Hot off the presses! Dec 10 Neuron

The Dec 10 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Taking Off the SOCS: Cytokine Signaling Spurs Regeneration
  - Neuron 64(5):591-592 (2009)
  Strategies to improve function after CNS injuries must contend with the failure of axons to regrow after transection in adult mammals. In this issue of Neuron, Smith et al. provide an important advance by demonstrating that SOCS3 acts as a key negative regulator of adult optic nerve regeneration.
• A New Class of Spinal Interneurons: The Origin and Function of C Boutons Is Solved
  - Neuron 64(5):593-595 (2009)
  C boutons, a major synaptic input to motor neurons, were first described years ago, but their origin and functional significance were unknown. In this issue of Neuron, a group of cholinergic interneurons located near the central canal is identified as the source of C boutons. The rhythmic activity in these neurons during locomotion increases motor neuronal excitability, thereby potentiating the strength of muscle contraction.
• Rab3 GTPase Lands Bruchpilot
  - Neuron 64(5):595-597 (2009)
  Active zones are the sites of neurotransmitter release, but their assembly mechanisms are poorly understood. In this issue of Neuron, Graf et al. perform a genetic screen in Drosophila and uncover a novel role for the Rab3 GTPase in organizing the active zone at the neuromuscular junction.
• Fields of Gain in the Brain
  - Neuron 64(5):598-600 (2009)
  For more than two decades, neuroscientists have debated the role of "gain fields" in sensorimotor transformations. In this issue of Neuron, Chang et al. demonstrate a tight correlation between eye and hand position gain fields in the "parietal reach region," strongly suggesting that they play a functional role in computing the reach command.
• Robert J. Wenthold (1948–2009)
  - Neuron 64(5):603-604 (2009)
  
• The Challenges Natural Images Pose for Visual Adaptation
  - Neuron 64(5):605-616 (2009)
  Advances in our understanding of natural image statistics and of gain control within the retinal circuitry are leading to new insights into the classic problem of retinal light adaptation. Here we review what we know about how rapid adaptation occurs during active exploration of the visual scene. Adaptational mechanisms must balance the competing demands of adapting quickly, locally, and reliably, and this balance must be maintained as lighting conditions change. Multiple adaptational mechanisms in different locations within the retina act in concert to accomplish this task, with lighting conditions dictating which mechanisms dominate.
• Frequency Transitions in Odor-Evoked Neural Oscillations
  - Neuron 64(5):692-706 (2009)
  In many species, sensory stimuli elicit the oscillatory synchronization of groups of neurons. What determines the properties of these oscillations? In the olfactory system of the moth, we found that odors elicited oscillatory synchronization through a neural mechanism like that described in locust and Drosophila. During responses to long odor pulses, oscillations suddenly slowed as net olfactory receptor neuron (ORN) output decreased; thus, stimulus intensity appeared to determine oscillation frequency. However, changing the concentration of the odor had little effect upon oscillatory frequency. Our recordings in vivo and computational models based on these results suggested that the main effect of increasing odor concentration was to recruit additional, less well-tuned ORNs whose firing rates were tightly constrained by adaptation and saturation. Thus, in the periphery, concentration is encoded mainly by the size of the responsive ORN population, and oscillation frequ! ency is set by the adaptation and saturation of this response.
• Using a Compound Gain Field to Compute a Reach Plan
  - Neuron 64(5):744-755 (2009)
  A gain field, the scaling of a tuned neuronal response by a postural signal, may help support neuronal computation. Here, we characterize eye and hand position gain fields in the parietal reach region (PRR). Eye and hand gain fields in individual PRR neurons are similar in magnitude but opposite in sign to one another. This systematic arrangement produces a compound gain field that is proportional to the distance between gaze location and initial hand position. As a result, the visual response to a target for an upcoming reach is scaled by the initial gaze-to-hand distance. Such a scaling is similar to what would be predicted in a neural network that mediates between eye- and hand-centered representations of target location. This systematic arrangement supports a role of PRR in visually guided reaching and provides strong evidence that gain fields are used for neural computations.

Hot off the presses! Sep 22 Neuron

The Sep 22 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Wnt Signaling as a Potential Therapeutic Target for Frontotemporal Dementia
  - Neuron 71(6):955-957 (2011)
  Progranulin mutations result in frontotemporal dementia, but the underlying pathophysiology has remained largely unexplained. New data by Geschwind and colleagues in this issue of Neuron uncovered that the Wnt/FZD2 signaling pathway is an early and critical contributor to disease pathology.
• Patterning Spinal Motor Activity in the Absence of Synaptic Excitation
  - Neuron 71(6):957-959 (2011)
  Alternate activation of antagonistic muscles across a joint is essential for movement. A new study, by Talpalar et al., in this issue of Neuron highlights the importance of spinal cord inhibitory interneurons in generating motor activity by showing that they can generate alternating flexor-extensor motor neuron firing in the absence of glutamatergic synaptic input.
• The Dynamics of Learning and Behavioral Flexibility
  - Neuron 71(6):959-961 (2011)
  Fundamental to behavior is the capacity to distinguish beneficial from detrimental environmental stimuli. In this issue of Neuron, a new study by Morrison et al. shows that underlying these processes are qualitatively different dynamical interactions between brain structures involved in processing the value of environmental stimuli.
