Hot off the presses! Oct 01 Nat Neurosci

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Latest Articles Include:

• Ensuring data integrity
  - Nat Neurosci 12(10):1205 (2009)
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• A neurocomputational jeremiad
  - Nat Neurosci 12(10):1207 (2009)
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• A night vision neuron gets a day job
  - Nat Neurosci 12(10):1209-1211 (2009)
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• Regional control of cortical lamination
  - Nat Neurosci 12(10):1211-1212 (2009)
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• Calcium: an insignificant thing
  - Nat Neurosci 12(10):1213-1214 (2009)
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• TR(I)Pping towards treatment for ischemia
  - Nat Neurosci 12(10):1215-1216 (2009)
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• Six degrees of separation: the amygdala regulates social behavior and perception
  - Nat Neurosci 12(10):1217-1218 (2009)
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• The timing of external input controls the sign of plasticity at local synapses
  - Nat Neurosci 12(10):1219-1221 (2009)
  The method by which local networks in the brain store information from extrinsic afferent inputs is not well understood. We found that the timing of afferent input can bidirectionally control the sign of spike timing–dependent plasticity at local synapses in rat hippocampus. This mechanism provides a means by which temporal information in external input can be encoded in the local matrix of synaptic weights.
• Selective suppression of hippocampal ripples impairs spatial memory
  - Nat Neurosci 12(10):1222-1223 (2009)
  Sharp wave–ripple (SPW-R) complexes in the hippocampus-entorhinal cortex are believed to be important for transferring labile memories from the hippocampus to the neocortex for long-term storage. We found that selective elimination of SPW-Rs during post-training consolidation periods resulted in performance impairment in rats trained on a hippocampus-dependent spatial memory task. Our results provide evidence for a prominent role of hippocampal SPW-Rs in memory consolidation.
• Intact rapid detection of fearful faces in the absence of the amygdala
  - Nat Neurosci 12(10):1224-1225 (2009)
  The amygdala is thought to process fear-related stimuli rapidly and nonconsciously. We found that an individual with complete bilateral amygdala lesions, who cannot recognize fear from faces, nonetheless showed normal rapid detection and nonconscious processing of those same fearful faces. We conclude that the amygdala is not essential for early stages of fear processing but, instead, modulates recognition and social judgment.
• Personal space regulation by the human amygdala
  - Nat Neurosci 12(10):1226-1227 (2009)
  The amygdala plays key roles in emotion and social cognition, but how this translates to face-to-face interactions involving real people remains unknown. We found that an individual with complete amygdala lesions lacked any sense of personal space. Furthermore, healthy individuals showed amygdala activation upon close personal proximity. The amygdala may be required to trigger the strong emotional reactions normally following personal space violations, thus regulating interpersonal distance in humans.
• AP2 regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex
  - Nat Neurosci 12(10):1229-1237 (2009)
  An important feature of the cerebral cortex is its layered organization, which is modulated in an area-specific manner. We found that the transcription factor AP2 regulates laminar fate in a region-specific manner. Deletion of AP2 (also known as Tcfap2c) during development resulted in a specific reduction of upper layer neurons in the occipital cortex, leading to impaired function and enhanced plasticity of the adult visual cortex. AP2 functions in apical progenitors, and its absence resulted in mis-specification of basal progenitors in the occipital cortex at the time at which upper layer neurons were generated. AP2 directly regulated the basal progenitor fate determinants Math3 (also known as Neurod4) and Tbr2, and its overexpression promoted the generation of layer II/III neurons in a time- and region-specific manner. Thus, AP2 acts as a regulator of basal progenitor fate, linking regional and laminar specification in the mouse developing cerebral cortex.
• SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development
  Azim E Jabaudon D Fame RM Macklis JD - Nat Neurosci 12(10):1238-1247 (2009)
  The neuronal diversity of the CNS emerges largely from controlled spatial and temporal segregation of cell type-specific molecular regulators. We found that the transcription factor SOX6 controls the molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors and the differentiation of cortical interneurons, regulating forebrain progenitor and interneuron heterogeneity. During corticogenesis in mice, SOX6 and SOX5 were largely mutually exclusively expressed in pallial and subpallial progenitors, respectively, and remained mutually exclusive in a reverse pattern in postmitotic neuronal progeny. Loss of SOX6 from pallial progenitors caused their inappropriate expression of normally subpallium-restricted developmental controls, conferring mixed dorsal-ventral identity. In postmitotic cortical interneurons, loss of SOX6 disrupted the differentiation and diversity of cortical interneuron subtypes, analogous to SOX5 control over cortical pro! jection neuron development. These data indicate that SOX6 is a central regulator of both progenitor and cortical interneuron diversity during neocortical development.
• Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh
  - Nat Neurosci 12(10):1248-1256 (2009)
  Neural stem cells (NSCs) are controlled by diffusible factors. The transcription factor Sox2 is expressed by NSCs and Sox2 mutations in humans cause defects in the brain and, in particular, in the hippocampus. We deleted Sox2 in the mouse embryonic brain. At birth, the mice showed minor brain defects; shortly afterwards, however, NSCs and neurogenesis were completely lost in the hippocampus, leading to dentate gyrus hypoplasia. Deletion of Sox2 in adult mice also caused hippocampal neurogenesis loss. The hippocampal developmental defect resembles that caused by late sonic hedgehog (Shh) loss. In mutant mice, Shh and Wnt3a were absent from the hippocampal primordium. A SHH pharmacological agonist partially rescued the hippocampal defect. Chromatin immunoprecipitation identified Shh as a Sox2 target. Sox2-deleted NSCs did not express Shh in vitro and were rapidly lost. Their replication was partially rescued by the addition of SHH and was almost fully rescued by conditio! ned medium from normal cells. Thus, NSCs control their status, at least partly, through Sox2-dependent autocrine mechanisms.
• Presynaptic CaV2 calcium channel traffic requires CALF-1 and the 2 subunit UNC-36
  - Nat Neurosci 12(10):1257-1265 (2009)
  Presynaptic voltage-gated calcium channels provide calcium for synaptic vesicle exocytosis. We show here that a green fluorescent protein–tagged 1 subunit of the Caenorhabditis elegans CaV2 channel, UNC-2, is localized to presynaptic active zones of sensory and motor neurons. Synaptic localization of CaV2 requires the 2 subunit UNC-36 and CALF-1 (Calcium Channel Localization Factor-1), a neuronal transmembrane protein that localizes to the endoplasmic reticulum. In calf-1 mutants, UNC-2 is retained in the endoplasmic reticulum, but other active-zone components and synaptic vesicles are delivered to synapses. Acute induction of calf-1 mobilizes preexisting UNC-2 for delivery to synapses, consistent with a direct trafficking role. The 2 subunit UNC-36 is likewise required for exit of UNC-2 from endoplasmic reticulum but has additional functions. Genetic and cell biological interactions suggest that CALF-1 couples intracellular traffic to functional maturation of CaV2 p! resynaptic calcium channels.
• EFHC1 interacts with microtubules to regulate cell division and cortical development
  - Nat Neurosci 12(10):1266-1274 (2009)
  Mutations in the EFHC1 gene are linked to juvenile myoclonic epilepsy (JME), one of the most frequent forms of idiopathic generalized epilepsies. JME is associated with subtle alterations of cortical and subcortical architecture, but the underlying pathological mechanism remains unknown. We found that EFHC1 is a microtubule-associated protein involved in the regulation of cell division. In vitro, EFHC1 loss of function disrupted mitotic spindle organization, impaired M phase progression, induced microtubule bundling and increased apoptosis. EFHC1 impairment in the rat developing neocortex by ex vivo and in utero electroporation caused a marked disruption of radial migration. We found that this effect was a result of cortical progenitors failing to exit the cell cycle and defects in the radial glia scaffold organization and in the locomotion of postmitotic neurons. Therefore, we propose that EFHC1 is a regulator of cell division and neuronal migration during cortical de! velopment and that disruption of its functions leads to JME.
• Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines
  - Nat Neurosci 12(10):1275-1284 (2009)
  Dynamic remodeling of spiny synapses is crucial for cortical circuit development, refinement and plasticity, whereas abnormal morphogenesis is associated with neuropsychiatric disorders. We found that activation of Epac2, a PKA-independent cAMP target and Rap guanine-nucleotide exchange factor (GEF), in cultured rat cortical neurons induced spine shrinkage, increased spine motility, removed synaptic GluR2/3-containing AMPA receptors and depressed excitatory transmission, whereas its inhibition promoted spine enlargement and stabilization. Epac2 was required for dopamine D1-like receptor–dependent spine shrinkage and GluR2 removal from spines. Epac2 interaction with neuroligin promoted its membrane recruitment and enhanced its GEF activity. Rare missense mutations in the EPAC2 (also known as RAPGEF4) gene, previously found in individuals with autism, affected basal and neuroligin-stimulated GEF activity, dendritic Rap signaling, synaptic protein distribution and spine! morphology. Thus, we identify a previously unknown mechanism that promotes dynamic remodeling and depression of spiny synapses, disruption of which may contribute to some aspects of disease.
• Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport
  - Nat Neurosci 12(10):1285-1292 (2009)
  Astrocytes are critical participants in synapse development and function, but their role in synaptic plasticity is unclear. Eph receptors and their ephrin ligands have been suggested to regulate neuron-glia interactions, and EphA4-mediated ephrin reverse signaling is required for synaptic plasticity in the hippocampus. Here we show that long-term potentiation (LTP) at the CA3–CA1 synapse is modulated by EphA4 in the postsynaptic CA1 cell and by ephrin-A3, a ligand of EphA4 that is found in astrocytes. Lack of EphA4 increased the abundance of glial glutamate transporters, and ephrin-A3 modulated transporter currents in astrocytes. Pharmacological inhibition of glial glutamate transporters rescued the LTP defects in EphA4 (Epha4) and ephrin-A3 (Efna3) mutant mice. Transgenic overexpression of ephrin-A3 in astrocytes reduces glutamate transporter levels and produces focal dendritic swellings possibly caused by glutamate excitotoxicity. These results suggest that EphA4/e! phrin-A3 signaling is a critical mechanism for astrocytes to regulate synaptic function and plasticity.
• Nicotine activates the chemosensory cation channel TRPA1
  - Nat Neurosci 12(10):1293-1299 (2009)
  Topical application of nicotine, as used in nicotine replacement therapies, causes irritation of the mucosa and skin. This reaction has been attributed to activation of nicotinic acetylcholine receptors (nAChRs) in chemosensory neurons. In contrast with this view, we found that the chemosensory cation channel transient receptor potential A1 (TRPA1) is crucially involved in nicotine-induced irritation. We found that micromolar concentrations of nicotine activated heterologously expressed mouse and human TRPA1. Nicotine acted in a membrane-delimited manner, stabilizing the open state(s) and destabilizing the closed state(s) of the channel. In the presence of the general nAChR blocker hexamethonium, nociceptive neurons showed nicotine-induced responses that were strongly reduced in TRPA1-deficient mice. Finally, TRPA1 mediated the mouse airway constriction reflex to nasal instillation of nicotine. The identification of TRPA1 as a nicotine target suggests that existing mod! els of nicotine-induced irritation should be revised and may facilitate the development of smoking cessation therapies with less adverse effects.
• Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia
  - Nat Neurosci 12(10):1300-1307 (2009)
  Cardiac arrest victims may experience transient brain hypoperfusion leading to delayed death of hippocampal CA1 neurons and cognitive impairment. We prevented this in adult rats by inhibiting the expression of transient receptor potential melastatin 7 (TRPM7), a transient receptor potential channel that is essential for embryonic development, is necessary for cell survival and trace ion homeostasis in vitro, and whose global deletion in mice is lethal. TRPM7 was suppressed in CA1 neurons by intrahippocampal injections of viral vectors bearing shRNA specific for TRPM7. This had no ill effect on animal survival, neuronal and dendritic morphology, neuronal excitability, or synaptic plasticity, as exemplified by robust long-term potentiation (LTP). However, TRPM7 suppression made neurons resistant to ischemic death after brain ischemia and preserved neuronal morphology and function. Also, it prevented ischemia-induced deficits in LTP and preserved performance in fear-assoc! iated and spatial-navigational memory tasks. Thus, regional suppression of TRPM7 is feasible, well tolerated and inhibits delayed neuronal death in vivo.
