Hot off the presses! Aug 01 Nat Neurosci

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Latest Articles Include:

• Changes in house rules
  - Nat Neurosci 12(8):955 (2009)
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• PDLIM5 is not a neuronal CaV2.2 adaptor protein
  - Nat Neurosci 12(8):957-958 (2009)
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• Reply to "PDLIM5 is not a neuronal CaV2.2 adaptor protein"
  - Nat Neurosci 12(8):958 (2009)
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• Who let the spikes out?
  - Nat Neurosci 12(8):959-960 (2009)
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• Practice makes perfect, even for breathing
  - Nat Neurosci 12(8):961-963 (2009)
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• Should I stay or should I go: genetic bases for uncertainty-driven exploration
  - Nat Neurosci 12(8):963-965 (2009)
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• Inactivating the activated: identifying functions of specific neural networks
  - Nat Neurosci 12(8):965-966 (2009)
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• Resolving single cone inputs to visual receptive fields
  - Nat Neurosci 12(8):967-969 (2009)
  With the current techniques available for mapping receptive fields, it is impossible to resolve the contribution of single cone photoreceptors to the response of central visual neurons. Using adaptive optics to correct for ocular aberrations, we delivered micron-scale spots of light to the receptive field centers of neurons in the macaque lateral geniculate nucleus. Parvocellular LGN neurons mapped in this manner responded with high reliability to stimulation of single cones.
• Representation of internal models of action in the autistic brain
  - Nat Neurosci 12(8):970-972 (2009)
  Children with autism spectrum disorder (ASD) have deficits in motor control, imitation and social function. Does a dysfunction in the neural basis of representing internal models of action contribute to these problems? We measured patterns of generalization as children learned to control a novel tool and found that the autistic brain built a stronger than normal association between self-generated motor commands and proprioceptive feedback; furthermore, the greater the reliance on proprioception, the greater the child's impairments in social function and imitation.
• The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1
  - Nat Neurosci 12(8):973-980 (2009)
  Defective responses to DNA single strand breaks underlie various neurodegenerative diseases. However, the exact role of this repair pathway during the development and maintenance of the nervous system is unclear. Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is characterized by the loss of cerebellar interneurons. This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation. Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function. Collectively, these data detail the in vivo link between DNA single strand break repair and neurogenesis and highlight the diverse consequences of specific types of genotoxic stress in the nervous system.
• A trophic role for Wnt-Ror kinase signaling during developmental pruning in Caenorhabditis elegans
  - Nat Neurosci 12(8):981-987 (2009)
  The molecular mechanism by which neurites are selected for elimination or incorporation into the mature circuit during developmental pruning remains unknown. The trophic theory postulates that local cues provided by target or surrounding cells act to inhibit neurite elimination. However, no widely conserved factor mediating this trophic function has been identified. We found that the developmental survival of specific neurites in Caenorhabditis elegans largely depends on detection of the morphogen Wnt by the Ror kinase CAM-1, which is a transmembrane tyrosine kinase with a Frizzled domain. Mutations in Wnt genes or in cam-1 enhanced neurite elimination, whereas overexpression of cam-1 inhibited neurite elimination in a Wnt-dependent manner. Moreover, mutations in these genes counteracted the effect of a mutation in mbr-1, which encodes a transcription factor that promotes neurite elimination. These results reveal the trophic role of an atypical Wnt pathway and reinforc! e the classical model of developmental pruning.
• A discrete alcohol pocket involved in GIRK channel activation
  - Nat Neurosci 12(8):988-995 (2009)
  Ethanol modifies neural activity in the brain by modulating ion channels. Ethanol activates G protein–gated inwardly rectifying K+ channels, but the molecular mechanism is not well understood. Here, we used a crystal structure of a mouse inward rectifier containing a bound alcohol and structure-based mutagenesis to probe a putative alcohol-binding pocket located in the cytoplasmic domains of GIRK channels. Substitutions with bulkier side-chains in the alcohol-binding pocket reduced or eliminated activation by alcohols. By contrast, alcohols inhibited constitutively open channels, such as IRK1 or GIRK2 engineered to strongly bind PIP2. Mutations in the hydrophobic alcohol-binding pocket of these channels had no effect on alcohol-dependent inhibition, suggesting an alternate site is involved in inhibition. Comparison of high-resolution structures of inwardly rectifying K+ channels suggests a model for activation of GIRK channels using this hydrophobic alcohol-binding p! ocket. These results provide a tool for developing therapeutic compounds that could mitigate the effects of alcohol.
• Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation
  - Nat Neurosci 12(8):996-1002 (2009)
  The distal end of the axon initial segment (AIS) is the preferred site for action potential initiation in cortical pyramidal neurons because of its high Na+ channel density. However, it is not clear why action potentials are not initiated at the proximal AIS, which has a similarly high Na+ channel density. We found that low-threshold Nav1.6 and high-threshold Nav1.2 channels preferentially accumulate at the distal and proximal AIS, respectively, and have distinct functions in action potential initiation and backpropagation. Patch-clamp recording from the axon cut end of pyramidal neurons in the rat prefrontal cortex revealed a high density of Na+ current and a progressive reduction in the half-activation voltage (up to 14 mV) with increasing distance from the soma at the AIS. Further modeling studies and simultaneous somatic and axonal recordings showed that distal Nav1.6 promotes action potential initiation, whereas proximal Nav1.2 promotes its backpropagation to the ! soma.