• All in a Sniff: Olfaction as a Model for Active Sensing
  - Neuron 71(6):962-973 (2011)
  Sensation is an active process involving the sampling and central processing of external stimuli selectively in space and time. Olfaction in particular depends strongly on active sensing due to the fact that—at least in mammals—inhalation of air into the nasal cavity is required for odor detection. This seemingly simple first step in odor sensation profoundly shapes nearly all aspects of olfactory system function, from the distribution of odorant receptors to the functional organization of central processing to the perception of odors. The dependence of olfaction on inhalation also allows for profound modulation of olfactory processing by changes in odor sampling strategies in coordination with attentional state and sensory demands. This review discusses the role of active sensing in shaping olfactory system function at multiple levels and draws parallels with other sensory modalities to highlight the importance of an active sensing perspective in understanding how! sensory systems work in the behaving animal.
• Seeing Things in Motion: Models, Circuits, and Mechanisms
  - Neuron 71(6):974-994 (2011)
  Motion vision provides essential cues for navigation and course control as well as for mate, prey, or predator detection. Consequently, neurons responding to visual motion in a direction-selective way are found in almost all species that see. However, directional information is not explicitly encoded at the level of a single photoreceptor. Rather, it has to be computed from the spatio-temporal excitation level of at least two photoreceptors. How this computation is done and how this computation is implemented in terms of neural circuitry and membrane biophysics have remained the focus of intense research over many decades. Here, we review recent progress made in this area with an emphasis on insects and the vertebrate retina.
• A Resource of Cre Driver Lines for Genetic Targeting of GABAergic Neurons in Cerebral Cortex
  - Neuron 71(6):995-1013 (2011)
  A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and beha! vior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain.
• Development of Cell Type-Specific Connectivity Patterns of Converging Excitatory Axons in the Retina
  - Neuron 71(6):1014-1021 (2011)
  To integrate information from different presynaptic cell types, dendrites receive distinct patterns of synapses from converging axons. How different afferents in vivo establish specific connectivity patterns with the same dendrite is poorly understood. Here, we examine the synaptic development of three glutamatergic bipolar cell types converging onto a common postsynaptic retinal ganglion cell. We find that after axons and dendrites target appropriate synaptic layers, patterns of connections among these neurons diverge through selective changes in the conversion of axo-dendritic appositions to synapses. This process is differentially regulated by neurotransmission, which is required for the shift from single to multisynaptic appositions of one bipolar cell type but not for maintenance and elimination, respectively, of connections from the other two types. Thus, synaptic specificity among converging excitatory inputs in the retina emerges via differential synaptic matur! ation of axo-dendritic appositions and is shaped by neurotransmission in a cell type-dependent manner.
• Regulation of AMPA Receptor Function by the Human Memory-Associated Gene KIBRA
  - Neuron 71(6):1022-1029 (2011)
  KIBRA has recently been identified as a gene associated with human memory performance. Despite the elucidation of the role of KIBRA in several diverse processes in nonneuronal cells, the molecular function of KIBRA in neurons is unknown. We found that KIBRA directly binds to the protein interacting with C-kinase 1 (PICK1) and forms a complex with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs), the major excitatory neurotransmitter receptors in the brain. KIBRA knockdown accelerates the rate of AMPAR recycling following N-methyl-D-aspartate receptor-induced internalization. Genetic deletion of KIBRA in mice impairs both long-term depression and long-term potentiation at hippocampal Schaffer collateral-CA1 synapses. Moreover, KIBRA knockout mice have severe deficits in contextual fear learning and memory. These results indicate that KIBRA regulates higher brain function by regulating AMPAR trafficking and synaptic plasticity.
• Functional Genomic Analyses Identify Pathways Dysregulated by Progranulin Deficiency, Implicating Wnt Signaling
  - Neuron 71(6):1030-1042 (2011)
  Progranulin (GRN) mutations cause frontotemporal dementia (FTD), but GRN's function in the CNS remains largely unknown. To identify the pathways downstream of GRN, we used weighted gene coexpression network analysis (WGCNA) to develop a systems-level view of transcriptional alterations in a human neural progenitor model of GRN-deficiency. This highlighted key pathways such as apoptosis and ubiquitination in GRN deficient human neurons, while revealing an unexpected major role for the Wnt signaling pathway, which was confirmed by analysis of gene expression data from postmortem FTD brain. Furthermore, we observed that the Wnt receptor Fzd2 was one of only a few genes upregulated at 6 weeks in a GRN knockout mouse, and that FZD2 reduction caused increased apoptosis, while its upregulation promoted neuronal survival in vitro. Together, these in vitro and in vivo data point to an adaptive role for altered Wnt signaling in GRN deficiency-mediated FTD, representing a potenti! al therapeutic target. Video Abstract View Within Article
• Axon Regeneration Pathways Identified by Systematic Genetic Screening in C. elegans
  - Neuron 71(6):1043-1057 (2011)
  The mechanisms underlying the ability of axons to regrow after injury remain poorly explored at the molecular genetic level. We used a laser injury model in Caenorhabditis elegans mechanosensory neurons to screen 654 conserved genes for regulators of axonal regrowth. We uncover several functional clusters of genes that promote or repress regrowth, including genes classically known to affect axon guidance, membrane excitability, neurotransmission, and synaptic vesicle endocytosis. The conserved Arf Guanine nucleotide Exchange Factor (GEF), EFA-6, acts as an intrinsic inhibitor of regrowth. By combining genetics and in vivo imaging, we show that EFA-6 inhibits regrowth via microtubule dynamics, independent of its Arf GEF activity. Among newly identified regrowth inhibitors, only loss of function in EFA-6 partially bypasses the requirement for DLK-1 kinase. Identification of these pathways significantly expands our understanding of the genetic basis of axonal injury respo! nses and repair.
