F. - Leuthold, A. C. - Pellizzer, G.
Journal: J Neurosci

It has been known for many years that the power of beta-band oscillatory activity in motor-related brain regions decreases during the preparation and execution of voluntary movements. However, it is not clear yet whether the amplitude of this desynchronization is modulated by any parameter of the motor task. Here, we examined whether the degree of uncertainty about the upcoming movement direction modulated beta-band desynchronization during motor preparation. To this end, we recorded whole-head neuromagnetic signals while human subjects performed an instructed-delay reaching task with one, two, or three possible target directions. We found that the reduction of power of beta-band activity (16-28 Hz) during motor preparation was scaled relative to directional uncertainty. Furthermore, we show that the change of beta-band power correlates with the change of latency of response associated with response uncertainty. Finally, we show that the main source of beta-band desynchronization was located in the peri-Rolandic region. The results establish directional uncertainty as an important determinant of beta-band power during motor preparation and indicate that neural activity in the sensorimotor cortex during motor preparation covaries with directional uncertainty.

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Development and regeneration of sensory transduction in auditory hair cells requires functional interaction between cadherin-23 and protocadherin-15.

Publication Date: 2010 Aug 25 PMID: 20739546
Authors: Lelli, A. - Kazmierczak, P. - Kawashima, Y. - Muller, U. - Holt, J. R.
Journal: J Neurosci

Tip links are extracellular filaments that connect pairs of hair cell stereocilia and convey tension to mechanosensitive channels. Recent evidence suggests that tip links are formed by calcium-dependent interactions between the N-terminal domains of cadherin-23 (CDH23) and protocadherin-15 (PCDH15). Mutations in either CDH23 or PCDH15 cause deafness in mice and humans, indicating the molecules are required for normal inner ear function. However, there is little physiological evidence to support a direct role for CDH23 and PCDH15 in hair cell mechanotransduction. To investigate the contributions of CDH23 and PCDH15 to mechanotransduction and tip-link formation, we examined outer hair cells of mouse cochleas during development and after chemical disruption of tip links. We found that tip links and mechanotransduction with all the qualitative properties of mature transduction recovered within 24 h after disruption. To probe tip-link formation, we measured transduction currents after extracellular application of recombinant CDH23 and PCDH15 fragments, which included putative interaction domains (EC1). Both fragments inhibited development and regeneration of transduction but did not disrupt transduction in mature cells. PCDH15 fragments that carried a mutation in EC1 that causes deafness in humans did not inhibit transduction development or regeneration. Immunolocalization revealed wild-type fragments bound near the tips of hair cell stereocilia. Scanning electron micrographs revealed that hair bundles exposed to fragments had a reduced number of linkages aligned along the morphological axis of sensitivity of the bundle. Together, the data provide direct evidence implicating CDH23 and PCDH15 proteins in the formation of tip links during development and regeneration of mechanotransduction.

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Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease.

Publication Date: 2010 Aug 25 PMID: 20739545
Authors: Paris, D. - Ganey, N. - Banasiak, M. - Laporte, V. - Patel, N. - Mullan, M. - Murphy, S. F. - Yee, G. T. - Bachmeier, C. - Ganey, C. - Beaulieu-Abdelahad, D. - Mathura, V. S. - Brem, S. - Mullan, M.
Journal: J Neurosci

Alzheimer's disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of beta-amyloid (Abeta) peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and Abeta peptides which have been shown to be antiangiogenic. To determine whether angiogenesis is compromised in the brains of two transgenic mouse models of AD overproducing Abeta peptides (Tg APPsw and Tg PS1/APPsw mice), we assessed the growth and vascularization of orthotopically implanted murine gliomas since they require a high degree of angiogenesis to sustain their growth. Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared with their wild-type littermates. In addition, we show that Abeta inhibits the angiogenesis stimulated by glioma cells when cocultured with human brain microvascular cells on a Matrigel layer. Altogether our data suggest that the brain of transgenic mouse models of AD does not constitute a favorable environment to support neoangiogenesis and may explain why vascular insults synergistically precipitate the cognitive presentation of AD.

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Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses.

Publication Date: 2010 Aug 18 PMID: 20720132
Authors: Xia, P. - Chen, H. S. - Zhang, D. - Lipton, S. A.
Journal: J Neurosci

Glutamate is the major excitatory neurotransmitter in the brain. The NMDA subtype of glutamate receptors (NMDAR) is known to mediate many physiological neural functions. However, excessive activation of NMDARs contributes to neuronal damage in various acute and chronic neurological disorders. To avoid unwanted adverse side effects, blockade of excessive NMDAR activity must therefore be achieved without affecting its physiological function. Memantine, an adamantane derivative, has been used for the treatment of Alzheimer's disease with an excellent clinical safety profile. We previously showed that memantine preferentially blocked neurotoxicity mediated by excessive NMDAR activity while relatively sparing normal neurotransmission, in part because of its uncompetitive antagonism with a fast off-rate. Here, using rat autaptic hippocampal microcultures, we show that memantine at therapeutic concentrations (1-10 microM) preferentially blocks extrasynaptic rather than synaptic currents mediated by NMDARs in the same neuron. We found that memantine blocks extrasynaptic NMDAR-mediated currents induced by bath application of 100 microM NMDA/10 microM glycine with a twofold higher potency than its blockade of the NMDAR component of evoked EPSCs (EPSCs(NMDAR)); this effect persists under conditions of pathological depolarization in the presence of 1 mm extracellular Mg(2+). Thus, our findings provide the first unequivocal evidence to explain the tolerability of memantine based on differential extrasynaptic/synaptic receptor blockade. At therapeutic concentrations, memantine effectively blocks excessive extrasynaptic NMDAR-mediated currents, while relatively sparing normal synaptic activity.

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Precise spatiotemporal patterns among visual cortical areas and their relation to visual stimulus processing.

Publication Date: 2010 Aug 18 PMID: 20720131
Authors: Ayzenshtat, I. - Meirovithz, E. - Edelman, H. - Werner-Reiss, U. - Bienenstock, E. - Abeles, M. - Slovin, H.
Journal: J Neurosci

Visual processing shows a highly distributed organization in which the presentation of a visual stimulus simultaneously activates neurons in multiple columns across several cortical areas. It has been suggested that precise spatiotemporal activity patterns within and across cortical areas play a key role in higher cognitive, motor, and visual functions. In the visual system, these patterns have been proposed to take part in binding stimulus features into a coherent object, i.e., to be involved in perceptual grouping. Using voltage-sensitive dye imaging (VSDI) in behaving monkeys (Macaca fascicularis, males), we simultaneously measured neural population activity in the primary visual cortex (V1) and extrastriate cortex (V2, V4) at high spatial and temporal resolution. We detected time point population events (PEs) in the VSDI signal of each pixel and found that they reflect transient increased neural activation within local populations by establishing their relation to spiking and local field potential activity. Then, we searched for repeating space and time relations between the detected PEs. We demonstrate the following: (1) spatiotemporal patterns occurring within (horizontal) and across (vertical) early visual areas repeat significantly above chance level; (2) information carried in only a few patterns can be used to reliably discriminate between stimulus categories on a single-trial level; (3) the spatiotemporal patterns yielding high classification performance are characterized by late temporal occurrence and top-down propagation, which are consistent with cortical mechanisms involving perceptual grouping. The pattern characteristics and the robust relation between the patterns and the stimulus categories suggest that spatiotemporal activity patterns play an important role in cortical mechanisms of higher visual processing.

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Age-related deterioration of rod vision in mice.

Publication Date: 2010 Aug 18 PMID: 20720130
Authors: Kolesnikov, A. V. - Fan, J. - Crouch, R. K. - Kefalov, V. J.
Journal: J Neurosci

Even in healthy individuals, aging leads to deterioration in visual acuity, contrast sensitivity, visual field, and dark adaptation. Little is known about the neural mechanisms that drive the age-related changes of the retina and, more specifically, photoreceptors. According to one hypothesis, the age-related deterioration in rod function is due to the limited availability of 11-cis-retinal for rod pigment formation. To determine how aging affects rod photoreceptors and to test the retinoid-deficiency hypothesis, we compared the morphological and functional properties of rods of adult and aged B6D2F1/J mice. We found that the number of rods and the length of their outer segments were significantly reduced in 2.5-year-old mice compared with 4-month-old animals. Aging also resulted in a twofold reduction in the total level of opsin in the retina. Behavioral tests revealed that scotopic visual acuity and contrast sensitivity were decreased by twofold in aged mice, and rod ERG recordings demonstrated reduced amplitudes of both a- and b-waves. Sensitivity of aged rods determined from single-cell recordings was also decreased by 1.5-fold, corresponding to not more than 1% free opsin in these photoreceptors, and kinetic parameters of dim flash response were not altered. Notably, the rate of rod dark adaptation was unaffected by age. Thus, our results argue against age-related deficiency of 11-cis-retinal in the B6D2F1/J mouse rod visual cycle. Surprisingly, the level of cellular dark noise was increased in aged rods, providing an alternative mechanism for their desensitization.

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A temporal hierarchy for conspecific vocalization discrimination in humans.

Publication Date: 2010 Aug 18 PMID: 20720129
Authors: De Lucia, M. - Clarke, S. - Murray, M. M.
Journal: J Neurosci

The ability to discriminate conspecific vocalizations is observed across species and early during development. However, its neurophysiologic mechanism remains controversial, particularly regarding whether it involves specialized processes with dedicated neural machinery. We identified spatiotemporal brain mechanisms for conspecific vocalization discrimination in humans by applying electrical neuroimaging analyses to auditory evoked potentials (AEPs) in response to acoustically and psychophysically controlled nonverbal human and animal vocalizations as well as sounds of man-made objects. AEP strength modulations in the absence of topographic modulations are suggestive of statistically indistinguishable brain networks. First, responses were significantly stronger, but topographically indistinguishable to human versus animal vocalizations starting at 169-219 ms after stimulus onset and within regions of the right superior temporal sulcus and superior temporal gyrus. This effect correlated with another AEP strength modulation occurring at 291-357 ms that was localized within the left inferior prefrontal and precentral gyri. Temporally segregated and spatially distributed stages of vocalization discrimination are thus functionally coupled and demonstrate how conventional views of functional specialization must incorporate network dynamics. Second, vocalization discrimination is not subject to facilitated processing in time, but instead lags more general categorization by approximately 100 ms, indicative of hierarchical processing during object discrimination. Third, although differences between human and animal vocalizations persisted when analyses were performed at a single-object level or extended to include additional (man-made) sound categories, at no latency were responses to human vocalizations stronger than those to all other categories. Vocalization discrimination transpires at times synchronous with that of face discrimination but is not functionally specialized.

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Presynaptic kainate receptor activation preserves asynchronous GABA release despite the reduction in synchronous release from hippocampal cholecystokinin interneurons.

Publication Date: 2010 Aug 18 PMID: 20720128
Authors: Daw, M. I. - Pelkey, K. A. - Chittajallu, R. - McBain, C. J.
Journal: J Neurosci

Inhibitory synaptic transmission in the hippocampus in mediated by a wide variety of different interneuron classes which are assumed to play different roles in network activity. Activation of presynaptic kainate receptors (KARs) has been shown to reduce inhibitory transmission but the interneuron class(es) at which they act is only recently beginning to emerge. Using paired recordings we show that KAR activation causes a decrease in presynaptic release from cholecystokinin (CCK)- but not parvalbumin-containing interneurons and that this decrease is observed when pyramidal cells, but not interneurons, are the postsynaptic target. We also show that although the synchronous release component is reduced, the barrage of asynchronous GABA release from CCK interneurons during sustained firing is unaffected by KAR activation. This indicates that presynaptic KARs preserve and act in concert with asynchronous release to switch CCK interneurons from a phasic inhibition mode to produce prolonged inhibition during periods of intense activity.

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Direction-selective ganglion cells show symmetric participation in retinal waves during development.

Publication Date: 2010 Aug 18 PMID: 20720127
Authors: Elstrott, J. - Feller, M. B.
Journal: J Neurosci

Direction-selective ganglion cells (DSGCs) fire robustly for stimuli moving along one direction of motion and are strongly inhibited by stimuli moving in the opposite, or null, direction. In contrast to direction-selective neurons in primary visual cortex, a role for neural activity in the development of direction-selective retinal circuits has not been established. Direction-selective responses are detected at eye opening, before which spontaneous correlated activity known as retinal waves provide directional input to ganglion cells. Indeed, we observed a significant bias in wave propagation along the nasal over temporal direction. Using simultaneous calcium imaging and cell-attached recordings from three genetically labeled DSGC types in mice, we observed that all three DSGC types fire action potentials during retinal waves. However, we found that the direction of wave propagation did not influence DSGC spiking. These results indicate that the mechanisms guiding the formation of the asymmetric inhibition underlying direction selectivity in the retina are not dependent upon the directional properties of retinal waves.

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Repeated stress impairs endocannabinoid signaling in the paraventricular nucleus of the hypothalamus.

Publication Date: 2010 Aug 18 PMID: 20720126
Authors: Wamsteeker, J. I. - Kuzmiski, J. B. - Bains, J. S.
Journal: J Neurosci

Endocannabinoids (eCBs) are ubiquitous retrograde signaling molecules in the nervous system that are recruited in response to robust neuronal activity or the activation of postsynaptic G-protein-coupled receptors. Physiologically, eCBs have been implicated as important mediators of the stress axis and they may contribute to the rapid feedback inhibition of the hypothalamic-pituitary-adrenal axis (HPA) by circulating corticosteroids (CORTs). Understanding the relationship between stress and eCBs, however, is complicated by observations that eCB signaling is itself sensitive to stress. The mechanisms that link stress to changes in synaptic eCB signaling and the impact of these changes on CORT-mediated negative feedback have not been resolved. Here, we show that repetitive immobilization stress, in juvenile male rats, causes a functional downregulation of CB(1) receptors in the paraventricular nucleus of the hypothalamus (PVN). This loss of CB(1) receptor signaling, which requires the activation of genomic glucocorticoid receptors, impairs both activity and receptor-dependent eCB signaling at GABA and glutamate synapses on parvocellular neuroendocrine cells in PVN. Our results provide a plausible mechanism for how stress can lead to alterations in CORT-mediated negative feedback and may contribute to the development of plasticity of HPA responses.

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Implicit perceptual anticipation triggered by statistical learning.

Publication Date: 2010 Aug 18 PMID: 20720125
Authors: Turk-Browne, N. B. - Scholl, B. J. - Johnson, M. K. - Chun, M. M.
Journal: J Neurosci

Our environments are highly regular in terms of when and where objects appear relative to each other. Statistical learning allows us to extract and represent these regularities, but how this knowledge is used by the brain during ongoing perception is unclear. We used rapid event-related fMRI to measure hemodynamic responses to individual visual images in a continuous stream that contained sequential contingencies. Sixteen human observers encountered these statistical regularities while performing an unrelated cognitive task, and were unaware of their existence. Nevertheless, the right anterior hippocampus showed greater hemodynamic responses to predictive stimuli, providing evidence for implicit anticipation as a consequence of unsupervised statistical learning. Hippocampal anticipation based on predictive stimuli correlated with subsequent processing of the predicted stimuli in occipital and parietal cortex, and anticipation in additional brain regions correlated with facilitated object recognition as reflected in behavioral priming. Additional analyses suggested that implicit perceptual anticipation does not contribute to explicit familiarity, but can result in predictive potentiation of category-selective ventral visual cortex. Overall, these findings show that future-oriented processing can arise incidentally during the perception of statistical regularities.

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Sonic hedgehog guides post-crossing commissural axons both directly and indirectly by regulating Wnt activity.

Publication Date: 2010 Aug 18 PMID: 20720124
Authors: Domanitskaya, E. - Wacker, A. - Mauti, O. - Baeriswyl, T. - Esteve, P. - Bovolenta, P. - Stoeckli, E. T.
Journal: J Neurosci

After midline crossing, axons of dorsolateral commissural neurons turn rostrally into the longitudinal axis of the spinal cord. In mouse, the graded distribution of Wnt4 attracts post-crossing axons rostrally. In contrast, in the chicken embryo, the graded distribution of Sonic hedgehog (Shh) guides post-crossing axons by a repulsive mechanism mediated by hedgehog-interacting protein. Based on these observations, we tested for a possible cooperation between the two types of morphogens. Indeed, we found that Wnts also act as axon guidance cues in the chicken spinal cord. However, in contrast to the mouse, Wnt transcription did not differ along the anteroposterior axis of the spinal cord. Rather, Wnt function was regulated by a gradient of the Wnt antagonist Sfrp1 (Secreted frizzled-related protein 1) that in turn was shaped by the Shh gradient. Thus, Shh affects post-crossing axon guidance both directly and indirectly by regulating Wnt function.

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A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease.

Publication Date: 2010 Aug 18 PMID: 20720123
Authors: Fukumoto, H. - Takahashi, H. - Tarui, N. - Matsui, J. - Tomita, T. - Hirode, M. - Sagayama, M. - Maeda, R. - Kawamoto, M. - Hirai, K. - Terauchi, J. - Sakura, Y. - Kakihana, M. - Kato, K. - Iwatsubo, T. - Miyamoto, M.
Journal: J Neurosci

We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.

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Motoneurons dedicated to either forward or backward locomotion in the nematode Caenorhabditis elegans.

Publication Date: 2010 Aug 18 PMID: 20720122
Authors: Haspel, G. - O'Donovan, M. J. - Hart, A. C.
Journal: J Neurosci

Multifunctional motoneurons and muscles, which are active during forward and backward locomotion are ubiquitous in animal models. However, studies in the nematode Caenorhabditis elegans suggest that some locomotor motoneurons are necessary only for forward locomotion (dorsal B-motoneurons, DB), while others (dorsal A-motoneurons, DA) are necessary only for backward locomotion. We tested this hypothesis directly by recording the activity of these motoneurons during semirestrained locomotion. For this purpose, we used epifluorescence imaging of the genetically encoded calcium sensor cameleon, expressed in specific motoneurons, while monitoring locomotor behavior through the microscope condenser using a second camera. We found that ventral and dorsal B-motoneurons (DB and VB) were coactive during forward locomotion while ventral A-motoneurons (VA) were only active during backward locomotion. The signals we recorded correlated with the direction of locomotion but not with the faster undulatory cycles. To our knowledge, these are the first recordings of motoneuron activity in C. elegans and the only direction-dedicated motoneurons described to date.

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Stability of the visual world during eye drift.

Publication Date: 2010 Aug 18 PMID: 20720121
Authors: Poletti, M. - Listorti, C. - Rucci, M.
Journal: J Neurosci

We are normally not aware of the microscopic eye movements that keep the retinal image in motion during visual fixation. In principle, perceptual cancellation of the displacements of the retinal stimulus caused by fixational eye movements could be achieved either by means of motor/proprioceptive information or by inferring eye movements directly from the retinal stimulus. In this study, we examined the mechanisms underlying visual stability during ocular drift, the primary source of retinal image motion during fixation on a stationary scene. By using an accurate system for gaze-contingent display control, we decoupled the eye movements of human observers from the changes in visual input that they normally cause. We show that the visual system relies on the spatiotemporal stimulus on the retina, rather than on extraretinal information, to discard the motion signals resulting from ocular drift. These results have important implications for the establishment of stable visual representations in the brain and argue that failure to visually determine eye drift contributes to well known motion illusions such as autokinesis and induced movement.

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Intrinsic circuit organization and theta-gamma oscillation dynamics in the entorhinal cortex of the rat.

Publication Date: 2010 Aug 18 PMID: 20720120
Authors: Quilichini, P. - Sirota, A. - Buzsaki, G.
Journal: J Neurosci

A thorough knowledge of the intrinsic circuit properties of the entorhinal cortex (EC) and the temporal dynamics these circuits support is essential for understanding how information is exchanged between the hippocampus and neocortex. Using intracellular and extracellular recordings in the anesthetized rat and anatomical reconstruction of single cells, we found that EC5 and EC2 principal neurons form large axonal networks mainly within their layers, interconnected by the more vertically organized axon trees of EC3 pyramidal cells. Principal cells showed layer-specific unique membrane properties and contributed differentially to theta and gamma oscillations. EC2 principal cells were most strongly phase modulated by EC theta. The multiple gamma oscillators, present in the various EC layers, were temporally coordinated by the phase of theta waves. Putative interneurons in all EC layers fired relatively synchronously within the theta cycle, coinciding with the maximum power of gamma oscillation. The special wiring architecture and unique membrane properties of EC neurons may underlie their behaviorally distinct firing patterns in the waking animal.

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Spectral integration in primary auditory cortex attributable to temporally precise convergence of thalamocortical and intracortical input.

Publication Date: 2010 Aug 18 PMID: 20720119
Authors: Happel, M. F. - Jeschke, M. - Ohl, F. W.
Journal: J Neurosci

Primary sensory cortex integrates sensory information from afferent feedforward thalamocortical projection systems and convergent intracortical microcircuits. Both input systems have been demonstrated to provide different aspects of sensory information. Here we have used high-density recordings of laminar current source density (CSD) distributions in primary auditory cortex of Mongolian gerbils in combination with pharmacological silencing of cortical activity and analysis of the residual CSD, to dissociate the feedforward thalamocortical contribution and the intracortical contribution to spectral integration. We found a temporally highly precise integration of both types of inputs when the stimulation frequency was in close spectral neighborhood of the best frequency of the measurement site, in which the overlap between both inputs is maximal. Local intracortical connections provide both directly feedforward excitatory and modulatory input from adjacent cortical sites, which determine how concurrent afferent inputs are integrated. Through separate excitatory horizontal projections, terminating in cortical layers II/III, information about stimulus energy in greater spectral distance is provided even over long cortical distances. These projections effectively broaden spectral tuning width. Based on these data, we suggest a mechanism of spectral integration in primary auditory cortex that is based on temporally precise interactions of afferent thalamocortical inputs and different short- and long-range intracortical networks. The proposed conceptual framework allows integration of different and partly controversial anatomical and physiological models of spectral integration in the literature.

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Nuclear factor kappaB controls acetylcholine receptor clustering at the neuromuscular junction.

Publication Date: 2010 Aug 18 PMID: 20720118
Authors: Wang, J. - Fu, X. Q. - Lei, W. L. - Wang, T. - Sheng, A. L. - Luo, Z. G.
Journal: J Neurosci

At the vertebrate neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is stimulated by motor neuron-derived glycoprotein Agrin and requires a number of intracellular signal or structural proteins, including AChR-associated scaffold protein Rapsyn. Here, we report a role of nuclear factor kappaB (NF-kappaB), a well known transcription factor involved in a variety of immune responses, in regulating AChR clustering at the NMJ. We found that downregulating the expression of RelA/p65 subunit of NF-kappaB or inhibiting NF-kappaB activity by overexpression of mutated form of IkappaB (inhibitor kappaB), which is resistant to proteolytic degradation and thus constitutively keeps NF-kappaB inactive in the cytoplasma, impeded the formation of AChR clusters in cultured C2C12 muscle cells stimulated by Agrin. In contrast, overexpression of RelA/p65 promoted AChR clustering. Furthermore, we investigated the mechanism by which NF-kappaB regulates AChR clustering. Interestingly, we found that downregulating the expression of RelA/p65 caused a marked reduction in the protein and mRNA level of Rapsyn and upregulation of RelA/p65 enhanced Rapsyn promoter activity. Mutation of NF-kappaB binding site on Rapsyn promoter prevented responsiveness to RelA/p65 regulation. Moreover, forced expression of Rapsyn in RelA/p65 downregulated muscle cells partially rescued AChR clusters, suggesting that NF-kappaB regulates AChR clustering, at least partially through the transcriptional regulation of Rapsyn. In line with this notion, genetic ablation of RelA/p65 selectively in the skeletal muscle caused a reduction of AChR density at the NMJ and a decrease in the level of Rapsyn. Thus, NF-kappaB signaling controls AChR clustering through transcriptional regulation of synaptic protein Rapsyn.

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Reward changes salience in human vision via the anterior cingulate.

Publication Date: 2010 Aug 18 PMID: 20720117
Authors: Hickey, C. - Chelazzi, L. - Theeuwes, J.
Journal: J Neurosci

Reward-related mesolimbic dopamine steers animal behavior, creating automatic approach toward reward-associated objects and avoidance of objects unlikely to be beneficial. Theories of dopamine suggest that this reflects underlying biases in perception and attention, with reward enhancing the representation of reward-associated stimuli such that attention is more likely to be deployed to the location of these objects. Using measures of behavior and brain electricity in male and female humans, we demonstrate this to be the case. Sensory and perceptual processing of reward-associated visual features is facilitated such that attention is deployed to objects characterized by these features in subsequent experimental trials. This is the case even when participants know that a strategic decision to attend to reward-associated features will be counterproductive and result in suboptimal performance. Other results show that the magnitude of visual bias created by reward is predicted by the response to reward feedback in anterior cingulate cortex, an area with strong connections to dopaminergic structures in the midbrain. These results demonstrate that reward has an impact on vision that is independent of its role in the strategic establishment of endogenous attention. We suggest that reward acts to change visual salience and thus plays an important and undervalued role in attentional control.

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Structural dynamics of synapses in vivo correlate with functional changes during experience-dependent plasticity in visual cortex.

Publication Date: 2010 Aug 18 PMID: 20720116
Authors: Tropea, D. - Majewska, A. K. - Garcia, R. - Sur, M.
Journal: J Neurosci

The impact of activity on neuronal circuitry is complex, involving both functional and structural changes whose interaction is largely unknown. We have used optical imaging of mouse visual cortex responses and two-photon imaging of superficial layer spines on layer 5 neurons to monitor network function and synaptic structural dynamics in the mouse visual cortex in vivo. Total lack of vision due to dark-rearing from birth dampens visual responses and shifts spine dynamics and morphologies toward an immature state. The effects of vision after dark rearing are strongly dependent on the timing of exposure: over a period of days, functional and structural changes are temporally related such that light stabilizes spines while increasing visually driven activity. The effects of long-term light exposure can be partially mimicked by experimentally enhancing inhibitory signaling in the darkness. Brief light exposure, however, results in a rapid, transient, NMDA-dependent increase of cortical responses, accompanied by increased dynamics of dendritic spines. These findings indicate that visual experience induces rapid reorganization of cortical circuitry followed by a period of stabilization, and demonstrate a close relationship between dynamic changes at single synapses and cortical network function.

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The postsynaptic adenomatous polyposis coli (APC) multiprotein complex is required for localizing neuroligin and neurexin to neuronal nicotinic synapses in vivo.

Publication Date: 2010 Aug 18 PMID: 20720115
Authors: Rosenberg, M. M. - Yang, F. - Mohn, J. L. - Storer, E. K. - Jacob, M. H.
Journal: J Neurosci

Synaptic efficacy requires that presynaptic and postsynaptic specializations align precisely and mature coordinately. The underlying mechanisms are poorly understood, however. We propose that adenomatous polyposis coli protein (APC) is a key coordinator of presynaptic and postsynaptic maturation. APC organizes a multiprotein complex that directs nicotinic acetylcholine receptor (nAChR) localization at postsynaptic sites in avian ciliary ganglion neurons in vivo. We hypothesize that the APC complex also provides retrograde signals that direct presynaptic active zones to develop in register with postsynaptic nAChR clusters. In our model, the APC complex provides retrograde signals via postsynaptic neuroligin that interacts extracellularly with presynaptic neurexin. S-SCAM (synaptic cell adhesion molecule) and PSD-93 (postsynaptic density-93) are scaffold proteins that bind to neuroligin. We identify S-SCAM as a novel component of neuronal nicotinic synapses. We show that S-SCAM, PSD-93, neuroligin and neurexin are enriched at alpha3*-nAChR synapses. PSD-93 and S-SCAM bind to APC and its binding partner beta-catenin, respectively. Blockade of selected APC and beta-catenin interactions, in vivo, leads to decreased postsynaptic accumulation of S-SCAM, but not PSD-93. Importantly, neuroligin synaptic clusters are also decreased. On the presynaptic side, there are decreases in neurexin and active zone proteins. Further, presynaptic terminals are less mature structurally and functionally. We define a novel neural role for APC by showing that the postsynaptic APC multiprotein complex is required for anchoring neuroligin and neurexin at neuronal synapses in vivo. APC human gene mutations correlate with autism spectrum disorders, providing strong support for the importance of the association, demonstrated here, between APC, neuroligin and neurexin.

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The scaffold protein NHERF2 determines the coupling of P2Y1 nucleotide and mGluR5 glutamate receptor to different ion channels in neurons.

Publication Date: 2010 Aug 18 PMID: 20720114
Authors: Filippov, A. K. - Simon, J. - Barnard, E. A. - Brown, D. A.
Journal: J Neurosci

Expressed metabotropic group 1 glutamate mGluR5 receptors and nucleotide P2Y1 receptors (P2Y1Rs) show promiscuous ion channel coupling in sympathetic neurons: their stimulation inhibits M-type [Kv7, K(M)] potassium currents and N-type (Ca(V)2.2) calcium currents (Kammermeier and Ikeda, 1999; Brown et al., 2000). These effects are mediated by G(q) and G(i/o) G-proteins, respectively. Via their C-terminal tetrapeptide, these receptors also bind to the PDZ domain of the scaffold protein NHERF2, which enhances their coupling to G(q)-mediated Ca(2+) signaling (Fam et al., 2005; Paquet et al., 2006b). We investigated whether NHERF2 could modulate coupling to neuronal ion channels. We find that coexpression of NHERF2 in sympathetic neurons (by intranuclear cDNA injections) does not affect the extent of M-type potassium current inhibition produced by either receptor but strongly reduced Ca(V)2.2 inhibition by both P2Y1R and mGluR5 activation. NHERF2 expression had no significant effect on Ca(V)2.2 inhibition by norepinephrine (via alpha(2)-adrenoceptors, which do not bind NHERF2), nor on Ca(V)2.2 inhibition produced by an expressed P2Y1R lacking the NHERF2-binding DTSL motif. Thus, NHERF2 selectively restricts downstream coupling of mGluR5 and P2Y1Rs in neurons to G(q)-mediated responses such as M-current inhibition. Differential distribution of NHERF2 in neurons may therefore determine coupling of mGluR5 receptors and P2Y1 receptors to calcium channels.

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Longitudinal evidence for functional specialization of the neural circuit supporting working memory in the human brain.

Publication Date: 2010 Aug 18 PMID: 20720113
Authors: Finn, A. S. - Sheridan, M. A. - Kam, C. L. - Hinshaw, S. - D'Esposito, M.
Journal: J Neurosci

Although children perform more poorly than adults on many cognitive measures, they are better able to learn things such as language and music. These differences could result from the delayed specialization of neural circuits and asynchronies in the maturation of neural substrates required for learning. Working memory--the ability to hold information in mind that is no longer present in the environment--comprises a set of cognitive processes required for many, if not all, forms of learning. A critical neural substrate for working memory (the prefrontal cortex) continues to mature through early adulthood. What are the functional consequences of this late maturation for working memory? Using a longitudinal design, we show that although individuals recruit prefrontal cortex as expected during both early and late adolescence during a working memory task, this recruitment is correlated with behavior only in late adolescence. The hippocampus is also recruited, but only during early, and not late, adolescence. Moreover, the hippocampus and prefrontal cortex are coactive in early adolescence regardless of task demands or performance, in contrast to the pattern seen in late adolescents and adults, when these regions are coactive only under high task demands. Together, these data demonstrate that neural circuitry underlying working memory changes during adolescent development. The diminishing contribution of the hippocampus in working memory function with age is an important observation that informs questions about how children and adults learn differently.

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Impaired speech repetition and left parietal lobe damage.

Publication Date: 2010 Aug 18 PMID: 20720112
Authors: Fridriksson, J. - Kjartansson, O. - Morgan, P. S. - Hjaltason, H. - Magnusdottir, S. - Bonilha, L. - Rorden, C.
Journal: J Neurosci

Patients with left hemisphere damage and concomitant aphasia usually have difficulty repeating others' speech. Although impaired speech repetition, the primary symptom of conduction aphasia, has been associated with involvement of the left arcuate fasciculus, its specific lesion correlate remains elusive. This research examined speech repetition among 45 stroke patients who underwent aphasia testing and MRI examination. Based on lesion-behavior mapping, the primary structural damage most closely associated with impaired speech repetition was found in the posterior portion of the left arcuate fasciculus. However, perfusion-weighted MRI revealed that tissue dysfunction, in the form of either frank damage or hypoperfusion, to the left inferior parietal lobe, rather than the underlying white matter, was associated with impaired speech repetition. This latter result suggests that integrity of the left inferior parietal lobe is important for speech repetition and, as importantly, highlights the importance of examining cerebral perfusion for the purpose of lesion-behavior mapping in acute stroke.

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Role of aberrant striatal dopamine D1 receptor/cAMP/protein kinase A/DARPP32 signaling in the paradoxical calming effect of amphetamine.

Publication Date: 2010 Aug 18 PMID: 20720111
Authors: Napolitano, F. - Bonito-Oliva, A. - Federici, M. - Carta, M. - Errico, F. - Magara, S. - Martella, G. - Nistico, R. - Centonze, D. - Pisani, A. - Gu, H. H. - Mercuri, N. B. - Usiello, A.
Journal: J Neurosci

Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP32) at Thr75 residue, but preserved D(2) receptor (D(2)R) function. However, although we demonstrated that striatal D(1) receptor (D(1)R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D(2)R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D(1)R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels.

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The muscarinic long-term enhancement of NMDA and AMPA receptor-mediated transmission at schaffer collateral synapses develop through different intracellular mechanisms.

Publication Date: 2010 Aug 18 PMID: 20720110
Authors: Fernandez de Sevilla, D. - Buno, W.
Journal: J Neurosci

We had described a muscarinic-mediated long-term synaptic enhancement at Schaffer collateral synapses caused by the insertion of AMPARs in spines of rat hippocampal CA1 pyramidal neurons that requires Ca(2+) release from IP3-sensitive stores (Fernandez de Sevilla et al., 2008). We now show that this AMPA-mediated LTP(IP3) is precisely matched by an amplification of NMDAR-mediated transmission. The enhanced AMPAR transmission involves SNARE protein activity and CaMKII activation. The amplification of NMDA transmission requires combined CaMKII, PKC, and SRC kinase activity without detectable surface incorporation of NMDARs, suggesting that changes in receptor properties mediate this process. The enhanced AMPAR- and NMDAR-mediated transmission markedly reduce the induction threshold of "Hebbian" LTP. We conclude that both modes of glutamatergic synaptic potentiation may play a critical functional role in the regulation of the learning machinery of the brain by adding flexibility to the demands of the hippocampal network.

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Lobster attack induces sensitization in the sea hare, Aplysia californica.

Publication Date: 2010 Aug 18 PMID: 20720109
Authors: Watkins, A. J. - Goldstein, D. A. - Lee, L. C. - Pepino, C. J. - Tillett, S. L. - Ross, F. E. - Wilder, E. M. - Zachary, V. A. - Wright, W. G.
Journal: J Neurosci

Studies of the neural mechanisms of learning, especially of sensitization, have benefitted from extensive research on the model species, Aplysia californica (hereafter Aplysia). Considering this volume of literature on mechanisms, it is surprising that our understanding of the ecological context of sensitization in Aplysia is completely lacking. Indeed, the widespread use of strong electric shock to induce sensitization (an enhancement of withdrawal reflexes following noxious stimulation) is completely unnatural and leaves unanswered the question of whether this simple form of learning has any ecological relevance. We hypothesized that sublethal attack by a co-occurring predator, the spiny lobster, Panulirus interruptus, might be a natural sensitizing stimulus. We tested reflex withdrawal of the tail-mantle and head of individual Aplysia before and after attack by lobsters. Lobster attack significantly increased the amplitude of both reflexes, with a temporal onset that closely matched that observed with electric shock. This result suggests that electric shock may indeed mimic at least one naturally occurring sensitizing stimulus, suggesting, for the first time, an ecological context for this well studied form of learning.

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Mechanisms of regulation of oligodendrocyte development by p38 mitogen-activated protein kinase.

Publication Date: 2010 Aug 18 PMID: 20720108
Authors: Chew, L. J. - Coley, W. - Cheng, Y. - Gallo, V.
Journal: J Neurosci

Many extracellular and intrinsic factors regulate oligodendrocyte development, but their signaling pathways remain poorly understood. Although the p38 mitogen-activated protein kinase (MAPK)-dependent pathway is implicated in oligodendrocyte progenitor cell (OPC) lineage progression, its molecular targets involved in myelinogenesis are mostly unidentified. We have analyzed mechanisms by which p38MAPK regulates oligodendrocyte development and demonstrate that p38MAPK inhibition prevents OPC lineage progression and inhibits MBP (myelin basic protein) promoter activity and Sox10 function. In white-matter tissue, differential levels of MAPK phosphorylation are observed in oligodendrocyte lineage cells. Phosphorylated p38MAPK was found in CC1- and CNP-expressing differentiated oligodendrocytes of the adult brain and was temporally associated with a decline in the levels of phosphorylated extracellular signal-regulated kinase (ERK) in cells of this lineage. PDGF stimulates the phosphorylation of ERK, p38MAPK, and c-Jun N-terminal kinase (JNK), and p38MAPK inhibition was associated with increased ERK, JNK, and c-Jun phosphorylation. In the presence of PDGF, simultaneous inhibition of p38MAPK and either MAPK kinase (MEK) or JNK significantly alleviates the repression of myelin gene expression and lineage progression induced by p38MAPK inhibition alone. Dominant-negative c-Jun reverses the inhibition of myelin promoter activity by active MEK1 or dominant-negative p38MAPKalpha mutants, and phosphorylated c-Jun was detected at the MBP promoter after p38MAPK inhibition, indicating c-Jun as a negative mediator of p38MAPK action. Our findings indicate that p38MAPK activity in the brain supports myelin gene expression through distinct mechanisms via positive and negative regulatory targets. We show that oligodendrocyte differentiation involves p38-mediated Sox10 regulation and cross talk with parallel ERK and JNK pathways to repress c-Jun activity.

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The alpha-syntrophin PH and PDZ domains scaffold acetylcholine receptors, utrophin, and neuronal nitric oxide synthase at the neuromuscular junction.

Publication Date: 2010 Aug 18 PMID: 20720107
Authors: Adams, M. E. - Anderson, K. N. - Froehner, S. C.
Journal: J Neurosci

At the neuromuscular junction (NMJ), the dystrophin protein complex provides a scaffold that functions to stabilize acetylcholine receptor (AChR) clusters. Syntrophin, a key component of that scaffold, is a multidomain adapter protein that links a variety of signaling proteins and ion channels to the dystrophin protein complex. Without syntrophin, utrophin and neuronal nitric oxide synthase mu (nNOSmu) fail to localize to the NMJ and the AChRs are distributed abnormally. Here we investigate the contribution of syntrophin domains to AChR distribution and to localization of utrophin and nNOSmu at the NMJ. Transgenic mice expressing alpha-syntrophin lacking portions of the first pleckstrin homology (PH) domain (DeltaPH1a or DeltaPH1b) or the entire PDZ domain (DeltaPDZ) were bred onto the alpha-syntrophin null background. As expected the DeltaPDZ transgene did not restore the NMJ localization of nNOS. The DeltaPH1a transgene did restore postsynaptic nNOS but surprisingly did not restore sarcolemmal nNOS (although sarcolemmal aquaporin-4 was restored). Mice lacking the alpha-syntrophin PDZ domain or either half of the PH1 domain were able to restore utrophin to the NMJ but did not correct the aberrant AChR distribution of the alpha-syntrophin knock-out mice. However, mice expressing both the transgenic DeltaPDZ and the transgenic DeltaPH1a constructs did restore normal AChR distribution, demonstrating that both domains are required but need not be confined within the same protein to function. We conclude that the PH1 and PDZ domains of alpha-syntrophin work in concert to facilitate the localization of AChRs and nNOS at the NMJ.

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Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

Publication Date: 2010 Aug 18 PMID: 20720106
Authors: Villette, V. - Poindessous-Jazat, F. - Simon, A. - Lena, C. - Roullot, E. - Bellessort, B. - Epelbaum, J. - Dutar, P. - Stephan, A.
Journal: J Neurosci

The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

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The development of the corpus callosum in the healthy human brain.

Publication Date: 2010 Aug 18 PMID: 20720105
Authors: Luders, E. - Thompson, P. M. - Toga, A. W.
Journal: J Neurosci

The corpus callosum changes structurally throughout life, but most dramatically during childhood and adolescence. Even so, existing studies of callosal development tend to use parcellation schemes that may not capture the complex spatial profile of anatomical changes. Thus, more detailed mapping of callosal growth processes is desirable to create a normative reference. This will help to relate and interpret other structural, functional, and behavioral measurements, both from healthy subjects and pediatric patients. We applied computational surface-based mesh-modeling methods to analyze callosal morphology at extremely high spatial resolution. We mapped callosal development and explored sex differences in a large and well matched sample of healthy children and adolescents (n = 190) aged 5-18 years. Except for the rostrum in females, callosal thickness increased across the whole surface, with sex- and region-specific rates of growth, and at times shrinkage. The temporally distinct changes in callosal thickness are likely to be a consequence of varying degrees of axonal myelination, redirection, and pruning. Alternating phases of callosal growth and shrinkage may reflect a permanent adjustment and fine-tuning of fibers connecting homologous cortical areas during childhood and adolescence. Our findings emphasize the importance of taking into account sex differences in future studies, as existing developmental effects might remain disguised (or biased toward the effect of the dominant sex in unbalanced statistical designs) when pooling male and female samples.

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Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome.

Publication Date: 2010 Aug 18 PMID: 20720104
Authors: Chen, L. Y. - Rex, C. S. - Babayan, A. H. - Kramar, E. A. - Lynch, G. - Gall, C. M. - Lauterborn, J. C.
Journal: J Neurosci

The abnormal spine morphology found in fragile X syndrome (FXS) is suggestive of an error in the signaling cascades that organize the actin cytoskeleton. We report here that physiological activation of the small GTPase Rac1 and its effector p-21 activated kinase (PAK), two enzymes critically involved in actin management and functional synaptic plasticity, is impaired at hippocampal synapses in the Fmr1-knock-out (KO) mouse model of FXS. Theta burst afferent stimulation (TBS) caused a marked increase in the number of synapses associated with phosphorylated PAK in adult hippocampal slices from wild-type, but not Fmr1-KO, mice. Stimulation-induced activation of synaptic Rac1 was also absent in the mutants. The polymerization of spine actin that occurs immediately after theta stimulation appeared normal in mutant slices but the newly formed polymers did not properly stabilize, as evidenced by a prolonged vulnerability to a toxin (latrunculin) that disrupts dynamic actin filaments. Latrunculin also reversed long-term potentiation when applied at 10 min post-TBS, a time point at which the potentiation effect is resistant to interference in wild-type slices. We propose that a Rac>PAK signaling pathway needed for rapid stabilization of activity-induced actin filaments, and thus for normal spine morphology and lasting synaptic changes, is defective in FXS.

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Separable prefrontal cortex contributions to free recall.

Publication Date: 2010 Aug 18 PMID: 20720103
Authors: Long, N. M. - Oztekin, I. - Badre, D.
Journal: J Neurosci

In everyday life, we often must remember the past in the absence of helpful cues in the environment. In these cases, the brain directs retrieval by relying on internally maintained cues and strategies. Free recall is a widely used behavioral paradigm for studying retrieval with minimal cue support. During free recall, individuals often recall semantically related items consecutively--an effect termed semantic clustering--and previous studies have sought to understand clustering to gain leverage on the basic mechanisms supporting strategic recall. Successful recall and semantic clustering depend on the prefrontal cortex (PFC). However, as a result of methodological limitations, few functional magnetic resonance imaging (fMRI) studies have assessed the neural mechanisms at encoding that support subsequent recall, and none have tested the event-related correlates of recall itself. Thus, it remains open whether one or several frontal control mechanisms operate during encoding and recall. Here, we applied a recently developed method (Oztekin et al., 2010) to assess event-related fMRI signal changes during free recall. During encoding, dorsolateral prefrontal cortex (DLPFC) activation was predictive of subsequent semantic clustering. In contrast, subregions of ventrolateral prefrontal cortex (VLPFC) were predictive of subsequent recall, whether clustered or nonclustered, and were inversely associated with clustering during recall. These results suggest that DLPFC supports relational processes at encoding that are sufficient to produce category clustering effects during recall. Conversely, controlled retrieval mechanisms supported by VLPFC support item-specific search during recall.

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Ectopic Reelin induces neuronal aggregation with a normal birthdate-dependent "inside-out" alignment in the developing neocortex.

Publication Date: 2010 Aug 18 PMID: 20720102
Authors: Kubo, K. - Honda, T. - Tomita, K. - Sekine, K. - Ishii, K. - Uto, A. - Kobayashi, K. - Tabata, H. - Nakajima, K.
Journal: J Neurosci

Neurons in the developing mammalian neocortex form the cortical plate (CP) in an "inside-out" manner; that is, earlier-born neurons form the deeper layers, whereas later-born neurons migrate past the existing layers and form the more superficial layers. Reelin, a glycoprotein secreted by Cajal-Retzius neurons in the marginal zone (MZ), is crucial for this "inside-out" layering, because the layers are inverted in the Reelin-deficient mouse, reeler (Reln(rl)). Even though more than a decade has passed since the discovery of reelin, the biological effect of Reelin on individual migrating neurons remains unclear. In addition, although the MZ is missing in the reeler cortex, it is unknown whether Reelin directly regulates the development of the cell-body-sparse MZ. To address these issues, we expressed Reelin ectopically in the developing mouse cortex, and the results showed that Reelin caused the leading processes of migrating neurons to assemble in the Reelin-rich region, which in turn induced their cell bodies to form cellular aggregates around Reelin. Interestingly, the ectopic Reelin-rich region became cell-body-sparse and dendrite-rich, resembling the MZ, and the late-born neurons migrated past their predecessors toward the central Reelin-rich region within the aggregates, resulting in a birthdate-dependent "inside-out" alignment even ectopically. Reelin receptors and intracellular adaptor protein Dab1 were found to be necessary for formation of the aggregates. The above findings indicate that Reelin signaling is capable of inducing the formation of the dendrite-rich, cell-body-sparse MZ and a birthdate-dependent "inside-out" alignment of neurons independently of other factors/structures near the MZ.

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NADPH oxidase-dependent regulation of T-type Ca2+ channels and ryanodine receptors mediate the augmented exocytosis of catecholamines from intermittent hypoxia-treated neonatal rat chromaffin cells.

Publication Date: 2010 Aug 11 PMID: 20705601
Authors: Souvannakitti, D. - Nanduri, J. - Yuan, G. - Kumar, G. K. - Fox, A. P. - Prabhakar, N. R.
Journal: J Neurosci

Nearly 90% of premature infants experience the stress of intermittent hypoxia (IH) as a consequence of recurrent apneas (periodic cessation of breathing). In neonates, catecholamine secretion from the adrenal medulla is critical for maintaining homeostasis under hypoxic stress. We recently reported that IH treatment enhanced hypoxia-evoked catecholamine secretion and [Ca2+]i responses in neonatal rat adrenal chromaffin cells and involves reactive oxygen species (ROS). The purpose of the present study was to identify the source(s) of ROS generation and examine the mechanisms underlying the enhanced catecholamine secretion by IH. Neonatal rats of either sex (postal day 0-5) were exposed to either IH or normoxia. IH treatment increased NADPH oxidase (NOX) activity, upregulated NOX2 and NOX4 transcription in adrenal medullae, and a NOX inhibitor prevented the effects of IH on hypoxia-evoked chromaffin cell secretion. IH upregulated Cav3.1 and Cav3.2 T-type Ca2+ channel mRNAs via NOX/ROS signaling and augmented T-type Ca2+ current in IH-treated chromaffin cells. Mibefradil, a blocker of T-type Ca2+ channels attenuated the effects of hypoxia on [Ca2+]i and catecholamine secretion in IH-treated cells. In Ca2+-free medium, IH-treated cells exhibited higher basal [Ca2+]i levels and more pronounced [Ca2+]i responses to hypoxia compared with controls, and blockade of ryanodine receptors (RyRs) prevented these effects. RyR2 and RyR3 mRNAs were upregulated, RyR2 was S-glutathionylated in IH-treated adrenal medullae, and NOX/ROS inhibitors prevented these effects. These results demonstrate that neonatal IH treatment leads to NOX/ROS-dependent recruitment of T-type Ca2+ channels and RyRs, resulting in augmented [Ca2+]i mobilization and catecholamine secretion.

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Synaptic activity and activity-dependent competition regulates axon arbor maturation, growth arrest, and territory in the retinotectal projection.

Publication Date: 2010 Aug 11 PMID: 20702722
Authors: Ben Fredj, N. - Hammond, S. - Otsuna, H. - Chien, C. B. - Burrone, J. - Meyer, M. P.
Journal: J Neurosci

In the retinotectal projection, synapses guide retinal ganglion cell (RGC) axon arbor growth by promoting branch formation and by selectively stabilizing branches. To ask whether presynaptic function is required for this dual role of synapses, we have suppressed presynaptic function in single RGCs using targeted expression of tetanus toxin light-chain fused to enhanced green fluorescent protein (TeNT-Lc:EGFP). Time-lapse imaging of singly silenced axons as they arborize in the tectum of zebrafish larvae shows that presynaptic function is not required for stabilizing branches or for generating an arbor of appropriate complexity. However, synaptic activity does regulate two distinct aspects of arbor development. First, single silenced axons fail to arrest formation of highly dynamic but short-lived filopodia that are a feature of immature axons. Second, single silenced axons fail to arrest growth of established branches and so occupy significantly larger territories in the tectum than active axons. However, if activity-suppressed axons had neighbors that were also silent, axonal arbors appeared normal in size. A similar reversal in phenotype was observed when single TeNT-Lc:EGFP axons are grown in the presence of the NMDA receptor antagonist MK801 [(+)-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]. Although expansion of arbor territory is prevented when neighbors are silent, formation of transient filopodia is not. These results suggest that synaptic activity by itself regulates filopodia formation regardless of activity in neighboring cells but that the ability to arrest growth and focusing of axonal arbors in the target is an activity-dependent, competitive process.

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Inhibition of inflammatory pain by activating B-type natriuretic peptide signal pathway in nociceptive sensory neurons.

Publication Date: 2010 Aug 11 PMID: 20702721
Authors: Zhang, F. X. - Liu, X. J. - Gong, L. Q. - Yao, J. R. - Li, K. C. - Li, Z. Y. - Lin, L. B. - Lu, Y. J. - Xiao, H. S. - Bao, L. - Zhang, X. H. - Zhang, X.
Journal: J Neurosci

B-type natriuretic peptide (BNP) has been known to be secreted from cardiac myocytes and activate its receptor, natriuretic peptide receptor-A (NPR-A), to reduce ventricular fibrosis. However, the function of BNP/NPR-A pathway in the somatic sensory system has been unknown. In the present study, we report a novel function of BNP in pain modulation. Using microarray and immunoblot analyses, we found that BNP and NPR-A were expressed in the dorsal root ganglion (DRG) of rats and upregulated after intraplantar injection of complete Freund's adjuvant (CFA). Immunohistochemistry showed that BNP was expressed in calcitonin gene-related peptide (CGRP)-containing small neurons and IB4 (isolectin B4)-positive neurons, whereas NPR-A was present in CGRP-containing neurons. Application of BNP reduced the firing frequency of small DRG neurons in the presence of glutamate through opening large-conductance Ca2+-activated K+ channels (BKCa channels). Furthermore, intrathecal injection of BNP yielded inhibitory effects on formalin-induced flinching behavior and CFA-induced thermal hyperalgesia in rats. Blockade of BNP signaling by BNP antibodies or cGMP-dependent protein kinase (PKG) inhibitor KT5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12- epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1 0-carboxylic acid methyl ester] impaired the recovery from CFA-induced thermal hyperalgesia. Thus, BNP negatively regulates nociceptive transmission through presynaptic receptor NPR-A, and activation of the BNP/NPR-A/PKG/BKCa channel pathway in nociceptive afferent neurons could be a potential strategy for inflammatory pain therapy.

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Chronic electrical stimulation of the intact corticospinal system after unilateral injury restores skilled locomotor control and promotes spinal axon outgrowth.

Publication Date: 2010 Aug 11 PMID: 20702720
Authors: Carmel, J. B. - Berrol, L. J. - Brus-Ramer, M. - Martin, J. H.
Journal: J Neurosci

Injury to the brain or spinal cord usually preserves some corticospinal (CS) connections. These residual circuits sprout spontaneously and in response to activity-based treatments. We hypothesized that augmenting activity in spared CS circuits would restore the skilled motor control lost after injury and augment outgrowth of CS terminations in the spinal cord. After selective injury of one half of the CS tract (CST) in the rat, we applied 10 d of electrical stimulation to the forelimb area of motor cortex of the spared half and tested motor performance for 30 d. Rats with injury and CST stimulation showed substantial improvements in skilled paw placement while walking over a horizontal ladder. By the end of the testing period, the walking errors of the previously impaired forelimb in rats with injury and stimulation returned to baseline, while the errors remained elevated in rats with injury only. Whereas the time to perform the task returned to normal in all animals, the pattern of errors returned to normal only in the stimulated group. Electrical stimulation also caused robust outgrowth of CST axon terminations in the ipsilateral spinal cord, the side of impairment, compared with rats with injury only. The outgrowth was directed to the normal gray matter territory of ipsilateral CST axon terminations. Thus, stimulation of spared CS circuits induced substantial axon outgrowth to the largely denervated side of the spinal cord and restored normal motor control in the previously impaired limbs.

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Local neural processing and the generation of dynamic motor commands within the saccadic premotor network.

Publication Date: 2010 Aug 11 PMID: 20702719
Authors: Van Horn, M. R. - Mitchell, D. E. - Massot, C. - Cullen, K. E.
Journal: J Neurosci

The ability to accurately control movement requires the computation of a precise motor command. However, the computations that take place within premotor pathways to determine the dynamics of movements are not understood. Here we studied the local processing that generates dynamic motor commands by simultaneously recording spikes and local field potentials (LFPs) in the network that commands saccades. We first compared the information encoded by LFPs and spikes recorded from individual premotor and motoneurons (saccadic burst neurons, omnipause neurons, and motoneurons) in monkeys. LFP responses consistent with net depolarizations occurred in association with bursts of spiking activity when saccades were made in a neuron's preferred direction. In contrast, when saccades were made in a neuron's nonpreferred direction, neurons ceased spiking and the associated LFP responses were consistent with net hyperpolarizations. Surprisingly, hyperpolarizing and depolarizing LFPs encoded movement dynamics with equal robustness and accuracy. Second, we compared spiking responses at one hierarchical level of processing to LFPs at the next stage. Latencies and spike-triggered averages of LFP responses were consistent with each neuron's place within this circuit. LFPs reflected relatively local events (<500 microm) and encoded important features not available from the spiking train (i.e., hyperpolarizing response). Notably, quantification of their time-varying profiles revealed that a precise balance of depolarization and hyperpolarization underlies the production of precise saccadic eye movement commands at both motor and premotor levels. Overall, simultaneous recordings of LFPs and spiking responses provides an effective means for evaluating the local computations that take place to produce accurate motor commands.

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Combined genetic attenuation of myelin and semaphorin-mediated growth inhibition is insufficient to promote serotonergic axon regeneration.

Publication Date: 2010 Aug 11 PMID: 20702718
Authors: Lee, J. K. - Chow, R. - Xie, F. - Chow, S. Y. - Tolentino, K. E. - Zheng, B.
Journal: J Neurosci

After CNS injuries, axon growth inhibitors from the myelin and the scar tissue at the injury site are considered major impediments to axon regeneration. The presence of several classes of inhibitors with multiple members in each class suggests functional redundancy in growth inhibition. To test redundancy within the myelin inhibitory pathway, we analyzed raphe spinal serotonergic (5-HT) axon regeneration in mice deficient in two major myelin inhibitors, Nogo and MAG, and their common receptor NgR1 (or NgR). After a complete transection spinal cord injury, there was no significant enhancement of 5-HT axon regeneration beyond the injury site in either Nogo/MAG/NgR1 triple mutants or NgR1 single mutants. Occasional, genotype-independent traversal of 5-HT axons through GFAP-positive tissue bridges at the injury site implicates GFAP-negative lesion areas as especially inhibitory to 5-HT axons. To assess the contribution of class 3 Semaphorins that are expressed by GFAP-negative meningeal fibroblasts at the injury site, we analyzed mice deficient in PlexinA3 and PlexinA4, two key receptors for class 3 Semaphorins, with or without additional NgR1 deletion. No enhanced regeneration of 5-HT or corticospinal axons was detected in PlexinA3/PlexinA4 double mutants or PlexinA3/PlexinA4/NgR1 triple mutants through a complete transection injury. In contrast with previous reports, these data demonstrate that attenuating myelin or Semaphorin-mediated inhibition of axon growth is insufficient to promote 5-HT axon regeneration and further indicate that even attenuating both classes of inhibitory influences is insufficient to promote regeneration of injured axons through a complete transection spinal cord injury.

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Leading tip drives soma translocation via forward F-actin flow during neuronal migration.

Publication Date: 2010 Aug 11 PMID: 20702717
Authors: He, M. - Zhang, Z. H. - Guan, C. B. - Xia, D. - Yuan, X. B.
Journal: J Neurosci

Neuronal migration involves coordinated extension of the leading process and translocation of the soma, but the relative contribution of different subcellular regions, including the leading process and cell rear, in driving soma translocation remains unclear. By local manipulation of cytoskeletal components in restricted regions of cultured neurons, we examined the molecular machinery underlying the generation of traction force for soma translocation during neuronal migration. In actively migrating cerebellar granule cells in culture, a growth cone (GC)-like structure at the leading tip exhibits high dynamics, and severing the tip or disrupting its dynamics suppressed soma translocation within minutes. Soma translocation was also suppressed by local disruption of F-actin along the leading process but not at the soma, whereas disrupting microtubules along the leading process or at the soma accelerated soma translocation. Fluorescent speckle microscopy using GFP-alpha-actinin showed that a forward F-actin flow along the leading process correlated with and was required for soma translocation, and such F-actin flow depended on myosin II activity. In migrating neurons, myosin II activity was high at the leading tip but low at the soma, and increasing or decreasing this front-to-rear difference accelerated or impeded soma advance. Thus, the tip of the leading process actively pulls the soma forward during neuronal migration through a myosin II-dependent forward F-actin flow along the leading process.

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Sensory input drives multiple intracellular information streams in somatosensory cortex.

Publication Date: 2010 Aug 11 PMID: 20702716
Authors: Alenda, A. - Molano-Mazon, M. - Panzeri, S. - Maravall, M.
Journal: J Neurosci

Stable perception arises from the interaction between sensory inputs and internal activity fluctuations in cortex. Here we analyzed how different types of activity contribute to cortical sensory processing at the cellular scale. We performed whole-cell recordings in the barrel cortex of anesthetized rats while applying ongoing whisker stimulation and measured the information conveyed about the time-varying stimulus by different types of input (membrane potential) and output (spiking) signals. We found that substantial, comparable amounts of incoming information are carried by two types of membrane potential signal: slow, large (up-down state) fluctuations, and faster (>20 Hz), smaller-amplitude synaptic activity. Both types of activity fluctuation are therefore significantly driven by the stimulus on an ongoing basis. Each stream conveys essentially independent information. Output (spiking) information is contained in spike timing not just relative to the stimulus but also relative to membrane potential fluctuations. Information transfer is favored in up states relative to down states. Thus, slow, ongoing activity fluctuations and finer-scale synaptic activity generate multiple channels for incoming and outgoing information within barrel cortex neurons during ongoing stimulation.

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Small RNAs control sodium channel expression, nociceptor excitability, and pain thresholds.

Publication Date: 2010 Aug 11 PMID: 20702715
Authors: Zhao, J. - Lee, M. C. - Momin, A. - Cendan, C. M. - Shepherd, S. T. - Baker, M. D. - Asante, C. - Bee, L. - Bethry, A. - Perkins, J. R. - Nassar, M. A. - Abrahamsen, B. - Dickenson, A. - Cobb, B. S. - Merkenschlager, M. - Wood, J. N.
Journal: J Neurosci

To examine the role of small RNAs in peripheral pain pathways, we deleted the enzyme Dicer in mouse postmitotic damage-sensing neurons. We used a Nav1.8-Cre mouse to target those nociceptors important for inflammatory pain. The conditional null mice were healthy with a normal number of sensory neurons and normal acute pain thresholds. Behavioral studies showed that inflammatory pain was attenuated or abolished. Inflammatory mediators failed to enhance excitability of Nav1.8+ sensory neurons from null mutant mice. Acute noxious input into the dorsal horn of the spinal cord was apparently normal, but the increased input associated with inflammatory pain measured using c-Fos staining was diminished. Microarray and quantitative real-time reverse-transcription PCR (qRT-PCR) analysis showed that Dicer deletion lead to the upregulation of many broadly expressed mRNA transcripts in dorsal root ganglia. By contrast, nociceptor-associated mRNA transcripts (e.g., Nav1.8, P2xr3, and Runx-1) were downregulated, resulting in lower levels of protein and functional expression. qRT-PCR analysis also showed lowered levels of expression of nociceptor-specific pre-mRNA transcripts. MicroRNA microarray and deep sequencing identified known and novel nociceptor microRNAs in mouse Nav1.8+ sensory neurons that may regulate nociceptor gene expression.

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Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice.

Publication Date: 2010 Aug 11 PMID: 20702714
Authors: Xu, Y. F. - Gendron, T. F. - Zhang, Y. J. - Lin, W. L. - D'Alton, S. - Sheng, H. - Casey, M. C. - Tong, J. - Knight, J. - Yu, X. - Rademakers, R. - Boylan, K. - Hutton, M. - McGowan, E. - Dickson, D. W. - Lewis, J. - Petrucelli, L.
Journal: J Neurosci

Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.

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Cholesterol defect is marked across multiple rodent models of Huntington's disease and is manifest in astrocytes.

Publication Date: 2010 Aug 11 PMID: 20702713
Authors: Valenza, M. - Leoni, V. - Karasinska, J. M. - Petricca, L. - Fan, J. - Carroll, J. - Pouladi, M. A. - Fossale, E. - Nguyen, H. P. - Riess, O. - MacDonald, M. - Wellington, C. - DiDonato, S. - Hayden, M. - Cattaneo, E.
Journal: J Neurosci

Brain cholesterol, which is synthesized locally, is a major component of myelin and cell membranes and participates in neuronal functions, such as membrane trafficking, signal transduction, neurotransmitter release, and synaptogenesis. Here we show that brain cholesterol biosynthesis is reduced in multiple transgenic and knock-in Huntington's disease (HD) rodent models, arguably dependent on deficits in mutant astrocytes. Mice carrying a progressively increased number of CAG repeats show a more evident reduction in cholesterol biosynthesis. In postnatal life, the cholesterol-dependent activities of neurons mainly rely on the transport of cholesterol from astrocytes on ApoE-containing particles. Our data show that mRNA levels of cholesterol biosynthesis and efflux genes are severely reduced in primary HD astrocytes, along with impaired cellular production and secretion of ApoE. Consistently, in CSF of HD mice, ApoE is mostly associated with smaller lipoproteins, indicating reduced cholesterol transport on ApoE-containing lipoproteins circulating in the HD brain. These findings indicate that cholesterol defect is robustly marked in HD animals, implying that strategies aimed at selectively modulating brain cholesterol metabolism might be of therapeutic significance.

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The Gata3 transcription factor is required for the survival of embryonic and adult sympathetic neurons.

Publication Date: 2010 Aug 11 PMID: 20702712
Authors: Tsarovina, K. - Reiff, T. - Stubbusch, J. - Kurek, D. - Grosveld, F. G. - Parlato, R. - Schutz, G. - Rohrer, H.
Journal: J Neurosci

The transcription factor Gata3 is essential for the development of sympathetic neurons and adrenal chromaffin cells. As Gata3 expression is maintained up to the adult stage, we addressed its function in differentiated sympathoadrenal cells at embryonic and adult stages by conditional Gata3 elimination. Inactivation of Gata3 in embryonic DBH-expressing neurons elicits a strong reduction in neuron numbers due to apoptotic cell death and reduced proliferation. No selective effect on noradrenergic gene expression (TH and DBH) was observed. Interestingly, Gata3 elimination in DBH-expressing neurons of adult animals also results in a virtually complete loss of sympathetic neurons. In the Gata3-deficient population, the expression of anti-apoptotic genes (Bcl-2, Bcl-xL, and NFkappaB) is diminished, whereas the expression of pro-apoptotic genes (Bik, Bok, and Bmf) was increased. The expression of noradrenergic genes (TH and DBH) is not affected. These results demonstrate that Gata3 is continuously required for maintaining survival but not differentiation in the sympathetic neuron lineage up to mature neurons of adult animals.

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Mkp1 is a c-Jun target gene that antagonizes JNK-dependent apoptosis in sympathetic neurons.

Publication Date: 2010 Aug 11 PMID: 20702711
Authors: Kristiansen, M. - Hughes, R. - Patel, P. - Jacques, T. S. - Clark, A. R. - Ham, J.
Journal: J Neurosci

Developing sympathetic neurons depend on NGF for survival. When sympathetic neurons are deprived of NGF in vitro, a well documented series of events, including c-Jun N-terminal kinase (JNK) pathway activation, release of cytochrome c from the mitochondria, and caspase activation, culminates in the death of the neuron by apoptosis within 24-48 h. This process requires de novo gene expression, suggesting that increased expression of specific genes activates the cell death program. Using rat gene microarrays, we found that NGF withdrawal induces the expression of many genes, including mkp1, which encodes a MAPK phosphatase that can dephosphorylate JNKs. The increase in mkp1 mRNA level requires the MLK-JNK-c-Jun pathway, and we show that Mkp1 is an important regulator of JNK-dependent apoptosis in sympathetic neurons. In microinjection experiments, Mkp1 overexpression can inhibit JNK-mediated phosphorylation of c-Jun and protect sympathetic neurons from apoptosis, while Mkp1 knockdown accelerates NGF withdrawal-induced death. Accordingly, the number of superior cervical ganglion (SCG) neurons is reduced in mkp1-/- mice at P1 during the period of developmental sympathetic neuron death. We also show that c-Jun and ATF2 bind to two conserved ATF binding sites in the mkp1 promoter in vitro and in chromatin. Both of these ATF sites contribute to basal promoter activity and are required for mkp1 promoter induction after NGF withdrawal. These results demonstrate that Mkp1 is part of a negative feedback loop induced by the MLK-JNK-c-Jun signaling pathway that modulates JNK activity and the rate of neuronal death in rat sympathetic neurons following NGF withdrawal.

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The membrane potential waveform of bursting pacemaker neurons is a predictor of their preferred frequency and the network cycle frequency.

Publication Date: 2010 Aug 11 PMID: 20702710
Authors: Tseng, H. A. - Nadim, F.
Journal: J Neurosci

Many oscillatory networks involve neurons that exhibit intrinsic rhythmicity but possess a large variety of voltage-gated currents that interact in a complex fashion, making it difficult to determine which factors control frequency. Yet these neurons often have preferred (resonance) frequencies that can be close to the network frequency. Because the preferred frequency results from the dynamics of ionic currents, it can be assumed to depend on parameters that determine the neuron's oscillatory waveform shape. The pyloric network frequency in the crab Cancer borealis is correlated with the preferred frequency of its bursting pacemaker neurons anterior burster and pyloric dilator (PD). We measured the preferred frequency of the PD neuron in voltage clamp, which allows control of the oscillation voltage range and waveforms (sine waves and realistic oscillation waveforms), and showed that (1) the preferred frequency depends on the voltage range of the oscillating voltage waveform; (2) the slope of the waveform near its peak has a strongly negative correlation with the preferred frequency; and (3) correlations between parameters of the PD neuron oscillation waveform and its preferred frequency can be used to predict shifts in the network frequency. As predicted by these results, dynamic clamp shifts of the upper or lower voltage limits of the PD neuron waveform during ongoing oscillations changed the network frequency, consistent with the predictions from the preferred frequency. These results show that the voltage waveform of oscillatory neurons can be predictive of their preferred frequency and thus the network oscillation frequency.

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Appetitive and aversive goal values are encoded in the medial orbitofrontal cortex at the time of decision making.

Publication Date: 2010 Aug 11 PMID: 20702709
Authors: Plassmann, H. - O'Doherty, J. P. - Rangel, A.
Journal: J Neurosci

An essential feature of choice is the assignment of goal values (GVs) to the different options under consideration at the time of decision making. This computation is done when choosing among appetitive and aversive items. Several groups have studied the location of GV computations for appetitive stimuli, but the problem of valuation in aversive contexts at the time of decision making has been ignored. Thus, although dissociations between appetitive and aversive components of value signals have been shown in other domains such as anticipatory and outcome values, it is not known whether appetitive and aversive GVs are computed in similar brain regions or in separate ones. We investigated this question using two different functional magnetic resonance imaging studies while human subjects placed real bids in an economic auction for the right to eat/avoid eating liked/disliked foods. We found that activity in a common area of the medial orbitofrontal cortex and the dorsolateral prefrontal cortex correlated with both appetitive and aversive GVs. These findings suggest that these regions might form part of a common network.

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NCAM-induced neurite outgrowth depends on binding of calmodulin to NCAM and on nuclear import of NCAM and fak fragments.

Publication Date: 2010 Aug 11 PMID: 20702708
Authors: Kleene, R. - Mzoughi, M. - Joshi, G. - Kalus, I. - Bormann, U. - Schulze, C. - Xiao, M. F. - Dityatev, A. - Schachner, M.
Journal: J Neurosci

The neural cell adhesion molecule NCAM plays important functional roles not only during nervous system development, but also in the adult after injury and in synaptic plasticity. Homophilic binding of NCAM triggers intracellular signaling events resulting in cellular responses such as neurite outgrowth that require NCAM palmitoylation-dependent raft localization and activation of the nonreceptor tyrosine kinases fyn and fak. In this study, we show that stimulation of NCAM by a function-triggering NCAM antibody results in proteolytic processing of NCAM and fak. The C-terminal fragment of NCAM, consisting of the intracellular domain, the transmembrane domain, and a stub of the extracellular domain, and the N-terminal fragment of fak are imported into the nucleus. NCAM-stimulated fak activation, generation, and nuclear import of NCAM and fak fragments as well as neurite outgrowth are abolished by mutation of the calmodulin binding motif in the intracellular domain of NCAM that is responsible for the calcium-dependent binding of calmodulin to NCAM. This mutation interferes neither with NCAM cell surface expression, palmitoylation, and raft localization nor with fyn activation. The way by which the transmembrane NCAM fragment reaches the nucleus in a calmodulin- and calcium-dependent manner is by endocytotic transport via the endoplasmic reticulum and the cytoplasm. The generation and nuclear import of NCAM and phosphorylated fak fragments resulting from NCAM stimulation may represent a signal pathway activating cellular responses in parallel or in association with classical kinase- and phosphorylation-dependent signaling cascades.

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Nicotine blocks the hyperpolarization-activated current Ih and severely impairs the oscillatory behavior of oriens-lacunosum moleculare interneurons.

Publication Date: 2010 Aug 11 PMID: 20702707
Authors: Griguoli, M. - Maul, A. - Nguyen, C. - Giorgetti, A. - Carloni, P. - Cherubini, E.
Journal: J Neurosci

In the brain, high cognitive functions are encoded by coherent network oscillations. Key players are inhibitory interneurons that, by releasing GABA into principal cells, pace targeted cells. Among these, oriens-lacunosum moleculare (O-LM) interneurons that provide a theta frequency patterned output to distal dendrites of pyramidal cells are endowed with HCN channels responsible for the slowly activating inwardly rectifying Ih current and their pacemaking activity. Here we show that, in transgenic mice expressing EGFP (enhanced green fluorescent protein) in a subset of stratum oriens somatostatin-containing interneurons that mostly comprise O-LM cells, nicotine, the active component of tobacco, reduced Ih and the oscillatory behavior of O-LM interneurons. In cells hyperpolarized at -90 mV, nicotine suppressed the theta resonance in the same way as ZD 7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride), a selective blocker of Ih. Nicotine blocked Ih in a concentration-dependent way with an EC50 of 62 nm. Similar effects were produced by epibatidine, a structural analog of nicotine. The effects of nicotine and epibatidine were independent on nicotinic ACh receptor (nAChR) activation because they persisted in the presence of nAChR antagonists. Furthermore, nicotine slowed down the interspike depolarizing slope and the firing rate, thus severely disrupting the oscillatory behavior of O-LM cells. Molecular modeling suggests that, similarly to ZD 7288, nicotine and epibatidine directly bind to the inner pore of the HCN channels. It is therefore likely that nicotine severely influences rhythmogenesis and high cognitive functions in smokers.

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Monoamine oxidases regulate telencephalic neural progenitors in late embryonic and early postnatal development.

Publication Date: 2010 Aug 11 PMID: 20702706
Authors: Cheng, A. - Scott, A. L. - Ladenheim, B. - Chen, K. - Ouyang, X. - Lathia, J. D. - Mughal, M. - Cadet, J. L. - Mattson, M. P. - Shih, J. C.
Journal: J Neurosci

Monoamine neurotransmitters play major roles in regulating a range of brain functions in adults and increasing evidence suggests roles for monoamines in brain development. Here we show that mice lacking the monoamine metabolic enzymes MAO A and MAO B (MAO AB-deficient mice) exhibit diminished proliferation of neural stem cells (NSC) in the developing telencephalon beginning in late gestation [embryonic day (E) 17.5], a deficit that persists in neonatal and adult mice. These mice showed significantly increased monoamine levels and anxiety-like behaviors as adults. Assessments of markers of intermediate progenitor cells (IPC) and mitosis showed that NSC in the subventricular zone (SVZ), but not in the ventricular zone, are reduced in MAO AB-deficient mice. A developmental time course of monoamines in frontal cortical tissues revealed increased serotonin levels as early as E14.5, and a further large increase was found between E17.5 and postnatal day 2. Administration of an inhibitor of serotonin synthesis (parachlorophenylalanine) between E14.5 and E19.5 restored the IPC numbers and SVZ thickness, suggesting the role of serotonin in the suppression of IPC proliferation. Studies of neurosphere cultures prepared from the telencephalon at different embryonic and postnatal ages showed that serotonin stimulates proliferation in wild-type, but not in MAO AB-deficient, NSC. Together, these results suggest that a MAO-dependent long-lasting alteration in the proliferation capacity of NSC occurs late in embryonic development and is mediated by serotonin. Our findings reveal novel roles for MAOs and serotonin in the regulation of IPC proliferation in the developing brain.

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Neural mechanisms of belief inference during cooperative games.

Publication Date: 2010 Aug 11 PMID: 20702705
Authors: Yoshida, W. - Seymour, B. - Friston, K. J. - Dolan, R. J.
Journal: J Neurosci

Humans have the arguably unique ability to understand the mental representations of others. For success in both competitive and cooperative interactions, however, this ability must be extended to include representations of others' belief about our intentions, their model about our belief about their intentions, and so on. We developed a "stag hunt" game in which human subjects interacted with a computerized agent using different degrees of sophistication (recursive inferences) and applied an ecologically valid computational model of dynamic belief inference. We show that rostral medial prefrontal (paracingulate) cortex, a brain region consistently identified in psychological tasks requiring mentalizing, has a specific role in encoding the uncertainty of inference about the other's strategy. In contrast, dorsolateral prefrontal cortex encodes the depth of recursion of the strategy being used, an index of executive sophistication. These findings reveal putative computational representations within prefrontal cortex regions, supporting the maintenance of cooperation in complex social decision making.

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Network bistability mediates spontaneous transitions between normal and pathological brain states.

Publication Date: 2010 Aug 11 PMID: 20702704
Authors: Frohlich, F. - Sejnowski, T. J. - Bazhenov, M.
Journal: J Neurosci

Little is known about how cortical networks support the emergence of remarkably different activity patterns. Physiological activity interspersed with epochs of pathological hyperactivity in the epileptic brain represents a clinically relevant yet poorly understood case of such rich dynamic repertoire. Using a realistic computational model, we demonstrate that physiological sparse and pathological tonic-clonic activity may coexist in the same cortical network for identical afferent input level. Transient perturbations in the afferent input were sufficient to switch the network between these two stable states. The effectiveness of the potassium regulatory apparatus determined the stability of the physiological state and the threshold for seizure initiation. Our findings contrast with the common notions of (1) pathological brain activity representing dynamic instabilities and (2) necessary adjustments of experimental conditions to elicit different network states. Rather, we propose that the rich dynamic repertoire of cortical networks may be based on multistabilities intrinsic to the network.

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The role of the BDNF Val66Met polymorphism for the synchronization of error-specific neural networks.

Publication Date: 2010 Aug 11 PMID: 20702703
Authors: Beste, C. - Kolev, V. - Yordanova, J. - Domschke, K. - Falkenstein, M. - Baune, B. T. - Konrad, C.
Journal: J Neurosci

Behavioral adaptation depends on the recognition of response errors and processing of this error-information. Error processing is a specific cognitive function crucial for behavioral adaptation. Neurophysiologically, these processes are reflected by an event-related potential (ERP), the error negativity (Ne/ERN). Even though synchronization processes are important in information processing, its role and neurobiological foundation in behavioral adaptation are not understood. The brain-derived neurotrophic factor (BDNF) strongly modulates the establishment of neural connectivity that determines neural network dynamics and synchronization properties. Therefore altered synchronization processes may constitute a mechanism via which BDNF affects processes of error-induced behavioral adaptation. We investigate how variants of the BDNF gene regulate EEG-synchronization processes underlying error processing. Subjects (n=65) were genotyped for the functional BDNF Val66Met polymorphism (rs6265). We show that Val/Val genotype is associated with stronger error-specific phase-locking, compared with Met allele carriers. Posterror behavioral adaptation seems to be strongly dependent on these phase-locking processes and efficacy of EEG-phase-locking-behavioral coupling was genotype dependent. After correct responses, neurophysiological processes were not modulated by the polymorphism, underlining that BDNF becomes especially necessary in situations requiring behavioral adaptation. The results suggest that alterations in neural synchronization processes modulated by the genetic variants of BDNF Val66Met may be the mechanism by which cognitive functions are affected.

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Why variability facilitates spinal learning.

Publication Date: 2010 Aug 11 PMID: 20702702
Authors: Ziegler, M. D. - Zhong, H. - Roy, R. R. - Edgerton, V. R.
Journal: J Neurosci

Spinal Wistar Hannover rats trained to step bipedally on a treadmill with manual assistance of the hindlimbs have been shown to improve their stepping ability. Given the improvement in motor performance with practice and the ability of the spinal cord circuitry to learn to step more effectively when the mode of training allows variability, we examined why this intrinsic variability is an important factor. Intramuscular EMG electrodes were implanted to monitor and compare the patterns of activation of flexor (tibialis anterior) and extensor (soleus) muscles associated with a fixed-trajectory and assist-as-needed (AAN) step training paradigms in rats after a complete midthoracic (T8-T9) spinal cord transection. Both methods involved a robotic arm attached to each ankle of the rat to provide guidance during stepping. The fixed trajectory allowed little variance between steps, and the AAN provided guidance only when the ankle deviated a specified distance from the programmed trajectory. We hypothesized that an AAN paradigm would impose fewer disruptions of the control strategies intrinsic to the spinal locomotor circuitry compared with a fixed trajectory. Intrathecal injections of quipazine were given to each rat to facilitate stepping. Analysis confirmed that there were more corrections within a fixed-trajectory step cycle and consequently there was less coactivation of agonist and antagonist muscles during the AAN paradigm. These data suggest that some critical level of variation in the specific circuitry activated and the resulting kinematics reflect a fundamental feature of the neural control mechanisms even in a highly repetitive motor task.

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Autophagy-dependent rhodopsin degradation prevents retinal degeneration in Drosophila.

Publication Date: 2010 Aug 11 PMID: 20702701
Authors: Midorikawa, R. - Yamamoto-Hino, M. - Awano, W. - Hinohara, Y. - Suzuki, E. - Ueda, R. - Goto, S.
Journal: J Neurosci

Recent studies have demonstrated protective roles for autophagy in various neurodegenerative disorders, including the polyglutamine diseases; however, the role of autophagy in retinal degeneration has remained unclear. Accumulation of activated rhodopsin in some Drosophila mutants leads to retinal degeneration, and although it is known that activated rhodopsin is degraded in endosomal pathways in normal photoreceptor cells, the contribution of autophagy to rhodopsin regulation has remained elusive. This study reveals that activated rhodopsin is degraded by autophagy in collaboration with endosomal pathways to prevent retinal degeneration. Light-dependent retinal degeneration in the Drosophila visual system is caused by the knockdown or mutation of autophagy-essential components, such as autophagy-related protein 7 and 8 (atg-7/atg-8), or genes essential for PE (phosphatidylethanolamine) biogenesis and autophagosome formation, including Phosphatidylserine decarboxylase (Psd) and CDP-ethanolamine:diacylglycerol ethanolaminephosphotransferase (Ept). The knockdown of atg-7/8 or Psd/Ept produced an increase in the amount of rhodopsin localized to Rab7-positive late endosomes. This rhodopsin accumulation, followed by retinal degeneration, was suppressed by overexpression of Rab7, which accelerated the endosomal degradation pathway. These results indicate a degree of cross talk between the autophagic and endosomal/lysosomal pathways. Importantly, a reduction in rhodopsin levels rescued Psd knockdown-induced retinal degeneration. Additionally, the Psd knockdown-induced retinal degeneration phenotype was enhanced by Ppt1 inactivation, which causes infantile neuronal ceroid lipofuscinosis, implying that autophagy plays a significant role in its pathogenesis. Collectively, the current data reveal that autophagy suppresses light-dependent retinal degeneration in collaboration with the endosomal degradation pathway and that rhodopsin is a key substrate for autophagic degradation in this context.

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Temporally extended dopamine responses to perceptually demanding reward-predictive stimuli.

Publication Date: 2010 Aug 11 PMID: 20702700
Authors: Nomoto, K. - Schultz, W. - Watanabe, T. - Sakagami, M.
Journal: J Neurosci

Midbrain dopamine neurons respond to reward-predictive stimuli. In the natural environment reward-predictive stimuli are often perceptually complicated. Thus, to discriminate one stimulus from another, elaborate sensory processing is necessary. Given that previous studies have used simpler types of reward-predictive stimuli, it has yet to be clear whether and, if so, how dopamine neurons obtain reward information from perceptually complicated stimuli. To investigate this, we recorded the activities of monkey dopamine neurons while they were performing discrimination between two coherent motion directions in random-dot motion stimuli. These coherent directions were paired with different magnitudes of reward. We found that dopamine neurons showed reward-predictive responses to random-dot motion stimuli. Moreover, dopamine neurons showed temporally extended activity correlated with changes in reward prediction (i.e., reward prediction error) from coarse to fine scales between initial motion detection and subsequent motion discrimination phases. Noticeably, dopamine reward-predictive responses became differential in a later phase than previously reported. This response pattern was consistent with the time course of processing required for the estimation of expected reward value that parallels the motion direction discrimination processing. The results demonstrate that dopamine neurons are able to reflect the reward value of perceptually complicated stimuli, and suggest that dopamine neurons use the moment-to-moment reward prediction associated with environmental stimuli to compute a reward prediction error.

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The association of dynamin with synaptophysin regulates quantal size and duration of exocytotic events in chromaffin cells.

Publication Date: 2010 Aug 11 PMID: 20702699
Authors: Gonzalez-Jamett, A. M. - Baez-Matus, X. - Hevia, M. A. - Guerra, M. J. - Olivares, M. J. - Martinez, A. D. - Neely, A. - Cardenas, A. M.
Journal: J Neurosci

Although synaptophysin is one of the most abundant integral proteins of synaptic vesicle membranes, its contribution to neurotransmitter release remains unclear. One possibility is that through its association with dynamin it controls the fine tuning of transmitter release. To test this hypothesis, we took advantage of amperometric measurements of quantal catecholamine release from chromaffin cells. First, we showed that synaptophysin and dynamin interact in chromaffin granule-rich fractions and that this interaction relies on the C terminal of synaptophysin. Experimental maneuvers that are predicted to disrupt the association between these two proteins, such as injection of antibodies against dynamin or synaptophysin, or peptides homologous to the C terminal of synaptophysin, increased the quantal size and duration of amperometric spikes. In contrast, the amperometric current that precedes the spike remained unchanged, indicating that synaptophysin/dynamin association does not regulate the initial fusion pore, but it appears to target a later step of exocytosis to control the amount of catecholamines released during a single vesicle fusion event.

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Intralaminar and interlaminar activity within the rodent superior colliculus visualized with voltage imaging.

Publication Date: 2010 Aug 11 PMID: 20702698
Authors: Vokoun, C. R. - Jackson, M. B. - Basso, M. A.
Journal: J Neurosci

The superior colliculus (SC) is a midbrain structure that plays a role in converting sensation into action. Most SC research focuses on either in vivo extracellular recordings from behaving monkeys or patch-clamp recordings from smaller mammals in vitro. However, the activity of neuronal circuits is necessary to generate behavior, and neither of these approaches measures the simultaneous activity of large populations of neurons that make up circuits. Here, we describe experiments in which we measured changes in membrane potential across the SC map using voltage imaging of the rat SC in vitro. Our results provide the first high temporal and spatial resolution images of activity within the SC. Electrical stimulation of the SC evoked a characteristic two-component optical response containing a short latency initial-spike and a longer latency after-depolarization. Single-pulse stimulation in the superficial SC evoked a pattern of intralaminar and interlaminar spread that was distinct from the spread evoked by the same stimulus applied to the intermediate SC. Intermediate layer stimulation produced a more extensive and more ventrally located activation of the superficial layers than did stimulation in the superficial SC. Together, these results indicate the recruitment of dissimilar subpopulations of circuitry depending on the layer stimulated. Field potential recordings, pharmacological manipulations, and timing analyses indicate that the patterns of activity were physiologically relevant and largely synaptically driven. Therefore, voltage imaging is a powerful technique for the study of spatiotemporal dynamics of electrical signaling across neuronal populations, providing insight into neural circuits that underlie behavior.

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Drosophila larvae establish appetitive olfactory memories via mushroom body neurons of embryonic origin.

Publication Date: 2010 Aug 11 PMID: 20702697
Authors: Pauls, D. - Selcho, M. - Gendre, N. - Stocker, R. F. - Thum, A. S.
Journal: J Neurosci

Insect mushroom bodies are required for diverse behavioral functions, including odor learning and memory. Using the numerically simple olfactory pathway of the Drosophila melanogaster larva, we provide evidence that the formation of appetitive olfactory associations relies on embryonic-born intrinsic mushroom body neurons (Kenyon cells). The participation of larval-born Kenyon cells, i.e., neurons that become gradually integrated in the developing mushroom body during larval life, in this task is unlikely. These data provide important insights into how a small set of identified Kenyon cells can store and integrate olfactory information in a developing brain. To investigate possible functional subdivisions of the larval mushroom body, we anatomically disentangle its input and output neurons at the single-cell level. Based on this approach, we define 10 subdomains of the larval mushroom body that may be implicated in mediating specific interactions between the olfactory pathway, modulatory neurons, and neuronal output.

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CRMP5 interacts with tubulin to inhibit neurite outgrowth, thereby modulating the function of CRMP2.

Publication Date: 2010 Aug 11 PMID: 20702696
Authors: Brot, S. - Rogemond, V. - Perrot, V. - Chounlamountri, N. - Auger, C. - Honnorat, J. - Moradi-Ameli, M.
Journal: J Neurosci

Collapsin response mediator proteins (CRMPs) are involved in signaling of axon guidance and neurite outgrowth during neural development and regeneration. Among these, CRMP2 has been identified as an important actor in neuronal polarity and axon outgrowth, these activities being correlated with the reorganization of cytoskeletal proteins. In contrast, the function of CRMP5, expressed during brain development, remains obscure. Here, we find that, in contrast to CRMP2, CRMP5 inhibits tubulin polymerization and neurite outgrowth. Knockdown of CRMP5 expression by small interfering RNA confirms its inhibitory functions. CRMP5 forms a ternary complex with MAP2 and tubulin, the latter involving residues 475-522 of CRMP5, exposed at the molecule surface. Using different truncated CRMP5 constructs, we demonstrate that inhibition of neurite outgrowth by CRMP5 is mediated by tubulin binding. When both CRMP5 and CRMP2 are overexpressed, the inhibitory effect of CRMP5 abrogates neurite outgrowth promotion induced by CRMP2, suggesting that CRMP5 acts as a dominant signal. In cultured hippocampal neurons, CRMP5 shows no effect on axon growth, whereas it inhibits dendrite outgrowth and formation, at an early developmental stage, correlated with its strong expression in neurites. At later stages, when dendrites begin to extend, CRMP5 expression is absent. However, CRMP2 is constantly expressed. Overexpression of CRMP5 with CRMP2 inhibits CRMP2-induced outgrowth both on the axonal and dendritic levels. Deficiency of CRMP5 expression enhanced the CRMP2 effect. This antagonizing effect of CRMP5 is exerted through a tubulin-based mechanism. Thus, the CRMP5 binding to tubulin modulates CRMP2 regulation of neurite outgrowth and neuronal polarity during brain development.

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Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome.

Publication Date: 2010 Aug 11 PMID: 20702695
Authors: Gross, C. - Nakamoto, M. - Yao, X. - Chan, C. B. - Yim, S. Y. - Ye, K. - Warren, S. T. - Bassell, G. J.
Journal: J Neurosci

Fragile X syndrome (FXS) is an inherited neurologic disease caused by loss of fragile X mental retardation protein (FMRP), which is hypothesized to mediate negative regulation of mRNA translation at synapses. A prominent feature of FXS animal models is exaggerated signaling through group 1 metabotropic glutamate receptors (gp1 mGluRs), and therapeutic strategies to treat FXS are targeted mainly at gp1 mGluRs. Recent studies, however, indicate that a variety of receptor-mediated signal transduction pathways are dysregulated in FXS, suggesting that FMRP acts on a common downstream signaling molecule. Here, we show that deficiency of FMRP results in excess activity of phosphoinositide 3-kinase (PI3K), a downstream signaling molecule of many cell surface receptors. In Fmr1 knock-out neurons, excess synaptic PI3K activity can be reduced by perturbation of gp1 mGluR-mediated signaling. Remarkably, increased PI3K activity was also observed in FMRP-deficient non-neuronal cells in the absence of gp1 mGluRs. Here, we show that FMRP regulates the synthesis and synaptic localization of p110beta, the catalytic subunit of PI3K. In wild type, gp1 mGluR activation induces p110beta translation, p110beta protein expression, and PI3K activity. In contrast, both p110beta protein synthesis and PI3K activity are elevated and insensitive to gp1 mGluR stimulation in Fmr1 knock-out. This suggests that dysregulated PI3K signaling may underlie the synaptic impairments in FXS. In support of this hypothesis, we show that PI3K antagonists rescue three FXS-associated phenotypes: dysregulated synaptic protein synthesis, excess AMPA receptor internalization, and increased spine density. Targeting excessive PI3K activity might thus be a potent therapeutic strategy for FXS.

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Describing the brain in autism in five dimensions--magnetic resonance imaging-assisted diagnosis of autism spectrum disorder using a multiparameter classification approach.

Publication Date: 2010 Aug 11 PMID: 20702694
Authors: Ecker, C. - Marquand, A. - Mourao-Miranda, J. - Johnston, P. - Daly, E. M. - Brammer, M. J. - Maltezos, S. - Murphy, C. M. - Robertson, D. - Williams, S. C. - Murphy, D. G.
Journal: J Neurosci

Autism spectrum disorder (ASD) is a neurodevelopmental condition with multiple causes, comorbid conditions, and a wide range in the type and severity of symptoms expressed by different individuals. This makes the neuroanatomy of autism inherently difficult to describe. Here, we demonstrate how a multiparameter classification approach can be used to characterize the complex and subtle structural pattern of gray matter anatomy implicated in adults with ASD, and to reveal spatially distributed patterns of discriminating regions for a variety of parameters describing brain anatomy. A set of five morphological parameters including volumetric and geometric features at each spatial location on the cortical surface was used to discriminate between people with ASD and controls using a support vector machine (SVM) analytic approach, and to find a spatially distributed pattern of regions with maximal classification weights. On the basis of these patterns, SVM was able to identify individuals with ASD at a sensitivity and specificity of up to 90% and 80%, respectively. However, the ability of individual cortical features to discriminate between groups was highly variable, and the discriminating patterns of regions varied across parameters. The classification was specific to ASD rather than neurodevelopmental conditions in general (e.g., attention deficit hyperactivity disorder). Our results confirm the hypothesis that the neuroanatomy of autism is truly multidimensional, and affects multiple and most likely independent cortical features. The spatial patterns detected using SVM may help further exploration of the specific genetic and neuropathological underpinnings of ASD, and provide new insights into the most likely multifactorial etiology of the condition.

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A novel role for Kv1.3 blockers: protecting neural progenitor cells from a hostile inflammatory environment.

Publication Date: 2010 Aug 11 PMID: 20702693
Authors: Peng, H. - Huss, D. J.
Journal: J Neurosci

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A study of clustered data and approaches to its analysis.

Publication Date: 2010 Aug 11 PMID: 20702692
Authors: Galbraith, S. - Daniel, J. A. - Vissel, B.
Journal: J Neurosci

Statistical analysis is critical in the interpretation of experimental data across the life sciences, including neuroscience. The nature of the data collected has a critical role in determining the best statistical approach to take. One particularly prevalent type of data is referred to as "clustered data." Clustered data are characterized as data that can be classified into a number of distinct groups or "clusters" within a particular study. Clustered data arise most commonly in neuroscience when data are compiled across multiple experiments, for example in electrophysiological or optical recordings taken from synaptic terminals, with each experiment providing a distinct cluster of data. However, there are many other types of experimental design that can yield clustered data. Here, we provide a statistical model for intracluster correlation and systematically investigate a range of methods for analyzing clustered data. Our analysis reveals that it is critical to take data clustering into account and suggests appropriate statistical approaches that can be used to account for data clustering.