• Approach sensitivity in the retina processed by a multifunctional neural circuit
  Münch TA da Silveira RA Siegert S Viney TJ Awatramani GB Roska B - Nat Neurosci 12(10):1308-1316 (2009)
  The detection of approaching objects, such as looming predators, is necessary for survival. Which neurons and circuits mediate this function? We combined genetic labeling of cell types, two-photon microscopy, electrophysiology and theoretical modeling to address this question. We identify an approach-sensitive ganglion cell type in the mouse retina, resolve elements of its afferent neural circuit, and describe how these confer approach sensitivity on the ganglion cell. The circuit's essential building block is a rapid inhibitory pathway: it selectively suppresses responses to non-approaching objects. This rapid inhibitory pathway, which includes AII amacrine cells connected to bipolar cells through electrical synapses, was previously described in the context of night-time vision. In the daytime conditions of our experiments, the same pathway conveys signals in the reverse direction. The dual use of a neural pathway in different physiological conditions illustrates the ! efficiency with which several functions can be accommodated in a single circuit.
• Coding of stimulus sequences by population responses in visual cortex
  - Nat Neurosci 12(10):1317-1324 (2009)
  Neuronal populations in sensory cortex represent time-changing sensory input through a spatiotemporal code. What are the rules that govern this code? We measured membrane potentials and spikes from neuronal populations in cat visual cortex (V1) using voltage-sensitive dyes and electrode arrays. We first characterized the population response to a single orientation. As response amplitude grew, the population tuning width remained constant for membrane potential responses and became progressively sharper for spike responses. We then asked how these single-orientation responses combine to code for successive orientations. We found that they combined through simple linear summation. Linearity, however, was violated after stimulus offset, when responses exhibited an unexplained persistence. As a result of linearity, the interactions between responses to successive stimuli were minimal. Our results indicate that higher cortical areas may reconstruct the stimulus sequence fro! m V1 population responses through a simple instantaneous decoder. Therefore, spatial and temporal codes in area V1 operate largely independently.
• Fragmentation of grid cell maps in a multicompartment environment
  - Nat Neurosci 12(10):1325-1332 (2009)
  To determine whether entorhinal spatial representations are continuous or fragmented, we recorded neural activity in grid cells while rats ran through a stack of interconnected, zig-zagged compartments of equal shape and orientation (a hairpin maze). The distribution of spatial firing fields was markedly similar across all compartments in which running occurred in the same direction, implying that the grid representation was fragmented into repeating submaps. Activity at neighboring positions was least correlated at the transitions between different arms, indicating that the map split regularly at the turning points. We saw similar discontinuities among place cells in the hippocampus. No fragmentation was observed when the rats followed similar trajectories in the absence of internal walls, implying that stereotypic behavior alone cannot explain the compartmentalization. These results indicate that spatial environments are represented in entorhinal cortex and hippocamp! us as a mosaic of discrete submaps that correspond to the geometric structure of the space.
• Transformation of nonfunctional spinal circuits into functional states after the loss of brain input
  - Nat Neurosci 12(10):1333-1342 (2009)
  After complete spinal cord transections that removed all supraspinal inputs in adult rats, combinations of serotonergic agonists and epidural electrical stimulation were able to acutely transform spinal networks from nonfunctional to highly functional and adaptive states as early as 1 week after injury. Using kinematics, physiological and anatomical analyses, we found that these interventions could recruit specific populations of spinal circuits, refine their control via sensory input and functionally remodel these locomotor pathways when combined with training. The emergence of these new functional states enabled full weight-bearing treadmill locomotion in paralyzed rats that was almost indistinguishable from voluntary stepping. We propose that, in the absence of supraspinal input, spinal locomotion can emerge from a combination of central pattern-generating capability and the ability of these spinal circuits to use sensory afferent input to control stepping. These fi! ndings provide a strategy by which individuals with spinal cord injuries could regain substantial levels of motor control.
• Classical conditioning in the vegetative and minimally conscious state
  - Nat Neurosci 12(10):1343-1349 (2009)
  Pavlovian trace conditioning depends on the temporal gap between the conditioned and unconditioned stimuli. It requires, in mammals, functional medial temporal lobe structures and, in humans, explicit knowledge of the temporal contingency. It is therefore considered to be a plausible objective test to assess awareness without relying on explicit reports. We found that individuals with disorders of consciousness (DOCs), despite being unable to report awareness explicitly, were able to learn this procedure. Learning was specific and showed an anticipatory electromyographic response to the aversive conditioning stimulus, which was substantially stronger than to the control stimulus and was augmented as the aversive stimulus approached. The amount of learning correlated with the degree of cortical atrophy and was a good indicator of recovery. None of these effects were observed in control subjects under the effect of anesthesia (propofol). Our results suggest that individu! als with DOCs might have partially preserved conscious processing, which cannot be mediated by explicit reports and is not detected by behavioral assessment.