• GDE2 Regulates Subtype-Specific Motor Neuron Generation through Inhibition of Notch Signaling
  - Neuron 71(6):1058-1070 (2011)
  The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates! within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons.
• Identification of Minimal Neuronal Networks Involved in Flexor-Extensor Alternation in the Mammalian Spinal Cord
  - Neuron 71(6):1071-1084 (2011)
  Neural networks in the spinal cord control two basic features of locomotor movements: rhythm generation and pattern generation. Rhythm generation is generally considered to be dependent on glutamatergic excitatory neurons. Pattern generation involves neural circuits controlling left-right alternation, which has been described in great detail, and flexor-extensor alternation, which remains poorly understood. Here, we use a mouse model in which glutamatergic neurotransmission has been ablated in the locomotor region of the spinal cord. The isolated in vitro spinal cord from these mice produces locomotor-like activity—when stimulated with neuroactive substances—with prominent flexor-extensor alternation. Under these conditions, unlike in control mice, networks of inhibitory interneurons generate the rhythmic activity. In the absence of glutamatergic synaptic transmission, the flexor-extensor alternation appears to be generated by Ia inhibitory interneurons, which medi! ate reciprocal inhibition from muscle proprioceptors to antagonist motor neurons. Our study defines a minimal inhibitory network that is needed to produce flexor-extensor alternation during locomotion.
• Distinct Modes of AMPA Receptor Suppression at Developing Synapses by GluN2A and GluN2B: Single-Cell NMDA Receptor Subunit Deletion In Vivo
  - Neuron 71(6):1085-1101 (2011)
  During development there is an activity-dependent switch in synaptic N-Methyl-D-aspartate (NMDA) receptor subunit composition from predominantly GluN2B to GluN2A, though the precise role of this switch remains unknown. By deleting GluN2 subunits in single neurons during synaptogenesis, we find that both GluN2B and GluN2A suppress AMPA receptor expression, albeit by distinct means. Similar to GluN1, GluN2B deletion increases the number of functional synapses, while GluN2A deletion increases the strength of unitary connections without affecting the number of functional synapses. We propose a model of excitatory synapse maturation in which baseline activation of GluN2B-containing receptors prevents premature synapse maturation until correlated activity allows induction of functional synapses. This activity also triggers the switch to GluN2A, which dampens further potentiation. Furthermore, we analyze the subunit composition of synaptic NMDA receptors in CA1 pyramidal cell! s, provide electrophysiological evidence for a large population of synaptic triheteromeric receptors, and estimate the subunit-dependent open probability.
• DPP6 Establishes the A-Type K+ Current Gradient Critical for the Regulation of Dendritic Excitability in CA1 Hippocampal Neurons
  - Neuron 71(6):1102-1115 (2011)
  Subthreshold-activating A-type K+ currents are essential for the proper functioning of the brain, where they act to delay excitation and regulate firing frequency. In CA1 hippocampal pyramidal neuron dendrites, the density of A-type K+ current increases with distance from the soma, playing an important role in synaptic integration and plasticity. The mechanism underlying this gradient has, however, remained elusive. Here, dendritic recordings from mice lacking the Kv4 transmembrane auxiliary subunit DPP6 revealed that this protein is critical for generating the A-current gradient. Loss of DPP6 led to a decrease in A-type current, specifically in distal dendrites. Decreased current density was accompanied by a depolarizing shift in the voltage dependence of channel activation. Together these changes resulted in hyperexcitable dendrites with enhanced dendritic AP back-propagation, calcium electrogenesis, and induction of synaptic long-term potentiation. Despite enhanced ! dendritic excitability, firing behavior evoked by somatic current injection was mainly unaffected in DPP6-KO recordings, indicating compartmentalized regulation of neuronal excitability.
• Vesicular Zinc Promotes Presynaptic and Inhibits Postsynaptic Long-Term Potentiation of Mossy Fiber-CA3 Synapse
  - Neuron 71(6):1116-1126 (2011)
  The presence of zinc in glutamatergic synaptic vesicles of excitatory neurons of mammalian cerebral cortex suggests that zinc might regulate plasticity of synapses formed by these neurons. Long-term potentiation (LTP) is a form of synaptic plasticity that may underlie learning and memory. We tested the hypothesis that zinc within vesicles of mossy fibers (mf) contributes to mf-LTP, a classical form of presynaptic LTP. We synthesized an extracellular zinc chelator with selectivity and kinetic properties suitable for study of the large transient of zinc in the synaptic cleft induced by mf stimulation. We found that vesicular zinc is required for presynaptic mf-LTP. Unexpectedly, vesicular zinc also inhibits a form of postsynaptic mf-LTP. Because the mf-CA3 synapse provides a major source of excitatory input to the hippocampus, regulating its efficacy by these dual actions, vesicular zinc is critical to proper function of hippocampal circuitry in health and disease.
• Different Time Courses for Learning-Related Changes in Amygdala and Orbitofrontal Cortex
  - Neuron 71(6):1127-1140 (2011)
  The orbitofrontal cortex (OFC) and amygdala are thought to participate in reversal learning, a process in which cue-outcome associations are switched. However, current theories disagree on whether OFC directs reversal learning in the amygdala. Here, we show that during reversal of cues' associations with rewarding and aversive outcomes, neurons that respond preferentially to stimuli predicting aversive events update more quickly in amygdala than OFC; meanwhile, OFC neurons that respond preferentially to reward-predicting stimuli update more quickly than those in the amygdala. After learning, however, OFC consistently differentiates between impending reinforcements with a shorter latency than the amygdala. Finally, analysis of local field potentials (LFPs) reveals a disproportionate influence of OFC on amygdala that emerges after learning. We propose that reversal learning is supported by complex interactions between neural circuits spanning the amygdala and OFC, rather! than directed by any single structure.
• Hedging Your Bets by Learning Reward Correlations in the Human Brain
  - Neuron 71(6):1141-1152 (2011)
  Human subjects are proficient at tracking the mean and variance of rewards and updating these via prediction errors. Here, we addressed whether humans can also learn about higher-order relationships between distinct environmental outcomes, a defining ecological feature of contexts where multiple sources of rewards are available. By manipulating the degree to which distinct outcomes are correlated, we show that subjects implemented an explicit model-based strategy to learn the associated outcome correlations and were adept in using that information to dynamically adjust their choices in a task that required a minimization of outcome variance. Importantly, the experimentally generated outcome correlations were explicitly represented neuronally in right midinsula with a learning prediction error signal expressed in rostral anterior cingulate cortex. Thus, our data show that the human brain represents higher-order correlation structures between rewards, a core adaptive abi! lity whose immediate benefit is optimized sampling.

Hot off the presses! Jun 11 Neuron

The Jun 11 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Synaptobrevin, Sphingolipids, and Secretion: Lube 'n' Go at the Synapse
  Verhage M van Meer G - Neuron 62(5):603-605 (2009)
  For neurotransmitter release to occur, proteins and lipids have to work together. The classical view of this process is that a variety of proteins work hard to force the unwilling, fusion-aversive lipids into merging. In this issue of Neuron, a study by Darios et al. paints the opposite picture: a lipid metabolite stimulates the reluctant vSNARE synaptobrevin to engage in fusogenic protein complexes.
• Inhibitory Plasticity in Auditory Cortex
  Nelken I - Neuron 62(5):605-607 (2009)
  Arguably the most important property of neuronal circuits in general, and of cortical circuits in particular, is plasticity—the ability to change in response to past experience. While many studies of plasticity emphasize changes in excitatory transmission, in this issue of Neuron, Galindo-Leon et al. demonstrate the important role that increased inhibition may play in shaping cortical responses to behaviorally relevant stimuli.
• Video Game for Monkeys
  Schlag JD Schlag-Rey M - Neuron 62(5):608-609 (2009)
  Recent progress in neurophysiological recording has developed in two directions. One relies on multimicroelectrodes to study correlations in neuron firing. The other relies on sophisticated tasks to distinguish successive stages of neuronal processing. In this issue of Neuron, Shichinohe et al. take this second approach to analyze neuronal mechanisms of pursuit.
• Comparing the Bird in the Hand with the Ones in the Bush
  Bunge SA Wendelken C - Neuron 62(5):609-611 (2009)
  In this issue of Neuron, Boorman and colleagues shed new light on the roles of lateral frontopolar and ventromedial prefrontal cortices in task switching and decision making.
• Neurons that Fire Together Also Conspire Together: Is Normal Sleep Circuitry Hijacked to Generate Epilepsy?
  Beenhakker MP Huguenard JR - Neuron 62(5):612-632 (2009)
  Brain circuits oscillate during sleep. The same circuits appear to generate pathological oscillations. In this review, we discuss recent advances in our understanding of how epilepsy co-opts normal, sleep-related circuits to generate seizures.
• The Stoichiometry of AMPA Receptors and TARPs Varies by Neuronal Cell Type
  Shi Y Lu W Milstein AD Nicoll RA - Neuron 62(5):633-640 (2009)
  Synaptic AMPA receptors (AMPARs) are regulated by a family of auxiliary subunits known as transmembrane AMPA receptor regulatory proteins (TARPs). TARPs control the trafficking and gating of AMPARs. However, the number of TARP molecules that assemble within individual AMPAR channels is unknown. Here, we covalently link AMPARs to TARPs to investigate the properties of TARP/AMPAR complexes with known stoichiometry in HEK cells. We find that AMPARs are functional when associated with four, two, or no TARPs, and that the efficacy of the partial agonist kainate varies across these conditions, providing a sensitive assay for TARP/AMPAR stoichiometry. A comparison of these results with data obtained from hippocampal neurons demonstrates that native AMPARs associate with TARPs with a variable stoichiometry that depends on TARP expression level. Interestingly, AMPARs in hippocampal pyramidal neurons are saturated by TARP expression, while those in dentate gyrus granule neurons ! are not, indicating that variable TARP/AMPAR stoichiometry provides a mechanism for cell-type-specific regulation of AMPAR function.
• Retinoid Signaling and Neurogenin2 Function Are Coupled for the Specification of Spinal Motor Neurons through a Chromatin Modifier CBP
  Lee S Lee B Lee JW Lee SK - Neuron 62(5):641-654 (2009)
  Extracellular signals and cell-intrinsic transcription factors cooperatively instruct generation of diverse neurons. However, little is known about how neural progenitors integrate both cues and orchestrate chromatin changes for neuronal specification. Here, we report that extrinsic signal retinoic acid (RA) and intrinsic transcription factor Neurogenin2 (Ngn2) collaboratively trigger transcriptionally active chromatin in spinal motor neuron genes during development. Retinoic acid receptor (RAR) binds Ngn2 and is thereby recruited to motor neuron genes targeted by Ngn2. RA then facilitates the recruitment of a histone acetyltransferase CBP to the Ngn2/RAR-complex, markedly inducing histone H3/H4-acetylation. Correspondingly, timely inactivation of CBP and its paralog p300 results in profound defects in motor neuron specification and motor axonal projection, accompanied by significantly reduced histone H3-acetylation of the motor neuron enhancer. Our study uncovers the ! mechanism by which extrinsic RA-signal and intrinsic transcription factor Ngn2 cooperate for cell fate specification through their synergistic activity to trigger transcriptionally active chromatin.