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Persistent representation of juvenile experience in the adult songbird brain.

Publication Date: 2010 Aug 4 PMID: 20686001
Authors: Prather, J. F. - Peters, S. - Nowicki, S. - Mooney, R.
Journal: J Neurosci

Juveniles sometimes learn behaviors that they cease to express as adults. Whether the adult brain retains a record of experiences associated with behaviors performed transiently during development remains unclear. We addressed this issue by studying neural representations of song in swamp sparrows, a species in which juveniles learn and practice many more songs than they retain in their adult vocal repertoire. We exposed juvenile swamp sparrows to a suite of tutor songs and confirmed that, although many tutor songs were imitated during development, not all copied songs were retained into adulthood. We then recorded extracellularly in the sensorimotor nucleus HVC in anesthetized sparrows to assess neuronal responsiveness to songs in the adult repertoire, tutor songs, and novel songs. Individual HVC neurons almost always responded to songs in the adult repertoire and commonly responded even more strongly to a tutor song. Effective tutor songs were not simply those that were acoustically similar to songs in the adult repertoire. Moreover, the strength of tutor song responses was unrelated to the number of times that the bird sang copies of those songs in juvenile or adult life. Notably, several neurons responded most strongly to a tutor song performed only rarely and transiently during juvenile life, or even to a tutor song for which we could find no evidence of ever having been copied. Thus, HVC neurons representing songs in the adult repertoire also appear to retain a lasting record of certain tutor songs, including those imitated only transiently.

MeSH Categories: Acoustic Stimulation, Age Factors, Animals, Auditory Perception/physiology, Electrophysiology, High Vocal Center/*physiology, Learning/*physiology, Neuronal Plasticity/*physiology, Neurons/*physiology, Sparrows, Vocalization, Animal/*physiology

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In vivo activation of channelrhodopsin-2 reveals that normal patterns of spontaneous activity are required for motoneuron guidance and maintenance of guidance molecules.

Publication Date: 2010 Aug 4 PMID: 20686000
Authors: Kastanenka, K. V. - Landmesser, L. T.
Journal: J Neurosci

Spontaneous, highly rhythmic episodes of propagating bursting activity are present early during the development of chick and mouse spinal cords. Acetylcholine, and GABA and glycine, which are both excitatory at this stage, provide the excitatory drive. It was previously shown that a moderate decrease in the frequency of bursting activity, caused by in ovo application of the GABA(A) receptor blocker, picrotoxin, resulted in motoneurons making dorsal-ventral (D-V) pathfinding errors in the limb and in the altered expression of guidance molecules associated with this decision. To distinguish whether the pathfinding errors were caused by perturbation of the normal frequency of bursting activity or interference with GABA(A) receptor signaling, chick embryos were chronically treated in ovo with picrotoxin to block GABA(A) receptors, while light activation by channelrhodopsin-2 was used to restore bursting activity to the control frequency. The restoration of normal patterns of neural activity in the presence of picrotoxin prevented the D-V pathfinding errors in the limb and maintained the normal expression levels of EphA4, EphB1, and polysialic acid on neural cell adhesion molecule, three molecules previously shown to be necessary for this pathfinding choice. These observations demonstrate that developing spinal motor circuits are highly sensitive to the precise frequency and pattern of spontaneous activity, and that any drugs that alter this activity could result in developmental defects.

MeSH Categories: Action Potentials/physiology, Analysis of Variance, Animals, Chick Embryo, GABA Antagonists/pharmacology, Immunohistochemistry, Motor Neurons/drug effects/*metabolism, Nerve Tissue Proteins/*metabolism, Picrotoxin/pharmacology, Receptors, GABA-A/*metabolism, Rhodopsin/*metabolism, Spinal Cord/drug effects/*metabolism, Synaptic Transmission/physiology

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A novel transient glutamatergic population migrating from the pallial-subpallial boundary contributes to neocortical development.

Publication Date: 2010 Aug 4 PMID: 20685999
Authors: Teissier, A. - Griveau, A. - Vigier, L. - Piolot, T. - Borello, U. - Pierani, A.
Journal: J Neurosci

The generation of a precise number of neural cells and the determination of their laminar fate are tightly controlled processes during development of the cerebral cortex. Using genetic tracing in mice, we have identified a population of glutamatergic neurons generated by Dbx1-expressing progenitors at the pallial-subpallial boundary predominantly at embryonic day 12.5 (E12.5) and subsequent to Cajal-Retzius cells. We show that these neurons migrate tangentially to populate the cortical plate (CP) at all rostrocaudal and mediolateral levels by E14.5. At birth, they homogeneously populate cortical areas and represent <5% of cortical cells. However, they are distributed into neocortical layers according to their birthdates and express the corresponding markers of glutamatergic differentiation (Tbr1, ER81, Cux2, Ctip2). Notably, this population dies massively by apoptosis at the completion of corticogenesis and represents 50% of dying neurons in the postnatal day 0 cortex. Specific genetic ablation of these transient Dbx1-derived CP neurons leads to a 20% decrease in neocortical cell numbers in perinatal animals. Our results show that a previously unidentified transient population of glutamatergic neurons migrates from extraneocortical regions over long distance from their generation site and participates in neocortical radial growth in a non-cell-autonomous manner.

MeSH Categories: Animals, Apoptosis/physiology, Cell Count, Cell Movement/*physiology, Glutamic Acid/*metabolism, Immunohistochemistry, Mice, Neocortex/embryology/*metabolism, Neurogenesis/physiology, Neurons/*metabolism, Reverse Transcriptase Polymerase Chain Reaction, Vesicular Glutamate Transport Protein 2/metabolism, gamma-Aminobutyric Acid/metabolism

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LIM-homeobox gene Lhx5 is required for normal development of Cajal-Retzius cells.

Publication Date: 2010 Aug 4 PMID: 20685998
Authors: Miquelajauregui, A. - Varela-Echavarria, A. - Ceci, M. L. - Garcia-Moreno, F. - Ricano, I. - Hoang, K. - Frade-Perez, D. - Portera-Cailliau, C. - Tamariz, E. - De Carlos, J. A. - Westphal, H. - Zhao, Y.
Journal: J Neurosci

Cajal-Retzius (C-R) cells play important roles in the lamination of the mammalian cortex via reelin secretion. The genetic mechanisms underlying the development of these neurons have just begun to be unraveled. Here, we show that two closely related LIM-homeobox genes Lhx1 and Lhx5 are expressed in reelin+ cells in various regions in the mouse telencephalon at or adjacent to sites where the C-R cells are generated, including the cortical hem, the mantle region of the septal/retrobulbar area, and the ventral pallium. Whereas Lhx5 is expressed in all of these reelin-expressing domains, Lhx1 is preferentially expressed in the septal area and in a continuous domain spanning from lateral olfactory region to caudomedial territories. Genetic ablation of Lhx5 results in decreased reelin+ and p73+ cells in the neocortical anlage, in the cortical hem, and in the septal, olfactory, and caudomedial telencephalic regions. The overall reduction in number of C-R cells in Lhx5 mutants is accompanied by formation of ectopic reelin+ cell clusters at the caudal telencephalon. Based on differential expression of molecular markers and by fluorescent cell tracing in cultured embryos, we located the origin of reelin+ ectopic cell clusters at the caudomedial telencephalic region. We also confirmed the existence of a normal migration stream of reelin+ cells from the caudomedial area to telencephalic olfactory territories in wild-type embryos. These results reveal a complex role for Lhx5 in regulating the development and normal distribution of C-R cells in the developing forebrain.

MeSH Categories: Animals, Cell Adhesion Molecules, Neuronal/genetics/*metabolism, Cell Movement, Cerebral Cortex/*metabolism, Embryo Culture Techniques, Extracellular Matrix Proteins/genetics/*metabolism, Homeodomain Proteins/genetics/*metabolism, Immunohistochemistry, In Situ Hybridization, Mice, Mice, Knockout, Nerve Tissue Proteins/genetics/*metabolism, Neurons/*metabolism, Reverse Transcriptase Polymerase Chain Reaction, Serine Endopeptidases/genetics/*metabolism, Transcription Factors/genetics/*metabolism

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Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into huntington's disease molecular pathogenesis.

Publication Date: 2010 Aug 4 PMID: 20685997
Authors: Miller, J. - Arrasate, M. - Shaby, B. A. - Mitra, S. - Masliah, E. - Finkbeiner, S.
Journal: J Neurosci

An expanded polyglutamine (polyQ) stretch in the protein huntingtin (htt) induces self-aggregation into inclusion bodies (IBs) and causes Huntington's disease (HD). Defining precise relationships between early observable variables and neuronal death at the molecular and cellular levels should improve our understanding of HD pathogenesis. Here, we used an automated microscope that tracks thousands of neurons individually over their entire lifetime to quantify interconnected relationships between early variables, such as htt levels, polyQ length, and IB formation, and neuronal death in a primary striatal model of HD. The resulting model revealed that mutant htt increases the risk of death by tonically interfering with homeostatic coping mechanisms rather than producing accumulated damage to the neuron, htt toxicity is saturable, the rate-limiting steps for inclusion body formation and death can be traced to different conformational changes in monomeric htt, and IB formation reduces the impact of the starting levels of htt of a neuron on its risk of death. Finally, the model that emerges from our quantitative measurements places critical limits on the potential mechanisms by which mutant htt might induce neurodegeneration, which should help direct future research.

MeSH Categories: Animals, Cell Death/*genetics, Cells, Cultured, Corpus Striatum/cytology/metabolism/*pathology, Huntington Disease/genetics/metabolism/*pathology, Immunohistochemistry, Inclusion Bodies/genetics/metabolism/pathology, Nerve Degeneration/genetics/metabolism/pathology, Nerve Tissue Proteins/genetics/*metabolism, Neurons/cytology/metabolism/*pathology, Nuclear Proteins/genetics/*metabolism, Peptides/genetics/*metabolism, Rats, Regression Analysis

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The body inversion effect is mediated by face-selective, not body-selective, mechanisms.

Publication Date: 2010 Aug 4 PMID: 20685996
Authors: Brandman, T. - Yovel, G.
Journal: J Neurosci

Evidence suggesting that the brain has specialized mechanisms for processing human bodies include the discovery of body-selective brain areas and the behavioral body inversion effect (BIE). Interestingly, the BIE (worse discrimination of inverted vs upright bodies) disappears for headless bodies, implying a critical role of the head in this effect. Previous studies have shown that the face inversion effect is mediated by the fusiform face-selective area. Given the central role that the head plays in the behavioral BIE, we asked whether it is mediated by face-selective or body-selective areas. In two event-related functional magnetic resonance-adaptation experiments, we examined the representation of upright and inverted bodies in category-selective occipitotemporal areas. In the first experiment we presented whole (faceless) bodies, while in the second we presented headless bodies. Both experiments consisted of pairs of upright and inverted bodies that were either the same or different in posture. Body-selective areas showed similar adaptation effects for upright and inverted whole or headless bodies, suggesting similar discrimination for the two orientations regardless of the head. In contrast, face-selective areas showed an adaptation effect to upright but not inverted bodies, and for whole but not for headless bodies. Thus, the response of the face-selective, but not body-selective areas, is consistent with the behavioral BIE in that it shows better discrimination for upright than inverted bodies, for whole but not for headless bodies. These results suggest a critical role for the head in the processing of human bodies.

MeSH Categories: Adult, Analysis of Variance, Brain Mapping, Discrimination (Psychology)/physiology, Face, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Occipital Lobe/*physiology, Orientation/*physiology, Pattern Recognition, Visual/*physiology, Photic Stimulation, Recognition (Psychology)/physiology, Temporal Lobe/*physiology

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D-cycloserine reduces the context specificity of pavlovian extinction of cocaine cues through actions in the nucleus accumbens.

Publication Date: 2010 Aug 4 PMID: 20685995
Authors: Torregrossa, M. M. - Sanchez, H. - Taylor, J. R.
Journal: J Neurosci

Extinction therapy has been proposed as a method to reduce the motivational impact of drug-associated cues to prevent relapse. Cue extinction therapy, however, takes place in a novel context (e.g., treatment facility), and is unlikely to be effective due to the context specificity of extinction. We tested the hypothesis that d-cycloserine (DCS), which enhances extinction in other procedures, would enhance extinction of cocaine-associated cues in a novel context to reduce cue-induced reinstatement. Male Sprague Dawley rats were trained to self-administer cocaine associated with a cue. The cue was later extinguished in the drug-taking context (context A) or a novel context (context B) using a Pavlovian cue extinction procedure designed to mimic human cue exposure therapy. DCS was administered systemically or into a specific brain region immediately following the cue extinction sessions to enhance the consolidation of extinction learning. We demonstrate that DCS given postextinction session in context B reduces reinstatement in context A, indicating a reduction in the context specificity of extinction learning. The effect of systemic DCS was recapitulated by administration of DCS into the nucleus accumbens core, but not in the basolateral amygdala, dorsal hippocampus, infralimbic or prelimbic prefrontal cortex. DCS treatment caused a reduction in cue-induced reinstatement only when it was given after cue extinction sessions, and not when given 1) in the absence of extinction or 2) after a brief memory reactivation session. A pharmacological method that can render extinction context independent may provide an innovative method to reduce cue-induced relapse in addicts and to study the neurobiology of addiction.

MeSH Categories: Analysis of Variance, Animals, Behavior, Addictive, Cocaine/*administration & dosage/pharmacology, Conditioning, Operant/*drug effects/physiology, *Cues, Cycloserine/*pharmacology, Environment, Extinction, Psychological/*drug effects/physiology, Male, Nucleus Accumbens/*drug effects/physiology, Rats, Rats, Sprague-Dawley, Reward, Self Administration, Time Factors

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Causality attribution biases oculomotor responses.

Publication Date: 2010 Aug 4 PMID: 20685994
Authors: Badler, J. - Lefevre, P. - Missal, M.
Journal: J Neurosci

When viewing one object move after being struck by another, humans perceive that the action of the first object "caused" the motion of the second, not that the two events occurred independently. Although established as a perceptual and linguistic concept, it is not yet known whether the notion of causality exists as a fundamental, preattentional "Gestalt" that can influence predictive motor processes. Therefore, eye movements of human observers were measured while viewing a display in which a launcher impacted a tool to trigger the motion of a second "reaction" target. The reaction target could move either in the direction predicted by transfer of momentum after the collision ("causal") or in a different direction ("noncausal"), with equal probability. Control trials were also performed with identical target motion, either with a 100 ms time delay between the collision and reactive motion, or without the interposed tool. Subjects made significantly more predictive movements (smooth pursuit and saccades) in the causal direction during standard trials, and smooth pursuit latencies were also shorter overall. These trends were reduced or absent in control trials. In addition, pursuit latencies in the noncausal direction were longer during standard trials than during control trials. The results show that causal context has a strong influence on predictive movements.

MeSH Categories: Adult, Attention/physiology, Eye Movements/*physiology, Female, Humans, Male, Motion Perception/*physiology, Photic Stimulation, Psychomotor Performance/physiology, Reaction Time/physiology

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Temporal discounting of reward and the cost of time in motor control.

Publication Date: 2010 Aug 4 PMID: 20685993
Authors: Shadmehr, R. - Orban de Xivry, J. J. - Xu-Wilson, M. - Shih, T. Y.
Journal: J Neurosci

Why do movements take a characteristic amount of time, and why do diseases that affect the reward system alter control of movements? Suppose that the purpose of any movement is to position our body in a more rewarding state. People and other animals discount future reward as a hyperbolic function of time. Here, we show that across populations of people and monkeys there is a correlation between discounting of reward and control of movements. We consider saccadic eye movements and hypothesize that duration of a movement is equivalent to a delay of reward. The hyperbolic cost of this delay not only accounts for kinematics of saccades in adults, it also accounts for the faster saccades of children, who temporally discount reward more steeply. Our theory explains why saccade velocities increase when reward is elevated, and why disorders in the encoding of reward, for example in Parkinson's disease and schizophrenia, produce changes in saccade. We show that delay of reward elevates the cost of saccades, reducing velocities. Finally, we consider coordinated movements that include motion of eyes and head and find that their kinematics is also consistent with a hyperbolic, reward-dependent cost of time. Therefore, each voluntary movement carries a cost because its duration delays acquisition of reward. The cost depends on the value that the brain assigns to stimuli, and the rate at which it discounts this value in time. The motor commands that move our eyes reflect this cost of time.

MeSH Categories: Adolescent, Adult, Computer Simulation, Female, Fixation, Ocular, Humans, Male, Models, Neurological, Movement/*physiology, Reaction Time, *Reward, Saccades/*physiology, Time Factors

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Attentional facilitation throughout human visual cortex lingers in retinotopic coordinates after eye movements.

Publication Date: 2010 Aug 4 PMID: 20685992
Authors: Golomb, J. D. - Nguyen-Phuc, A. Y. - Mazer, J. A. - McCarthy, G. - Chun, M. M.
Journal: J Neurosci

With each eye movement, the image of the world received by the visual system changes dramatically. To maintain stable spatiotopic (world-centered) visual representations, the retinotopic (eye-centered) coordinates of visual stimuli are continually remapped, even before the eye movement is completed. Recent psychophysical work has suggested that updating of attended locations occurs as well, although on a slower timescale, such that sustained attention lingers in retinotopic coordinates for several hundred milliseconds after each saccade. To explore where and when this "retinotopic attentional trace" resides in the cortical visual processing hierarchy, we conducted complementary functional magnetic resonance imaging and event-related potential (ERP) experiments using a novel gaze-contingent task. Human subjects executed visually guided saccades while covertly monitoring a fixed spatiotopic target location. Although subjects responded only to stimuli appearing at the attended spatiotopic location, blood oxygen level-dependent responses to stimuli appearing after the eye movement at the previously, but no longer, attended retinotopic location were enhanced in visual cortical area V4 and throughout visual cortex. This retinotopic attentional trace was also detectable with higher temporal resolution in the anterior N1 component of the ERP data, a well established signature of attentional modulation. Together, these results demonstrate that, when top-down spatiotopic signals act to redirect visuospatial attention to new retinotopic locations after eye movements, facilitation transiently persists in the cortical regions representing the previously relevant retinotopic location.

MeSH Categories: Adult, Analysis of Variance, Attention/*physiology, Brain Mapping, Electroencephalography, Evoked Potentials, Visual/physiology, Eye Movements/*physiology, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Photic Stimulation, Retina/*physiology, Visual Cortex/*physiology, Visual Pathways/*physiology, Visual Perception/physiology

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Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells.

Publication Date: 2010 Aug 4 PMID: 20685991
Authors: Ables, J. L. - Decarolis, N. A. - Johnson, M. A. - Rivera, P. D. - Gao, Z. - Cooper, D. C. - Radtke, F. - Hsieh, J. - Eisch, A. J.
Journal: J Neurosci

Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER(T2)/R26R-YFP/Notch1(loxP/loxP) [Notch1inducible knock-out (iKO)] mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild-type (WT) mice (nestin-CreER(T2)/R26R-YFP/Notch1(w/w)) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared with WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 d post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 d post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 d of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch- and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.