• Ca2+ and calmodulin initiate all forms of endocytosis during depolarization at a nerve terminal
  - Nat Neurosci 12(8):1003-1010 (2009)
  Although endocytosis maintains synaptic transmission, how endocytosis is initiated is unclear. We found that calcium influx initiated all forms of endocytosis at a single nerve terminal in rodents, including clathrin-dependent slow endocytosis, bulk endocytosis, rapid endocytosis and endocytosis overshoot (excess endocytosis), with each being evoked with a correspondingly higher calcium threshold. As calcium influx increased, endocytosis gradually switched from very slow endocytosis to slow endocytosis to bulk endocytosis to rapid endocytosis and to endocytosis overshoot. The calcium-induced endocytosis rate increase was a result of the speeding up of membrane invagination and fission. Pharmacological experiments suggested that the calcium sensor mediating these forms of endocytosis is calmodulin. In addition to its role in recycling vesicles, calcium/calmodulin-initiated endocytosis facilitated vesicle mobilization to the readily releasable pool, probably by clearing ! fused vesicle membrane at release sites. Our findings provide a unifying mechanism for the initiation of various forms of endocytosis that are critical in maintaining exocytosis.
• SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway
  - Nat Neurosci 12(8):1011-1019 (2009)
  Synaptic plasticity is dependent on the differential sorting, delivery and retention of neurotransmitter receptors, but the mechanisms underlying these processes are poorly understood. We found that differential sorting of glutamate receptor subtypes began in the endoplasmic reticulum of rat hippocampal neurons. As AMPA receptors (AMPARs) were trafficked to the plasma membrane via the conventional somatic Golgi network, NMDA receptors (NMDARs) were diverted from the somatic endoplasmic reticulum into a specialized endoplasmic reticulum subcompartment that bypasses somatic Golgi, merging instead with dendritic Golgi outposts. This endoplasmic reticulum subcompartment was composed of highly mobile vesicles containing the NMDAR subunits NR1 and NR2B, the microtubule-dependent motor protein KIF17, and the postsynaptic adaptor proteins CASK and SAP97. Our data demonstrate that the retention and trafficking of NMDARs in this endoplasmic reticulum subcompartment requires both! CASK and SAP97. These findings indicate that NMDARs are sorted away from AMPARs via a non-conventional secretory pathway that utilizes dendritic Golgi outposts.
• Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry
  - Nat Neurosci 12(8):1020-1027 (2009)
  Genomic studies demonstrate that, although the majority of the mammalian genome is transcribed, only about 2% of these transcripts are code for proteins. We investigated how the long, polyadenylated Evf2 noncoding RNA regulates transcription of the homeodomain transcription factors DLX5 and DLX6 in the developing mouse forebrain. We found that, in developing ventral forebrain, Evf2 recruited DLX and MECP2 transcription factors to important DNA regulatory elements in the Dlx5/6 intergenic region and controlled Dlx5, Dlx6 and Gad1 expression through trans and cis-acting mechanisms. Evf2 mouse mutants had reduced numbers of GABAergic interneurons in early postnatal hippocampus and dentate gyrus. Although the numbers of GABAergic interneurons and Gad1 RNA levels returned to normal in Evf2 mutant adult hippocampus, reduced synaptic inhibition occurred. These results suggest that noncoding RNA–dependent balanced gene regulation in embryonic brain is critical for proper for! mation of GABA-dependent neuronal circuitry in adult brain.
• Genetic identification of an embryonic parafacial oscillator coupling to the preBötzinger complex
  - Nat Neurosci 12(8):1028-1035 (2009)
  The hindbrain transcription factors Phox2b and Egr2 (also known as Krox20) are linked to the development of the autonomic nervous system and rhombomere-related regulation of breathing, respectively. Mutations in these proteins can lead to abnormal breathing behavior as a result of an alteration in an unidentified neuronal system. We characterized a bilateral embryonic parafacial (e-pF) population of rhythmically bursting neurons at embryonic day (E) 14.5 in mice. These cells expressed Phox2b, were derived from Egr2-expressing precursors and their development was dependent on the integrity of the Egr2 gene. Silencing or eliminating the e-pF oscillator, but not the putative inspiratory oscillator (preBötzinger complex, preBötC), led to an abnormally slow rhythm, demonstrating that the e-pF controls the respiratory rhythm. The e-pF oscillator, the only one active at E14.5, entrained and then coupled with the preBötC, which emerged independently at E15.5. These data est! ablish the dual organization of the respiratory rhythm generator at the time of its inception, when it begins to drive fetal breathing.
• Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc
  - Nat Neurosci 12(8):1036-1041 (2009)
  Addictive drugs hijack mechanisms of learning and memory that normally underlie reinforcement of natural rewards and induce synaptic plasticity of glutamatergic transmission in the mesolimbic dopamine (DA) system. In the ventral tegmental area (VTA), a single exposure to cocaine efficiently triggers NMDA receptor–dependent synaptic plasticity in DA neurons, whereas plasticity in the nucleus accumbens (NAc) occurs only after repeated injections. Whether these two forms of plasticity are independent or hierarchically organized remains unknown. We combined ex vivo electrophysiology in acute brain slices with behavioral assays modeling drug relapse in mice and found that the duration of the cocaine-evoked synaptic plasticity in the VTA is gated by mGluR1. Overriding mGluR1 in vivo made the potentiation in the VTA persistent. This led to synaptic plasticity in the NAc, which contributes to cocaine-seeking behavior after protracted withdrawal. Impaired mGluR1 function in v! ulnerable individuals could represent a first step in the recruitment of the neuronal network that underlies drug addiction.
• Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning
  - Nat Neurosci 12(8):1042-1049 (2009)
  Although feedforward inhibition onto Purkinje cells was first documented 40 years ago, we understand little of how inhibitory interneurons contribute to cerebellar function in behaving animals. Using a mouse line (PC-2) in which GABAA receptor–mediated synaptic inhibition is selectively removed from Purkinje cells, we examined how feedforward inhibition from molecular layer interneurons regulates adaptation of the vestibulo-ocular reflex. Although impairment of baseline motor performance was relatively mild, the ability to adapt the phase of the vestibulo-ocular reflex and to consolidate gain adaptations was strongly compromised. Purkinje cells showed abnormal patterns of simple spikes, both during and in the absence of evoked compensatory eye movements. On the basis of modeling our experimental data, we propose that feedforward inhibition, by controlling the fine-scale patterns of Purkinje cell activity, enables the induction of plasticity in neurons of the cerebell! ar and vestibular nuclei.
• Disparity- and velocity-based signals for three-dimensional motion perception in human MT+
  - Nat Neurosci 12(8):1050-1055 (2009)
  How does the primate visual system encode three-dimensional motion? The macaque middle temporal area (MT) and the human MT complex (MT+) have well-established sensitivity to two-dimensional frontoparallel motion and static disparity. However, evidence for sensitivity to three-dimensional motion has remained elusive. We found that human MT+ encodes two binocular cues to three-dimensional motion: changing disparities over time and interocular comparisons of retinal velocities. By varying important properties of moving dot displays, we distinguished these three-dimensional motion signals from their constituents, instantaneous binocular disparity and monocular retinal motion. An adaptation experiment confirmed direction selectivity for three-dimensional motion. Our results indicate that MT+ carries critical binocular signals for three-dimensional motion processing, revealing an important and previously overlooked role for this well-studied brain area.
• Sensory transformations and the use of multiple reference frames for reach planning
  - Nat Neurosci 12(8):1056-1061 (2009)
  The sensory signals that drive movement planning arrive in a variety of 'reference frames', and integrating or comparing them requires sensory transformations. We propose a model in which the statistical properties of sensory signals and their transformations determine how these signals are used. This model incorporates the patterns of gaze-dependent errors that we found in our human psychophysics experiment when the sensory signals available for reach planning were varied. These results challenge the widely held ideas that error patterns directly reflect the reference frame of the underlying neural representation and that it is preferable to use a single common reference frame for movement planning. We found that gaze-dependent error patterns, often cited as evidence for retinotopic reach planning, can be explained by a transformation bias and are not exclusively linked to retinotopic representations. Furthermore, the presence of multiple reference frames allows for o! ptimal use of available sensory information and explains task-dependent reweighting of sensory signals.
• Prefrontal and striatal dopaminergic genes predict individual differences in exploration and exploitation
  - Nat Neurosci 12(8):1062-1068 (2009)
  The basal ganglia support learning to exploit decisions that have yielded positive outcomes in the past. In contrast, limited evidence implicates the prefrontal cortex in the process of making strategic exploratory decisions when the magnitude of potential outcomes is unknown. Here we examine neurogenetic contributions to individual differences in these distinct aspects of motivated human behavior, using a temporal decision-making task and computational analysis. We show that two genes controlling striatal dopamine function, DARPP-32 (also called PPP1R1B) and DRD2, are associated with exploitative learning to adjust response times incrementally as a function of positive and negative decision outcomes. In contrast, a gene primarily controlling prefrontal dopamine function (COMT) is associated with a particular type of 'directed exploration', in which exploratory decisions are made in proportion to Bayesian uncertainty about whether other choices might produce outcomes t! hat are better than the status quo. Quantitative model fits reveal that genetic factors modulate independent parameters of a reinforcement learning system.
• Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization
  - Nat Neurosci 12(8):1069-1073 (2009)
  Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new to! ol for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors.