Publication Date: 2010 Sep PMID: 20711186
Authors: Deng, J. V. - Rodriguiz, R. M. - Hutchinson, A. N. - Kim, I. H. - Wetsel, W. C. - West, A. E.
Journal: Nat Neurosci

MeCP2 is a methyl DNA-binding transcriptional regulator that contributes to the development and function of CNS synapses; however, the requirement for MeCP2 in stimulus-regulated behavioral plasticity is not fully understood. Here we show that acute viral manipulation of MeCP2 expression in the nucleus accumbens (NAc) bidirectionally modulates amphetamine (AMPH)-induced conditioned place preference. Mecp2 hypomorphic mutant mice have more NAc GABAergic synapses and show deficient AMPH-induced structural plasticity of NAc dendritic spines. Furthermore, these mice show deficient plasticity of striatal immediate early gene inducibility after repeated AMPH administration. Notably, psychostimulants induce phosphorylation of MeCP2 at Ser421, a site that regulates MeCP2's function as a repressor. Phosphorylation is selectively induced in GABAergic interneurons of the NAc, and its extent strongly predicts the degree of behavioral sensitization. These data reveal new roles for MeCP2 both in mesolimbocortical circuit development and in the regulation of psychostimulant-induced behaviors.

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Publication Date: 2010 Sep PMID: 20711185
Authors: Im, H. I. - Hollander, J. A. - Bali, P. - Kenny, P. J.
Journal: Nat Neurosci

The X-linked transcriptional repressor methyl CpG binding protein 2 (MeCP2), known for its role in the neurodevelopmental disorder Rett syndrome, is emerging as an important regulator of neuroplasticity in postmitotic neurons. Cocaine addiction is commonly viewed as a disorder of neuroplasticity, but the potential involvement of MeCP2 has not been explored. Here we identify a key role for MeCP2 in the dorsal striatum in the escalating cocaine intake seen in rats with extended access to the drug, a process that mimics the increasingly uncontrolled cocaine use seen in addicted humans. MeCP2 regulates cocaine intake through homeostatic interactions with microRNA-212 (miR-212) to control the effects of cocaine on striatal brain-derived neurotrophic factor (BDNF) levels. These data suggest that homeostatic interactions between MeCP2 and miR-212 in dorsal striatum may be important in regulating vulnerability to cocaine addiction.

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Publication Date: 2010 Sep PMID: 20711184
Authors: Altimus, C. M. - Guler, A. D. - Alam, N. M. - Arman, A. C. - Prusky, G. T. - Sampath, A. P. - Hattar, S.
Journal: Nat Neurosci

In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. Using mice that lack functional rods or in which rods are the only functional photoreceptors, we found that rods were solely responsible for photoentrainment at scotopic light intensities. Rods were also capable of driving circadian photoentrainment at photopic intensities at which they were incapable of supporting a visually guided behavior. Using mice in which cone photoreceptors were ablated, we found that rods signal through cones at high light intensities, but not at low light intensities. Thus, rods use two distinct retinal circuits to drive ipRGC function to support circadian photoentrainment across a wide range of light intensities.

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Publication Date: 2010 Sep PMID: 20711183
Authors: Smith, S. L. - Hausser, M.
Journal: Nat Neurosci

Visual cortex shows smooth retinotopic organization on the macroscopic scale, but it is unknown how receptive fields are organized at the level of neighboring neurons. This information is crucial for discriminating among models of visual cortex. We used in vivo two-photon calcium imaging to independently map ON and OFF receptive field subregions of local populations of layer 2/3 neurons in mouse visual cortex. Receptive field subregions were often precisely shared among neighboring neurons. Furthermore, large subregions seem to be assembled from multiple smaller, non-overlapping subregions of other neurons in the same local population. These experiments provide, to our knowledge, the first characterization of the diversity of receptive fields in a dense local network of visual cortex and reveal elementary units of receptive field organization. Our results suggest that a limited pool of afferent receptive fields is available to a local population of neurons and reveal new organizational principles for the neural circuitry of the mouse visual cortex.