• Neural Activity Regulates Synaptic Properties and Dendritic Structure In Vivo through Calcineurin/NFAT Signaling
  Schwartz N Schohl A Ruthazer ES - Neuron 62(5):655-669 (2009)
  The calcium-regulated protein phosphatase Calcineurin (CaN) participates in synaptic plasticity and the regulation of transcription factors, including Nuclear Factor of Activated T cells (NFAT). To understand how CaN contributes to neuronal circuit development, whole-cell mEPSC recordings and multiphoton imaging were performed in the visual system of living Xenopus laevis tadpoles electroporated to express either a CaN phosphatase inhibitor or N-VIVIT, a nuclear localization sequence-tagged VIVIT peptide that blocks the binding of CaN to select substrates including NFAT. Both strategies increased mEPSC frequency and dendritic arbor complexity in tectal neurons over 3 days. Expression of either of two constitutively active Xenopus NFATs (CA-NFATs) restored normal synaptic properties in neurons expressing N-VIVIT. However, the morphological phenotype was only rescued by a CA-NFAT bearing an intact regulatory domain, implying that transcriptional control of morphological ! and electrophysiological properties of neurons is mediated by distinct NFAT interactions.
• Activity-Dependent Tuning of Inhibitory Neurotransmission Based on GABAAR Diffusion Dynamics
  Bannai H Lévi S Schweizer C Inoue T Launey T Racine V Sibarita JB Mikoshiba K Triller A - Neuron 62(5):670-682 (2009)
  An activity-dependent change in synaptic efficacy is a central tenet in learning, memory, and pathological states of neuronal excitability. The lateral diffusion dynamics of neurotransmitter receptors are one of the important parameters regulating synaptic efficacy. We report here that neuronal activity modifies diffusion properties of type-A GABA receptors (GABAAR) in cultured hippocampal neurons: enhanced excitatory synaptic activity decreases the cluster size of GABAARs and reduces GABAergic mIPSC. Single-particle tracking of the GABAAR γ2 subunit labeled with quantum dots reveals that the diffusion coefficient and the synaptic confinement domain size of GABAAR increases in parallel with neuronal activity, depending on Ca2+ influx and calcineurin activity. These results indicate that GABAAR diffusion dynamics are directly linked to rapid and plastic modifications of inhibitory synaptic transmission in response to changes in intracellular Ca2+ concentration. This tr! ansient activity-dependent reduction of inhibition would favor the onset of LTP during conditioning.
• Sphingosine Facilitates SNARE Complex Assembly and Activates Synaptic Vesicle Exocytosis
  Darios F Wasser C Shakirzyanova A Giniatullin A Goodman K Munoz-Bravo JL Raingo J Jorgacevski J Kreft M Zorec R Rosa JM Gandia L Gutiérrez LM Binz T Giniatullin R Kavalali ET Davletov B - Neuron 62(5):683-694 (2009)
  Synaptic vesicles loaded with neurotransmitters fuse with the plasma membrane to release their content into the extracellular space, thereby allowing neuronal communication. The membrane fusion process is mediated by a conserved set of SNARE proteins: vesicular synaptobrevin and plasma membrane syntaxin and SNAP-25. Recent data suggest that the fusion process may be subject to regulation by local lipid metabolism. Here, we have performed a screen of lipid compounds to identify positive regulators of vesicular synaptobrevin. We show that sphingosine, a releasable backbone of sphingolipids, activates synaptobrevin in synaptic vesicles to form the SNARE complex implicated in membrane fusion. Consistent with the role of synaptobrevin in vesicle fusion, sphingosine upregulated exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and hippocampal neurons, but not in neurons obtained from synaptobrevin-2 knockout mice. Further mechanistic insig! hts suggest that sphingosine acts on the synaptobrevin/phospholipid interface, defining a novel function for this important lipid regulator.
• Synchronization of Midbrain Dopaminergic Neurons Is Enhanced by Rewarding Events
  Joshua M Adler A Prut Y Vaadia E Wickens JR Bergman H - Neuron 62(5):695-704 (2009)
  The basal ganglia network is divided into two functionally related subsystems: the neuromodulators and the main axis. It is assumed that neuromodulators adjust cortico-striatal coupling. This adjustment might depend on the response properties and temporal interactions between neuromodulators. We studied functional interactions between simultaneously recorded pairs of neurons in the basal ganglia while monkeys performed a classical conditioning task that included rewarding, neutral, and aversive events. Neurons that belong to a single neuromodulator group exhibited similar average responses, whereas main axis neurons responded in a highly diverse manner. Dopaminergic neuromodulators transiently increased trial-to-trial (noise) correlation following rewarding but not aversive events, whereas cholinergic neurons of the striatum decreased their trial-to-trial correlation. These changes in functional connectivity occurred at different epochs of the trial. Thus, the coding s! cheme of neuromodulators (but not main axis neurons) can be viewed as a single-dimensional code that is further enriched by dynamic neuronal interactions.