MeSH Categories: Adult Stem Cells/*metabolism, Animals, Cell Count, Hippocampus/*metabolism, Immunohistochemistry, Mice, Mice, Transgenic, Neurogenesis/*physiology, Neurons/metabolism, Physical Conditioning, Animal/physiology, Receptor, Notch1/*metabolism

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Stress-evoked tyrosine phosphorylation of signal regulatory protein alpha regulates behavioral immobility in the forced swim test.

Publication Date: 2010 Aug 4 PMID: 20685990
Authors: Ohnishi, H. - Murata, T. - Kusakari, S. - Hayashi, Y. - Takao, K. - Maruyama, T. - Ago, Y. - Koda, K. - Jin, F. J. - Okawa, K. - Oldenborg, P. A. - Okazawa, H. - Murata, Y. - Furuya, N. - Matsuda, T. - Miyakawa, T. - Matozaki, T.
Journal: J Neurosci

Severe stress induces changes in neuronal function that are implicated in stress-related disorders such as depression. The molecular mechanisms underlying the response of the brain to stress remain primarily unknown, however. Signal regulatory protein alpha (SIRPalpha) is an Ig-superfamily protein that undergoes tyrosine phosphorylation and binds the protein tyrosine phosphatase Shp2. Here we show that mice expressing a form of SIRPalpha that lacks most of the cytoplasmic region manifest prolonged immobility (depression-like behavior) in the forced swim (FS) test. FS stress induced marked tyrosine phosphorylation of SIRPalpha in the brain of wild-type mice through activation of Src family kinases. The SIRPalpha ligand CD47 was important for such SIRPalpha phosphorylation, and CD47-deficient mice also manifested prolonged immobility in the FS test. Moreover, FS stress-induced tyrosine phosphorylation of both the NR2B subunit of the NMDA subtype of glutamate receptor and the K+-channel subunit Kvbeta2 was regulated by SIRPalpha. Thus, tyrosine phosphorylation of SIRPalpha is important for regulation of depression-like behavior in the response of the brain to stress.

MeSH Categories: Animals, Animals, Genetically Modified, Blotting, Western, Cell Line, Cerebral Cortex/*metabolism, Hippocampus/*metabolism, Humans, Immobility Response, Tonic/*physiology, Mice, Microdialysis, Phosphorylation, Receptors, Immunologic/genetics/*metabolism, Stress, Physiological/*physiology, Stress, Psychological/metabolism/*physiopathology, Swimming

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Fine thermotactic discrimination between the optimal and slightly cooler temperatures via a TRPV channel in chordotonal neurons.

Publication Date: 2010 Aug 4 PMID: 20685989
Authors: Kwon, Y. - Shen, W. L. - Shim, H. S. - Montell, C.
Journal: J Neurosci

Animals select their optimal environmental temperature, even when faced with alternatives that differ only slightly. This behavior is critical as small differences in temperature of only several degrees can have a profound effect on the survival and rate of development of poikilothermic animals, such as the fruit fly. Here, we demonstrate that Drosophila larvae choose their preferred temperature of 17.5 degrees C over slightly cooler temperatures (14-16 degrees C) through activation of chordotonal neurons. Mutations affecting a transient receptor potential (TRP) vanilloid channel, Inactive (Iav), which is expressed specifically in chordotonal neurons, eliminated the ability to choose 17.5 degrees C over 14-16 degrees C. The impairment in selecting 17.5 degrees C resulted from absence of an avoidance response, which is normally mediated by an increase in turns at the lower temperatures. We conclude that the decision to select the preferred over slightly cooler temperatures requires iav and is achieved by activating chordotonal neurons, which in turn induces repulsive behaviors, due to an increase in high angle turns.

MeSH Categories: Analysis of Variance, Animals, Animals, Genetically Modified, Behavior, Animal/physiology, Choice Behavior/physiology, Discrimination (Psychology)/*physiology, Drosophila, Drosophila Proteins/*genetics, Ion Channels/*genetics, Locomotion/genetics, Neurons/*physiology, Sensory Thresholds/*physiology, Temperature, Temperature Sense/*physiology

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Negative valence widens generalization of learning.

Publication Date: 2010 Aug 4 PMID: 20685988
Authors: Schechtman, E. - Laufer, O. - Paz, R.
Journal: J Neurosci

Learning includes the ability to generalize to new situations and respond to similar, yet not identical stimuli. We use stimulus generalization in humans to show that tones that were negatively reinforced induce wider generalization curves than tones that were positively reinforced, and these in turn induce wider curves than neutral memory. Importantly, these wider generalization curves persist even if outcomes for all tones are made identical, indicating that the learning induced a perceptual change, and not merely a decision bias. Moreover, it persists after taking into account loss-aversion, suggesting it is a result of valence per se, and not intensity that reflects overweighting of the aversive stimuli. This effect of emotional valence on learning suggests different locations of plasticity and network mechanisms in the brain. Particularly, it suggests that brain areas that mediate reinforcement and emotions are involved during the learning process to induce a neural representation that can support this broader behavioral generalization. In addition, these findings highlight a model for anxiety and trauma disorders in which aversive experiences affect more than they should, sometimes even in seemingly irrational situations.

MeSH Categories: Acoustic Stimulation, Adult, Analysis of Variance, Association Learning/*physiology, Female, Generalization (Psychology)/*physiology, Humans, Logistic Models, Male, Psychomotor Performance/physiology

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Selection of prime actor in humans during bimanual object manipulation.

Publication Date: 2010 Aug 4 PMID: 20685987
Authors: Theorin, A. - Johansson, R. S.
Journal: J Neurosci

In bimanual object manipulation tasks, people flexibly assign one hand as a prime actor while the other assists. Little is known, however, about the neural mechanisms deciding the role assignment. We addressed this issue in a task in which participants moved a cursor to hit targets on a screen by applying precisely coupled symmetrical opposing linear and twist forces on a tool held freely between the hands. In trials presented in an unpredictable order, the action of either the left or the right hand was spatially congruent with the cursor movements, which automatically rendered the left or right hand the dominant actor, respectively. Functional magnetic resonance imaging indicated that the hand-selection process engaged prefrontal cortical areas belonging to an executive control network presumed critical for judgment and decision-making and to a salience network attributed to evaluation of utility of actions. Task initiation, which involved switching between task sets, had a superordinate role with reference to hand selection. Behavioral and brain imaging data indicated that participants initially expressed two competing action representations, matching either mapping rule, before selecting the appropriate one based on the consequences of the initial manual actions. We conclude that implicit processes engaging the prefrontal cortex reconcile selections among action representations that compete for the establishment of a dominant actor in bimanual object manipulation tasks. The representation selected is the one that optimizes performance by relying on the superior capacity of the brain to process spatial congruent, as opposed to noncongruent, mappings between manual actions and desired movement goals.

MeSH Categories: Adult, Analysis of Variance, Brain Mapping, Choice Behavior/physiology, Executive Function/*physiology, Female, Functional Laterality/*physiology, Humans, Image Processing, Computer-Assisted, Judgment/physiology, Magnetic Resonance Imaging, Male, Prefrontal Cortex/*physiology, Psychomotor Performance/*physiology

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Lipoprotein particles cross the blood-brain barrier in Drosophila.

Publication Date: 2010 Aug 4 PMID: 20685986
Authors: Brankatschk, M. - Eaton, S.
Journal: J Neurosci

The blood-brain barrier (BBB) regulates passage of nutrients and signaling molecules from the circulation into the brain. Whether lipoproteins cross the BBB in vivo has been controversial, and no clear requirement for circulating lipoproteins in brain development has been shown. We address these issues in Drosophila, which has an functionally conserved BBB, and lipoproteins that resemble those of vertebrates. We show that the Drosophila lipoprotein lipophorin exists in two isoforms. Both isoforms cross the BBB, but accumulate on distinct subsets of cells within the brain. In addition to acting as a lipid carrier, lipophorin carries both sterol-linked and GPI-linked proteins into the circulation and transports them across the BBB. Finally, lipophorin promotes neuroblast proliferation by a mechanism that does not depend on delivery of dietary lipids. Transport of lipophorin and its cargo across the BBB represents a novel mechanism by which peripherally synthesized proteins might enter the brain and influence its development. Furthermore, lipid-linkage may be an efficient method to transport therapeutic molecules across the BBB.

MeSH Categories: Animals, Blood-Brain Barrier/*metabolism, Brain/growth & development/*metabolism, Drosophila, Drosophila Proteins/metabolism, Immunohistochemistry, Lipoproteins/*metabolism, Protein Transport

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Biochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development.

Publication Date: 2010 Aug 4 PMID: 20685985
Authors: Young-Pearse, T. L. - Suth, S. - Luth, E. S. - Sawa, A. - Selkoe, D. J.
Journal: J Neurosci

Although clinically distinct, schizophrenia and Alzheimer's disease are common and devastating disorders that profoundly impair cognitive function. For Alzheimer's disease, key mechanistic insights have emerged from genetic studies that identified causative mutations in amyloid precursor protein (APP) and presenilin. Several genes have been associated with schizophrenia and other major psychoses, and understanding their normal functions will help elucidate the underlying causes of these disorders. One such gene is disrupted-in-schizophrenia 1 (DISC1). DISC1 and APP have been implicated separately in cortical development, with each having roles in both neuronal migration and neurite outgrowth. Here, we report a previously unrecognized biochemical and functional interaction between DISC1 and APP. Using in utero electroporation in the living rat brain, we show that DISC1 acts downstream of APP and Disabled-1 to regulate cortical precursor cell migration. Specifically, overexpression of DISC1 rescues the migration defect caused by a loss of APP expression. Moreover, knockdown of APP in cultured embryonic neurons results in altered subcellular localization of DISC1. Using transfected cells and normal brain tissue, we show that APP and DISC1 coimmunoprecipitate and that the intracellular domain of APP interacts with the N-terminal domain of DISC1. Based on these findings, we hypothesize that the APP cytoplasmic region transiently interacts with DISC1 to help regulate the translocation of DISC1 to the centrosome, where it plays a key role in controlling neuronal migration during cortical development.

MeSH Categories: Amyloid beta-Protein Precursor/genetics/*metabolism, Animals, Blotting, Western, Cell Movement/*physiology, Cells, Cultured, Cerebral Cortex/*embryology/metabolism, Electroporation, Fluorescent Antibody Technique, Immunoprecipitation, Microscopy, Confocal, Nerve Tissue Proteins/genetics/*metabolism, Neurons/*metabolism, Rats, Rats, Sprague-Dawley, Transfection

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Group III metabotropic glutamate receptors inhibit startle-mediating giant neurons in the caudal pontine reticular nucleus but do not mediate synaptic depression/short-term habituation of startle.

Publication Date: 2010 Aug 4 PMID: 20685984
Authors: Schmid, S. - Brown, T. - Simons-Weidenmaier, N. - Weber, M. - Fendt, M.
Journal: J Neurosci

Short-term habituation is a basic form of learning that is analyzed in different species and using different behavioral models. Previous studies on mechanisms of short-term habituation yielded evidence for a potential role of group III metabotropic glutamate receptors (mGluRIIIs). Here we tested the hypothesis that mGluRIII mediate short-term habituation of startle in rats, combining electrophysiological experiments in vitro with behavioral studies in vivo. We applied different mGluRIII agonists and antagonists on rat brainstem slices while recording from startle-mediating neurons in the caudal pontine reticular nucleus (PnC) and monitoring synaptic depression presumably underlying habituation. Furthermore, we injected the mGluRIII antagonist (RS)-alpha-phosphonophenylglycine (MPPG) and the agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) into the PnC of rats in vivo and measured its effect on startle habituation. Our results show that activation of mGluRIIIs in the PnC strongly inhibits startle-mediating giant neurons in vitro. Accordingly, L-AP4 reduced startle responses in vivo. However, synaptic depression in the slice was not disrupted by mGluRIII antagonists or agonists. Correspondingly, the in vivo application of the mGluRIII antagonist MPPG failed to show any effect on short-term habituation of startle responses. We therefore conclude that mGluRs are expressed within the primary startle pathway and that they inhibit startle responses upon activation; however, this inhibition does not play any role in synaptic depression and short-term habituation of startle. This is in contrast to the role of mGluRIIIs in other forms of habituation and supports the notion that there are different mechanisms involved in habituation of sensory-evoked behaviors.

MeSH Categories: Alanine/analogs & derivatives/pharmacology, Analysis of Variance, Animals, Electrophysiology, Evoked Potentials, Auditory/drug effects/physiology, Excitatory Postsynaptic Potentials/drug effects/physiology, Habituation, Psychophysiologic/drug effects/*physiology, Long-Term Synaptic Depression/drug effects/*physiology, Male, Neurons/drug effects/*physiology, Phosphoserine/pharmacology, Pons/drug effects/*physiology, Propionic Acids/pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate/*antagonists & inhibitors, Reticular Formation/drug effects/*physiology, Startle Reaction/*physiology, Synaptic Transmission/drug effects/physiology

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Triphasic dynamics of stimulus-dependent information flow between single neurons in macaque inferior temporal cortex.

Publication Date: 2010 Aug 4 PMID: 20685983
Authors: Hirabayashi, T. - Takeuchi, D. - Tamura, K. - Miyashita, Y.
Journal: J Neurosci

The functional connectivity between cortical neurons is not static and is known to exhibit contextual modulations in terms of the coupling strength. Here we hypothesized that the information flow in a cortical local circuit exhibits complex forward-and-back dynamics, and conducted Granger causality analysis between the neuronal spike trains that were simultaneously recorded from macaque inferior temporal (IT) cortex while the animals performed a visual object discrimination task. Spikes from neuron pairs with a displaced peak on the cross-correlogram (CCG) showed Granger causality in the gamma-frequency range (30-80 Hz) with the dominance in the direction consistent with the CCG peak (forward direction). Although, in a classical view, the displaced CCG peak has been interpreted as an indicative of a pauci-synaptic serial linkage, temporal dynamics of the gamma Granger causality after stimulus onset exhibited a more complex triphasic pattern, with a transient forward component followed by a slowly developing backward component and subsequent reappearance of the forward component. These triphasic dynamics of causality were not explained by the firing rate dynamics and were not observed for cell pairs that exhibited a center peak on the CCG. Furthermore, temporal dynamics of Granger causality depended on the feature configuration within the presented object. Together, these results demonstrate that the classical view of functional connectivity could be expanded to incorporate more complex forward-and-back dynamics and also imply that multistage processing in the recognition of visual objects might be implemented by multiphasic dynamics of directional information flow between single neurons in a local circuit in the IT cortex.

MeSH Categories: Action Potentials/*physiology, Analysis of Variance, Animals, Discrimination (Psychology)/*physiology, Electrodes, Implanted, Macaca, Models, Neurological, Nerve Net/physiology, Neurons/*physiology, Pattern Recognition, Visual/*physiology, Temporal Lobe/*physiology, Visual Pathways/physiology

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Centrosome motility is essential for initial axon formation in the neocortex.

Publication Date: 2010 Aug 4 PMID: 20685982
Authors: de Anda, F. C. - Meletis, K. - Ge, X. - Rei, D. - Tsai, L. H.
Journal: J Neurosci

The mechanisms underlying the normal development of neuronal morphology remain a fundamental question in neurobiology. Studies in cultured neurons have suggested that the position of the centrosome and the Golgi may predict the site of axon outgrowth. During neuronal migration in the developing cortex, however, the centrosome and Golgi are oriented toward the cortical plate at a time when axons grow toward the ventricular zone. In the current work, we use in situ live imaging to demonstrate that the centrosome and the accompanying polarized cytoplasm exhibit apical translocation in newborn cortical neurons preceding initial axon outgrowth. Disruption of centrosomal activity or downregulation of the centriolar satellite protein PCM-1 affects axon formation. We further show that downregulation of the centrosomal protein Cep120 impairs microtubule organization, resulting in increased centrosome motility. Decreased centrosome motility resulting from microtubule stabilization causes an aberrant centrosomal localization, leading to misplaced axonal outgrowth. Our results reveal the dynamic nature of the centrosome in developing cortical neurons, and implicate centrosome translocation and microtubule organization during the multipolar stage as important determinants of axon formation.

MeSH Categories: Analysis of Variance, Animals, Autoantigens/metabolism, Axons/*metabolism, Cell Cycle Proteins/metabolism, Cell Death, Cell Line, Cell Movement/*physiology, Cell Polarity, Cells, Cultured, Centrosome/*metabolism, Down-Regulation, Electroporation, Embryo Culture Techniques, Fluorescent Antibody Technique, Golgi Apparatus/metabolism, Humans, Mice, Microscopy, Confocal, Microtubules/metabolism, Neocortex/*metabolism, Neurons/*metabolism

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Power-law dynamics in an auditory-nerve model can account for neural adaptation to sound-level statistics.

Publication Date: 2010 Aug 4 PMID: 20685981
Authors: Zilany, M. S. - Carney, L. H.
Journal: J Neurosci

Neurons in the auditory system respond to recent stimulus-level history by adapting their response functions according to the statistics of the stimulus, partially alleviating the so-called "dynamic-range problem." However, the mechanism and source of this adaptation along the auditory pathway remain unknown. Inclusion of power-law dynamics in a phenomenological model of the inner hair cell (IHC)-auditory nerve (AN) synapse successfully explained neural adaptation to sound-level statistics, including the time course of adaptation of the mean firing rate and changes in the dynamic range observed in AN responses. A direct comparison between model responses to a dynamic stimulus and to an "inversely gated" static background suggested that AN dynamic-range adaptation largely results from the adaptation produced by the response history. These results support the hypothesis that the potential mechanism underlying the dynamic-range adaptation observed at the level of the auditory nerve is located peripheral to the spike generation mechanism and central to the IHC receptor potential.

MeSH Categories: Auditory Pathways/*physiology, Auditory Perception/*physiology, Auditory Threshold/physiology, Cochlear Nerve/*physiology, Computer Simulation, Models, Neurological, Sound

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Generation and therapeutic efficacy of highly oligomer-specific beta-amyloid antibodies.

Publication Date: 2010 Aug 4 PMID: 20685980
Authors: Hillen, H. - Barghorn, S. - Striebinger, A. - Labkovsky, B. - Muller, R. - Nimmrich, V. - Nolte, M. W. - Perez-Cruz, C. - van der Auwera, I. - van Leuven, F. - van Gaalen, M. - Bespalov, A. Y. - Schoemaker, H. - Sullivan, J. P. - Ebert, U.
Journal: J Neurosci

Oligomers of the beta-amyloid (Abeta) peptide have been indicated in early neuropathologic changes in Alzheimer's disease. Here, we present a synthetic Abeta(20-42) oligomer (named globulomer) with a different conformation to monomeric and fibrillar Abeta peptide, enabling the generation of highly Abeta oligomer-specific monoclonal antibodies. The globulomer-derived antibodies specifically detect oligomeric but not monomeric or fibrillar Abeta in various Abeta preparations. The globulomer-specific antibody A-887755 was able to prevent Abeta oligomer binding and dynamin cleavage in primary hippocampal neurons and to reverse globulomer-induced reduced synaptic transmission. In amyloid precursor protein (APP) transgenic mice, vaccination with Abeta globulomer and treatment with A-887755 improved novel object recognition. The cognitive improvement is likely attributable to reversing a deficit in hippocampal synaptic spine density in APP transgenic mice as observed after treatment with A-887755. Our findings demonstrate that selective reduction of Abeta oligomers by immunotherapy is sufficient to normalize cognitive behavior and synaptic deficits in APP transgenic mice.