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Publication Date: 2010 Sep PMID: 20694004
Authors: Liu, K. - Lu, Y. - Lee, J. K. - Samara, R. - Willenberg, R. - Sears-Kraxberger, I. - Tedeschi, A. - Park, K. K. - Jin, D. - Cai, B. - Xu, B. - Connolly, L. - Steward, O. - Zheng, B. - He, Z.
Journal: Nat Neurosci

Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

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Publication Date: 2010 Sep PMID: 20694003
Authors: Smith-Hicks, C. - Xiao, B. - Deng, R. - Ji, Y. - Zhao, X. - Shepherd, J. D. - Posern, G. - Kuhl, D. - Huganir, R. L. - Ginty, D. D. - Worley, P. F. - Linden, D. J.
Journal: Nat Neurosci

It has been suggested that gene expression and protein synthesis are required for both long-term memory consolidation and late phases of long-term potentiation and long-term depression (LTD). The necessary genes and the specific transcription factor binding sites in their promoters remain unknown. We found that inhibition of the transcription factor SRF or its cofactor MAL blocked the late phase of LTD in mouse cultured cerebellar Purkinje cells, as did deletion of the immediate early gene Arc. Using neuronal bacterial artificial chromosome (BAC) transfection, we found that, in Arc-/- cells transfected with a wild-type Arc BAC, late-phase LTD was rescued. However, mutation of one SRF-binding site in the Arc promoter (SRE 6.9) blocked this rescue. Co-transfection of wild-type Arc and SRF engineered to bind mutated SRE 6.9 restored late-phase LTD in Arc-/-, SRE 6.9 mutant BAC cells. Thus, SRF binding to SRE 6.9 in the Arc promoter is required for the late phase of cerebellar LTD.

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Publication Date: 2010 Sep PMID: 20694002
Authors: Richards, B. A. - Voss, O. P. - Akerman, C. J.
Journal: Nat Neurosci

During the development of sensory systems, receptive fields are modified by stimuli in the environment. This is thought to rely on learning algorithms that are sensitive to correlations in spike timing between cells, but the manner in which developing circuits selectively exploit correlations that are related to sensory inputs is unknown. We recorded from neurons in the developing optic tectum of Xenopus laevis and found that repeated presentation of moving visual stimuli induced receptive field changes that reflected the properties of the stimuli and that this form of learning was disrupted when GABAergic transmission was blocked. Consistent with a role for spike timing-dependent mechanisms, GABA blockade altered spike-timing patterns in the tectum and increased correlations between cells that would affect plasticity at intratectal synapses. This is a previously unknown role for GABAergic signals in development and highlights the importance of regulating the statistics of spiking activity for learning.

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Publication Date: 2010 Sep PMID: 20694001
Authors: Jurado, S. - Biou, V. - Malenka, R. C.
Journal: Nat Neurosci

AKAP79/150 is a protein scaffold that is thought to position specific kinases (protein kinase A and C) and phosphatases (calcineurin) in appropriate synaptic domains so that their activities can regulate excitatory synaptic strength. Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin.

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Publication Date: 2010 Sep PMID: 20680010
Authors: Bouvier, J. - Thoby-Brisson, M. - Renier, N. - Dubreuil, V. - Ericson, J. - Champagnat, J. - Pierani, A. - Chedotal, A. - Fortin, G.
Journal: Nat Neurosci

Breathing is a bilaterally synchronous behavior that relies on a respiratory rhythm generator located in the brainstem. An essential component of this generator is the preBotzinger complex (preBotC), which paces inspirations. Little is known about the developmental origin of the interneuronal populations forming the preBotC oscillator network. We found that the homeobox gene Dbx1 controls the fate of glutamatergic interneurons required for preBotC rhythm generation in the mouse embryo. We also found that a conditional inactivation in Dbx1-derived cells of the roundabout homolog 3 (Robo3) gene, which is necessary for axonal midline crossing, resulted in left-right de-synchronization of the preBotC oscillator. Together, these findings identify Dbx1-derived interneurons as the core rhythmogenic elements of the preBotC oscillator and indicate that Robo3-dependent guidance signaling in these cells is required for bilaterally synchronous activity.