• Inhibitory Plasticity in a Lateral Band Improves Cortical Detection of Natural Vocalizations
  Galindo-Leon EE Lin FG Liu RC - Neuron 62(5):705-716 (2009)
  The interplay between excitation and inhibition in the auditory cortex is crucial for the processing of acoustic stimuli. However, the precise role that inhibition plays in the distributed cortical encoding of natural vocalizations has not been well studied. We recorded single units (SUs) and local field potentials (LFPs) in the awake mouse auditory cortex while presenting pup isolation calls to animals that either do (mothers) or do not (virgins) recognize the sounds as behaviorally relevant. In both groups, we observed substantial call-evoked inhibition. However, in mothers this was earlier, longer, stronger, and more stereotyped compared to virgins. This difference was most apparent for recording sites tuned to tone frequencies lower than the pup calls' high-ultrasonic frequency range. We hypothesize that this auditory cortical inhibitory plasticity improves pup call detection in a relatively specific manner by increasing the contrast between call-evoked responses a! rising from high-ultrasonic and lateral frequency neural populations.
• Memory and Decision Making in the Frontal Cortex during Visual Motion Processing for Smooth Pursuit Eye Movements
  Shichinohe N Akao T Kurkin S Fukushima J Kaneko CR Fukushima K - Neuron 62(5):717-732 (2009)
  Cortical motor areas are thought to contribute "higher-order processing," but what that processing might include is unknown. Previous studies of the smooth pursuit-related discharge of supplementary eye field (SEF) neurons have not distinguished activity associated with the preparation for pursuit from discharge related to processing or memory of the target motion signals. Using a memory-based task designed to separate these components, we show that the SEF contains signals coding retinal image-slip-velocity, memory, and assessment of visual motion direction, the decision of whether to pursue, and the preparation for pursuit eye movements. Bilateral muscimol injection into SEF resulted in directional errors in smooth pursuit, errors of whether to pursue, and impairment of initial correct eye movements. These results suggest an important role for the SEF in memory and assessment of visual motion direction and the programming of appropriate pursuit eye movements.
• How Green Is the Grass on the Other Side? Frontopolar Cortex and the Evidence in Favor of Alternative Courses of Action
  Boorman ED Behrens TE Woolrich MW Rushworth MF - Neuron 62(5):733-743 (2009)
  Behavioral flexibility is the hallmark of goal-directed behavior. Whereas a great deal is known about the neural substrates of behavioral adjustment when it is explicitly cued by features of the external environment, little is known about how we adapt our behavior when such changes are made on the basis of uncertain evidence. Using a Bayesian reinforcement-learning model and fMRI, we show that frontopolar cortex (FPC) tracks the relative advantage in favor of switching to a foregone alternative when choices are made voluntarily. Changes in FPC functional connectivity occur when subjects finally decide to switch to the alternative behavior. Moreover, interindividual variation in the FPC signal predicts interindividual differences in effectively adapting behavior. By contrast, ventromedial prefrontal cortex (vmPFC) encodes the relative value of the current decision. Collectively, these findings reveal complementary prefrontal computations essential for promoting short- a! nd long-term behavioral flexibility.

Hot off the presses! Aug 13 Neuron

The Aug 13 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• IGF-1: Elixir for Motor Neuron Diseases
  Papanikolaou T Ellerby LM - Neuron 63(3):277-278 (2009)
  Modulation of testosterone levels is a therapeutic approach for spinal and bulbar muscular atrophy (SBMA), a polyglutamine disorder that affects the motor neurons. The article by Palazzolo et al. in this issue of Neuron provides compelling evidence that the expression of insulin growth hormone is a potential therapeutic for SBMA.
• Too Fat to Fly? New Brain Circuits Regulate Obesity in Drosophila
  Kaun KR Heberlein U - Neuron 63(3):279-281 (2009)
  In mammals, fat store levels are regulated by brain centers that control food intake and metabolism. A new study by Al-Anzi and colleagues in this issue of Neuron identifies neurons with similar functions in Drosophila, further establishing the fly as a legitimate model to study obesity.
• The Pre/Post LTP Debate
  Lisman JE - Neuron 63(3):281-284 (2009)
  The pre/post debate involves the question of whether long-term potentiation (LTP) is mediated by enhancement of release, enhancement of postsynaptic receptors, or both. Recent papers have presented evidence for purely postsynaptic or purely presynaptic changes, and a paper by Ahmed and Siegelbam (in this issue of Neuron) suggests a mechanism by which release is enhanced. This debate is increasingly constrained by technical advances that allow central synapses to be studied with increasing precision. A possible of way of reconciling conflicting evidence is suggested.
• A Nonvisual Look at the Functional Organization of Visual Cortex
  Peelen MV Kastner S - Neuron 63(3):284-286 (2009)
  In this issue of Neuron, Mahon et al. show that the ventral visual cortex of congenitally blind individuals, who have never experienced the visual world, has an object-category organization similar to that found in sighted individuals. Here, we discuss the implications of this finding for our understanding of the "visual" cortex.
• The Role of Apolipoprotein E in Alzheimer's Disease
  Kim J Basak JM Holtzman DM - Neuron 63(3):287-303 (2009)
  The 4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer's disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, how apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Aβ aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE.