MeSH Categories: Alzheimer Disease/drug therapy/immunology, Amyloid beta-Protein/*immunology, Amyloid beta-Protein Precursor/*genetics, Analysis of Variance, Animals, Antibodies, Monoclonal/immunology/*therapeutic use, Cells, Cultured, Disease Models, Animal, Female, Hippocampus/cytology/immunology, Immunoprecipitation, Male, Mice, Mice, Transgenic, Neurons/cytology/immunology, Rats, Rats, Wistar, Recognition (Psychology)

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Ca(v)3.2 T-type Ca2+ channel-dependent activation of ERK in paraventricular thalamus modulates acid-induced chronic muscle pain.

Publication Date: 2010 Aug 4 PMID: 20685979
Authors: Chen, W. K. - Liu, I. Y. - Chang, Y. T. - Chen, Y. C. - Chen, C. C. - Yen, C. T. - Shin, H. S. - Chen, C. C.
Journal: J Neurosci

Treatments for chronic musculoskeletal pain, such as lower back pain, fibromyalgia, and myofascial pain syndrome, remain inadequate because of our poor understanding of the mechanisms that underlie these conditions. Although T-type Ca2+ channels (T-channels) have been implicated in peripheral and central pain sensory pathways, their role in chronic musculoskeletal pain is still unclear. Here, we show that acid-induced chronic mechanical hyperalgesia develops in Ca(v)3.1-deficient and wild-type but not in Ca(v)3.2-deficient male and female mice. We also show that T-channels are required for the initiation, but not maintenance, of acid-induced chronic muscle pain. Blocking T-channels using ethosuximide prevented chronic mechanical hyperalgesia in wild-type mice when administered intraperitoneally or intracerebroventricularly, but not intramuscularly or intrathecally. Furthermore, we found an acid-induced, Ca(v)3.2 T-channel-dependent activation of ERK (extracellular signal-regulated kinase) in the anterior nucleus of paraventricular thalamus (PVA), and prevention of the ERK activation abolished the chronic mechanical hyperalgesia. Our findings suggest that Ca(v)3.2 T-channel-dependent activation of ERK in PVA is required for the development of acid-induced chronic mechanical hyperalgesia.

MeSH Categories: Analysis of Variance, Animals, Calcium Channels, T-Type/genetics/*metabolism, Extracellular Signal-Regulated MAP Kinases/*metabolism, Female, Hyperalgesia/*metabolism/physiopathology, Immunohistochemistry, Male, Mice, Mice, Knockout, Muscle, Skeletal/*metabolism/physiopathology, Pain/*metabolism/physiopathology, Pain Measurement, Pain Threshold/physiology, Thalamus/*metabolism

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Basolateral amygdala cdk5 activity mediates consolidation and reconsolidation of memories for cocaine cues.

Publication Date: 2010 Aug 4 PMID: 20685978
Authors: Li, F. Q. - Xue, Y. X. - Wang, J. S. - Fang, Q. - Li, Y. Q. - Zhu, W. L. - He, Y. Y. - Liu, J. F. - Xue, L. F. - Shaham, Y. - Lu, L.
Journal: J Neurosci

Cocaine use and relapse involves learned associations between cocaine-associated environmental contexts and discrete stimuli and cocaine effects. Initially, these contextual and discrete cues undergo memory consolidation after being paired with cocaine exposure. During abstinence, cocaine cue memories can undergo memory reconsolidation after cue exposure without the drug. We used a conditioned place preference (CPP) procedure in rats to study the role of neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) in consolidation and reconsolidation of cocaine cue memories. We found that the expression of cocaine CPP in drug-free tests 1 d after CPP training (four pairings of 10 mg/kg cocaine with one context and four pairings of saline with a different context) increased Cdk5 activity, and levels of the Cdk5 activator p35 in basolateral but not central amygdala. We also found that basolateral (but not central) amygdala injections of the Cdk5 inhibitor beta-butyrolactone (100 ng/side) immediately (but not 6 h) after cocaine-context pairings during training prevented subsequent cocaine CPP expression. After training, acute basolateral (but not central) amygdala beta-butyrolactone injections immediately before testing prevented the expression of cocaine CPP; this effect was also observed on a second test performed 1 d later, suggesting an effect on reconsolidation of cocaine cue memories. In support, basolateral beta-butyrolactone injections, given immediately (but not 6 h) after a single exposure to the cocaine-paired context, prevented cocaine CPP expression 1 and 14 d after the injections. Results indicate that basolateral amygdala Cdk5 activity is critical for consolidation and reconsolidation of the memories of cocaine-associated environmental cues.

MeSH Categories: 4-Butyrolactone/analogs & derivatives/pharmacology, Amygdala/drug effects/*metabolism, Analysis of Variance, Animals, Association Learning/drug effects/*physiology, Blotting, Western, Cocaine/*administration & dosage, Conditioning (Psychology)/drug effects/physiology, Cues, Cyclin-Dependent Kinase 5/antagonists & inhibitors/*metabolism, Male, Memory/drug effects/*physiology, Rats, Rats, Sprague-Dawley

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The representation of S-cone signals in primary visual cortex.

Publication Date: 2010 Aug 4 PMID: 20685977
Authors: Johnson, E. N. - Van Hooser, S. D. - Fitzpatrick, D.
Journal: J Neurosci

Recent studies of middle-wavelength-sensitive and long-wavelength-sensitive cone responses in primate primary visual cortex (V1) have challenged the view that color and form are represented by distinct neuronal populations. Individual V1 neurons exhibit hallmarks of both color and form processing (cone opponency and orientation selectivity), and many display cone interactions that do not fit classic chromatic/achromatic classifications. Comparable analysis of short-wavelength-sensitive (S) cone responses has yet to be achieved and is of considerable interest because S-cones are the basis for the primordial mammalian chromatic pathway. Using intrinsic and two-photon imaging techniques in the tree shrew, we assessed the properties of V1 layer 2/3 neurons responsive to S-cone stimulation. These responses were orientation selective, exhibited distinct spatiotemporal properties, and reflected integration of S-cone inputs via opponent, summing, and intermediate configurations. Our observations support a common framework for the representation of cone signals in V1, one that endows orientation-selective neurons with a range of chromatic, achromatic, and mixed response properties.

MeSH Categories: Animals, Brain Mapping, Electrophysiology, Models, Neurological, Neurons/*physiology, Orientation/physiology, Photic Stimulation, Tupaiidae, Visual Cortex/*physiology, Visual Pathways/*physiology, Visual Perception/*physiology

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Long and short multifunicular projections of sacral neurons are activated by sensory input to produce locomotor activity in the absence of supraspinal control.

Publication Date: 2010 Aug 4 PMID: 20685976
Authors: Etlin, A. - Blivis, D. - Ben-Zwi, M. - Lev-Tov, A.
Journal: J Neurosci

Afferent input from load and joint receptors has been shown to reactivate the central pattern generators for locomotion (CPGs) in spinal cord injury patients and thereby improve their motor function and mobility. Elucidation of the pathways interposed between the afferents and CPGs is critical for the determination of the capacity of sensory input to activate the CPGs when the continuity of the white matter tracts is impaired following spinal cord injury. Using electrophysiological recordings, confocal imaging studies of spinal neurons and surgical manipulations of the white matter, we show that the capacity of sacrocaudal afferent (SCA) input to produce locomotor activity in isolated rat spinal cords depends not only on long ascending pathways, but also on recruitment of sacral proprioneurons interposed between the second order neurons and the hindlimb CPGs. We argue that large heterogeneous populations of second-order and proprioneurons whose crossed and uncrossed axons project rostrally through the ventral, ventrolateral/lateral and dorsolateral white matter funiculi contribute to the generation of the rhythm by the stimulated sacrocaudal input. The complex organization and multiple projection patterns of these populations enable the sacrocaudal afferent input to activate the CPGs even if the white matter pathways are severely damaged. Further studies are required to clarify the mechanisms involved in SCA-induced locomotor activity and assess its potential use for the rescue of lost motor functions after spinal cord injury.

MeSH Categories: Afferent Pathways/physiology, Analysis of Variance, Animals, Electrophysiology, Female, Locomotion/*physiology, Male, Microscopy, Confocal, Motor Activity/*physiology, Neurons/*physiology, Rats, Spinal Cord/*physiology

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Functional magnetic resonance imaging reveals the neural substrates of arm transport and grip formation in reach-to-grasp actions in humans.

Publication Date: 2010 Aug 4 PMID: 20685975
Authors: Cavina-Pratesi, C. - Monaco, S. - Fattori, P. - Galletti, C. - McAdam, T. D. - Quinlan, D. J. - Goodale, M. A. - Culham, J. C.
Journal: J Neurosci

Picking up a cup requires transporting the arm to the cup (transport component) and preshaping the hand appropriately to grasp the handle (grip component). Here, we used functional magnetic resonance imaging to examine the human neural substrates of the transport component and its relationship with the grip component. Participants were shown three-dimensional objects placed either at a near location, adjacent to the hand, or at a far location, within reach but not adjacent to the hand. Participants performed three tasks at each location as follows: (1) touching the object with the knuckles of the right hand; (2) grasping the object with the right hand; or (3) passively viewing the object. The transport component was manipulated by positioning the object in the far versus the near location. The grip component was manipulated by asking participants to grasp the object versus touching it. For the first time, we have identified the neural substrates of the transport component, which include the superior parieto-occipital cortex and the rostral superior parietal lobule. Consistent with past studies, we found specialization for the grip component in bilateral anterior intraparietal sulcus and left ventral premotor cortex; now, however, we also find activity for the grasp even when no transport is involved. In addition to finding areas specialized for the transport and grip components in parietal cortex, we found an integration of the two components in dorsal premotor cortex and supplementary motor areas, two regions that may be important for the coordination of reach and grasp.

MeSH Categories: Adult, Analysis of Variance, Arm/*physiology, Brain Mapping, Female, Hand Strength/*physiology, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Movement/*physiology, Occipital Lobe/*physiology, Parietal Lobe/*physiology, Psychomotor Performance/physiology, Reaction Time/physiology

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Motivated cognitive control: reward incentives modulate preparatory neural activity during task-switching.

Publication Date: 2010 Aug 4 PMID: 20685974
Authors: Savine, A. C. - Braver, T. S.
Journal: J Neurosci

It is increasingly appreciated that executive control processes need to be understood in terms of motivational as well as cognitive mechanisms. The current study examined the impact of performance-contingent reward incentives (monetary bonuses) on neural activity dynamics during cued task-switching performance. Behavioral measures indicated that performance was improved and task-switch costs selectively reduced on incentive trials. Trial-by-trial fluctuations in incentive value were associated with activation in reward-related brain regions (dopaminergic midbrain, paracingulate cortex) and also modulated the dynamics of switch-selective activation in the brain cognitive control network. Within lateral prefrontal cortex (PFC), both additive (inferior frontal junction) and interactive [dorsolateral PFC (DLPFC)] incentive effects were observed. In DLPFC, incentive modulation of activation predicted task-switching behavioral performance, but with hemispherically dissociable effects. Furthermore, in left DLPFC, incentive modulation specifically enhanced task-cue-related activation, and this activation in turn predicted that the trial would be subsequently rewarded (because of optimal performance). The results suggest that motivational incentives have a selective effect on brain regions that subserve cognitive control processes during task-switching and, moreover, that one mechanism of effect might be the enhancement of cue-related task preparation within left DLPFC.

MeSH Categories: Adolescent, Adult, Analysis of Variance, Brain Mapping, Cognition/*physiology, Cues, Executive Function/*physiology, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Mesencephalon/*physiology, Nerve Net/physiology, Neurons/*physiology, Neuropsychological Tests, Photic Stimulation, Prefrontal Cortex/*physiology, Psychomotor Performance/physiology, Reward

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Prostatic acid phosphatase reduces thermal sensitivity and chronic pain sensitization by depleting phosphatidylinositol 4,5-bisphosphate.

Publication Date: 2010 Aug 4 PMID: 20685973
Authors: Sowa, N. A. - Street, S. E. - Vihko, P. - Zylka, M. J.
Journal: J Neurosci

Prostatic acid phosphatase (PAP) is expressed in nociceptive dorsal root ganglion (DRG) neurons, functions as an ectonucleotidase, and generates adenosine extracellularly. Here, we found that PAP inhibits noxious thermal sensitivity and sensitization that is associated with chronic pain through sustained activation of the adenosine A(1) receptor (A(1)R) and phospholipase C-mediated depletion of phosphatidylinositol 4,5-bisphosphate (PIP(2)). In mice, intrathecal injection of PAP reduced PIP(2) levels in DRGs, inhibited thermosensation through TRPV1, and enduringly reduced thermal hyperalgesia and mechanical allodynia caused by inflammation, nerve injury, and pronociceptive receptor activation. This included inhibitory effects on lysophosphatidic acid, purinergic (ATP), bradykinin, and protease-activated (thrombin) receptors. Conversely, PIP(2) levels were significantly elevated in DRGs from Pap(-/-) mice, and this correlated with enhanced thermal hyperalgesia and mechanical allodynia in Pap(-/-) mice. To directly test the importance of PIP(2) in nociception, we intrathecally injected PIP(2) into mice. This transiently (2 h) elevated PIP(2) levels in lumbar DRGs and transiently (2 h) enhanced thermosensation. Additionally, thermal hyperalgesia and mechanical allodynia were enduringly enhanced when PIP(2) levels were elevated coincident with injury/pronociceptive receptor stimulation. Nociceptive sensitization was not affected if PIP(2) levels were elevated in the absence of ongoing pronociceptive receptor stimulation. Together, our data suggest that PIP(2) levels in DRGs directly influence thermosensation and the magnitude of nociceptive sensitization. Moreover, our data suggest there is an underlying "phosphoinositide tone" that can be manipulated by an adenosine-generating ectonucleotidase. This tone regulates how effectively acute nociceptive insults promote the transition to chronic pain.

MeSH Categories: Animals, Calcium/metabolism, Cell Line, Electrophysiology, Ganglia, Spinal/*drug effects/metabolism, Hot Temperature, Humans, Hyperalgesia/*metabolism, Male, Mice, Mice, Transgenic, Nociceptors/*drug effects/metabolism, Pain Measurement, Pain Threshold/*drug effects/physiology, Phosphatidylinositol 4,5-Diphosphate/*metabolism, Protein Tyrosine Phosphatases/*pharmacology, Receptor, Adenosine A1/metabolism, TRPV Cation Channels/genetics/metabolism, Type C Phospholipases/metabolism

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SNARE force synchronizes synaptic vesicle fusion and controls the kinetics of quantal synaptic transmission.

Publication Date: 2010 Aug 4 PMID: 20685972
Authors: Guzman, R. E. - Schwarz, Y. N. - Rettig, J. - Bruns, D.
Journal: J Neurosci

Neuronal communication relies on rapid and discrete intercellular signaling but neither the molecular mechanisms of the exocytotic machinery that define the timing of the action potential-evoked response nor those controlling the kinetics of transmitter release from single synaptic vesicles are known. Here, we investigate how interference with the putative force transduction between the complex-forming SNARE (soluble N-ethylamide-sensitive factor attachment protein receptor) domain and the transmembrane anchor of synaptobrevin II (SybII) affects action potential-evoked currents and spontaneous, quantal transmitter release at mouse hippocampal synapses. The results indicate that SybII-generated membrane stress effectively determines the kinetics of the action potential-evoked response and show that SNARE force modulates the concentration profile of cleft glutamate by controlling the rate of transmitter release from the single synaptic vesicle. Thus, multiple SybII actions determine the exquisite temporal regulation of neuronal signaling.

MeSH Categories: Action Potentials/physiology, Analysis of Variance, Animals, Cells, Cultured, Electric Stimulation, Electrophysiology, Excitatory Postsynaptic Potentials/physiology, Hippocampus/cytology/metabolism, Immunohistochemistry, Membrane Fusion/*physiology, Mice, Mice, Knockout, Miniature Postsynaptic Potentials/physiology, Neurons/cytology/metabolism, SNARE Proteins/*metabolism, Synapses/*metabolism, Synaptic Transmission/*physiology, Synaptic Vesicles/*metabolism, Time Factors, Vesicle-Associated Membrane Protein 2/genetics/metabolism

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Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b.

Publication Date: 2010 Aug 4 PMID: 20685971
Authors: Strumbos, J. G. - Brown, M. R. - Kronengold, J. - Polley, D. B. - Kaczmarek, L. K.
Journal: J Neurosci

Fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates synaptic plasticity by repressing translation of specific mRNAs. We found that FMRP binds mRNA encoding the voltage-gated potassium channel Kv3.1b in brainstem synaptosomes. To explore the regulation of Kv3.1b by FMRP, we investigated Kv3.1b immunoreactivity and potassium currents in the auditory brainstem sound localization circuit of male mice. The unique features of this circuit allowed us to control neuronal activity in vivo by exposing animals to high-frequency, amplitude-modulated stimuli, which elicit predictable and stereotyped patterns of input to the anterior ventral cochlear nucleus (AVCN) and medial nucleus of the trapezoid body (MNTB). In wild-type (WT) animals, Kv3.1b is expressed along a tonotopic gradient in the MNTB, with highest levels in neurons at the medial, high-frequency end. At baseline, Fmr1(-/-) mice, which lack FMRP, displayed dramatically flattened tonotopicity in Kv3.1b immunoreactivity and K(+) currents relative to WT controls. Moreover, after 30 min of acoustic stimulation, levels of Kv3.1b immunoreactivity were significantly elevated in both the MNTB and AVCN of WT, but not Fmr1(-/-), mice. These results suggest that FMRP is necessary for maintenance of the gradient in Kv3.1b protein levels across the tonotopic axis of the MNTB, and are consistent with a role for FMRP as a repressor of protein translation. Using numerical simulations, we demonstrate that Kv3.1b tonotopicity may be required for accurate encoding of stimulus features such as modulation rate, and that disruption of this gradient, as occurs in Fmr1(-/-) animals, degrades processing of this information.

MeSH Categories: Acoustic Stimulation, Animals, Auditory Pathways/*physiology, Blotting, Western, Brain Stem/*physiology, Evoked Potentials, Auditory, Brain Stem/*physiology, Fragile X Mental Retardation Protein/*genetics/metabolism, Immunohistochemistry, Male, Mice, Mice, Knockout, Neurons, RNA, Messenger/genetics/metabolism, Shaw Potassium Channels/*metabolism, Sound Localization

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When feature-based attention distorts neural representations.

Publication Date: 2010 Aug 4 PMID: 20685970
Authors: Kaul, C. - White, A. L.
Journal: J Neurosci

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