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Publication Date: 2010 Sep PMID: 20676105
Authors: Tritsch, N. X. - Rodriguez-Contreras, A. - Crins, T. T. - Wang, H. C. - Borst, J. G. - Bergles, D. E.
Journal: Nat Neurosci

We found rat central auditory neurons to fire action potentials in a precise sequence of mini-bursts before the age of hearing onset. This stereotyped pattern was initiated by hair cells in the cochlea, which trigger brief bursts of action potentials in auditory neurons each time they fire a Ca2+ spike. By generating theta-like activity, hair cells may limit the influence of synaptic depression in developing auditory circuits and promote consolidation of synapses.

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Publication Date: 2010 Sep PMID: 20676104
Authors: Foldy, C. - Lee, S. H. - Morgan, R. J. - Soltesz, I.
Journal: Nat Neurosci

Parvalbumin-expressing, fast-spiking basket cells are important for the generation of synchronous, rhythmic population activities in the hippocampus. We found that GABAA receptor-mediated synaptic inputs from murine parvalbumin-expressing basket cells were selectively modulated by the membrane voltage- and intracellular chloride-dependent chloride channel ClC-2. Our data reveal a previously unknown cell type-specific regulation of intracellular chloride homeostasis in the perisomatic region of hippocampal pyramidal neurons.

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Publication Date: 2010 Sep PMID: 20676103
Authors: Zhang, X. - Bertaso, F. - Yoo, J. W. - Baumgartel, K. - Clancy, S. M. - Lee, V. - Cienfuegos, C. - Wilmot, C. - Avis, J. - Hunyh, T. - Daguia, C. - Schmedt, C. - Noebels, J. - Jegla, T.
Journal: Nat Neurosci

We found the voltage-gated K+ channel Kv12.2 to be a potent regulator of excitability in hippocampal pyramidal neurons. Genetic deletion and pharmacologic block of Kv12.2 substantially reduced the firing threshold of these neurons. Kv12.2-/- (also known as Kcnh3-/-) mice showed signs of persistent neuronal hyperexcitability including frequent interictal spiking, spontaneous seizures and increased sensitivity to the chemoconvulsant pentylenetetrazol.

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Publication Date: 2010 Sep 2 PMID: 20811475
Authors: Tamietto, M. - de Gelder, B.
Journal: Nat Rev Neurosci

Many emotional stimuli are processed without being consciously perceived. Recent evidence indicates that subcortical structures have a substantial role in this processing. These structures are part of a phylogenetically ancient pathway that has specific functional properties and that interacts with cortical processes. There is now increasing evidence that non-consciously perceived emotional stimuli induce distinct neurophysiological changes and influence behaviour towards the consciously perceived world. Understanding the neural bases of the non-conscious perception of emotional signals will clarify the phylogenetic continuity of emotion systems across species and the integration of cortical and subcortical activity in the human brain.

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Publication Date: 2010 Sep PMID: 20803794
Authors: McCarthy, N.
Journal: Nat Rev Neurosci



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Publication Date: 2010 Sep PMID: 20803793
Authors: Wiedemann, C.
Journal: Nat Rev Neurosci



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Publication Date: 2010 Sep PMID: 20803792
Authors: Welberg, L.
Journal: Nat Rev Neurosci



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Publication Date: 2010 Sep PMID: 20803791
Authors: Kingwell, K.
Journal: Nat Rev Neurosci



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Publication Date: 2010 Sep PMID: 20803790
Authors: Welberg, L.
Journal: Nat Rev Neurosci



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Publication Date: 2010 Sep PMID: 20803789
Authors: Wiedemann, C.
Journal: Nat Rev Neurosci



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Publication Date: 2010 Sep PMID: 20803787
Authors: Bodo, C.
Journal: Nat Rev Neurosci



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