• Linking Genetically Defined Neurons to Behavior through a Broadly Applicable Silencing Allele
  Kim JC Cook MN Carey MR Shen C Regehr WG Dymecki SM - Neuron 63(3):305-315 (2009)
  Tools for suppressing synaptic transmission gain power when able to target highly selective neuron subtypes, thereby sharpening attainable links between neuron type, behavior, and disease; and when able to silence most any neuron subtype, thereby offering broad applicability. Here, we present such a tool, RC::PFtox, that harnesses breadth in scope along with high cell-type selection via combinatorial gene expression to deliver tetanus toxin light chain (tox), an inhibitor of vesicular neurotransmission. When applied in mice, we observed cell-type-specific disruption of vesicle exocytosis accompanied by loss of excitatory postsynaptic currents and commensurately perturbed behaviors. Among various test populations, we applied RC::PFtox to silence serotonergic neurons, en masse or a subset defined combinatorially. Of the behavioral phenotypes observed upon en masse serotonergic silencing, only one mapped to the combinatorially defined subset. These findings provide eviden! ce for separability by genetic lineage of serotonin-modulated behaviors; collectively, these findings demonstrate broad utility of RC::PFtox for dissecting neuron functions.
• Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy
  Palazzolo I Stack C Kong L Musaro A Adachi H Katsuno M Sobue G Taylor JP Sumner CJ Fischbeck KH Pennuto M - Neuron 63(3):316-328 (2009)
  Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target ! tissue for therapeutic intervention in SBMA.
• Obesity-Blocking Neurons in Drosophila
  Al-Anzi B Sapin V Waters C Zinn K Wyman RJ Benzer S - Neuron 63(3):329-341 (2009)
  In mammals, fat store levels are communicated by leptin and insulin signaling to brain centers that regulate food intake and metabolism. By using transgenic manipulation of neural activity, we report the isolation of two distinct neuronal populations in flies that perform a similar function, the c673a-Gal4 and fruitless-Gal4 neurons. When either of these neuronal groups is silenced, fat store levels increase. This change is mediated through an increase in food intake and altered metabolism in c673a-Gal4-silenced flies, while silencing fruitless-Gal4 neurons alters only metabolism. Hyperactivation of either neuronal group causes depletion of fat stores by increasing metabolic rate and decreasing fatty acid synthesis. Altering the activities of these neurons causes changes in expression of genes known to regulate fat utilization. Our results show that the fly brain measures fat store levels and can induce changes in food intake and metabolism to maintain them within norm! al limits.
• Downregulation of NR3A-Containing NMDARs Is Required for Synapse Maturation and Memory Consolidation
  Roberts AC Díez-García J Rodriguiz RM López IP Luján R Martínez-Turrillas R Picó E Henson MA Bernardo DR Jarrett TM Clendeninn DJ López-Mascaraque L Feng G Lo DC Wesseling JF Wetsel WC Philpot BD Pérez-Otaño I - Neuron 63(3):342-356 (2009)
  NR3A is the only NMDA receptor (NMDAR) subunit that downregulates sharply prior to the onset of sensitive periods for plasticity, yet the functional importance of this transient expression remains unknown. To investigate whether removal/replacement of juvenile NR3A-containing NMDARs is involved in experience-driven synapse maturation, we used a reversible transgenic system that prolonged NR3A expression in the forebrain. We found that removal of NR3A is required to develop strong NMDAR currents, full expression of long-term synaptic plasticity, a mature synaptic organization characterized by more synapses and larger postsynaptic densities, and the ability to form long-term memories. Deficits associated with prolonged NR3A were reversible, as late-onset suppression of transgene expression rescued both synaptic and memory impairments. Our results suggest that NR3A behaves as a molecular brake to prevent the premature strengthening and stabilization of excitatory synapses! and that NR3A removal might thereby initiate critical stages of synapse maturation during early postnatal neural development.
• A Role for SNAP25 in Internalization of Kainate Receptors and Synaptic Plasticity
  Selak S Paternain AV Aller IM Picó E Rivera R Lerma J - Neuron 63(3):357-371 (2009)
  Regulation of surface insertion and internalization of AMPA and NMDA receptors has emerged as a key mechanism for the control of synaptic strength. Regulatory elements for synaptic kainate receptors (KARs) are, however, largely undetermined. We have found that SNAP25 is critical for the synaptic removal of KARs, acting via GluK5 (i.e., KA2) subunits. SNAP25 coimmunoprecipitates with protein complexes containing PICK1, GRIP1, and GluK5 and colocalizes with GluK5 in both hippocampal neurons and transfected HEK293 cells. In hippocampal slices, purified SNAP25 antibodies and blocking peptides caused a GluK5-dependent run-up of KARs-mediated EPSC (EPSCKAR) recorded from CA3 pyramidal neurons when included in the patch pipette and prevented activity-dependent long-term depression of EPSCKAR. As EPSCKAR LTD, SNAP25/PICK1/GluK5 interactions are dynamically regulated by PKC.
• Recruitment of N-Type Ca2+ Channels during LTP Enhances Low Release Efficacy of Hippocampal CA1 Perforant Path Synapses
  Ahmed MS Siegelbaum SA - Neuron 63(3):372-385 (2009)
  The entorhinal cortex provides both direct and indirect inputs to hippocampal CA1 neurons through the perforant path and Schaffer collateral synapses, respectively. Using both two-photon imaging of synaptic vesicle cycling and electrophysiological recordings, we found that the efficacy of transmitter release at perforant path synapses is lower than at Schaffer collateral inputs. This difference is due to the greater contribution to release by presynaptic N-type voltage-gated Ca2+ channels at the Schaffer collateral than perforant path synapses. Induction of long-term potentiation that depends on activation of NMDA receptors and L-type voltage-gated Ca2+ channels enhances the low efficacy of release at perforant path synapses by increasing the contribution of N-type channels to exocytosis. This represents a previously uncharacterized presynaptic mechanism for fine-tuning release properties of distinct classes of synapses onto a common postsynaptic neuron and for regulat! ing synaptic function during long-term synaptic plasticity.
• Serial, Covert Shifts of Attention during Visual Search Are Reflected by the Frontal Eye Fields and Correlated with Population Oscillations
  Buschman TJ Miller EK - Neuron 63(3):386-396 (2009)
  Attention regulates the flood of sensory information into a manageable stream, and so understanding how attention is controlled is central to understanding cognition. Competing theories suggest visual search involves serial and/or parallel allocation of attention, but there is little direct, neural evidence for either mechanism. Two monkeys were trained to covertly search an array for a target stimulus under visual search (endogenous) and pop-out (exogenous) conditions. Here, we present neural evidence in the frontal eye fields (FEF) for serial, covert shifts of attention during search but not pop-out. Furthermore, attention shifts reflected in FEF spiking activity were correlated with 18–34 Hz oscillations in the local field potential, suggesting a "clocking" signal. This provides direct neural evidence that primates can spontaneously adopt a serial search strategy and that these serial covert shifts of attention are directed by the FEF. It also suggests that ne! uron population oscillations may regulate the timing of cognitive processing.
• Category-Specific Organization in the Human Brain Does Not Require Visual Experience
  Mahon BZ Anzellotti S Schwarzbach J Zampini M Caramazza A - Neuron 63(3):397-405 (2009)
  Distinct regions within the ventral visual pathway show neural specialization for nonliving and living stimuli (e.g., tools, houses versus animals, faces). The causes of these category preferences are widely debated. Using functional magnetic resonance imaging, we find that the same regions of the ventral stream that show category preferences for nonliving stimuli and animals in sighted adults show the same category preferences in adults who are blind since birth. Both blind and sighted participants had larger blood oxygen-level dependent (BOLD) responses in the medial fusiform gyrus for nonliving stimuli compared to animal stimuli and differential BOLD responses in lateral occipital cortex for animal stimuli compared to nonliving stimuli. These findings demonstrate that the medial-to-lateral bias by conceptual domain in the ventral visual pathway does not require visual experience in order to develop and suggest the operation of innately determined domain-specific con! straints on the organization of object knowledge.
• Motor Learning Is Optimally Tuned to the Properties of Motor Noise
  van Beers RJ - Neuron 63(3):406-417 (2009)
  In motor learning, our brain uses movement errors to adjust planning of future movements. This process has traditionally been studied by examining how motor planning is adjusted in response to visuomotor or dynamic perturbations. Here, I show that the learning strategy can be better identified from the statistics of movements made in the absence of perturbations. The strategy identified this way differs from the learning mechanism assumed in mainstream models for motor learning. Crucial for this strategy is that motor noise arises partly centrally, in movement planning, and partly peripherally, in movement execution. Corrections are made by modification of central planning signals from the previous movement, which include the effects of planning but not execution noise. The size of the corrections is such that the movement variability is minimized. This physiologically plausible strategy is optimally tuned to the properties of motor noise, and likely underlies learning! in many motor tasks.

Hot off the presses! Jul 16 Neuron

The Jul 16 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Baby Got Brain: Fgf10 Sets Rostral Cortical Size
  - Neuron 63(1):1-3 (2009)
  Brain growth occurs throughout embryogenesis and early postnatal life, but its foundation is laid in the primitive neuroepithelium. In this issue of Neuron, Sahara and O'Leary identify Fgf10 as a key regulator of the neuroepithelial to radial glial transition and subsequently of size of the rostral forebrain.
• According to GOSPEL: Filling in the GAP(DH) of NO-Mediated Neurotoxicity
  - Neuron 63(1):3-6 (2009)
  In addition to its role in glycolysis, GAPDH has been implicated as a mediator of neurotoxicity triggered by nitrosative stress. In this issue of Neuron, Sen et al. identify a novel, negative regulator of this GAPDH neurotoxic pathway termed GOSPEL, which, like GAPDH itself, is regulated by S-nitrosylation.
• It's Lonely at the Top: Winning Climbing Fibers Ascend Dendrites Solo
  - Neuron 63(1):6-8 (2009)
  In mammals, climbing fiber axons compete for sole innervation at each Purkinje cell. At the same time, synapses disappear from Purkinje somata and appear in great numbers on the dendrites. In this issue of Neuron, Hashimoto et al. show that, by the time climbing fibers ascend the dendrites, the winner and losers are already decided.
• Deal Breaker: Semaphorin and Specificity in the Spinal Stretch Reflex Circuit
  - Neuron 63(1):8-11 (2009)
  Stretch reflex circuits are a prime example of wiring specificity in the vertebrate spinal cord. Homonymous sensory afferents and motoneurons typically form monosynaptic connections, while neurons innervating antagonistic or unrelated muscles do not. Pecho-Vrieseling et al. now show that the semaphorin Sema3E and its receptor Plexin-D1 prevent monosynaptic connectivity in the cutaneous maximus muscle stretch reflex circuit.
• Shotgun Proteomics in Neuroscience
  - Neuron 63(1):12-26 (2009)
  Mass spectrometry-based proteomics is increasingly used to address basic and clinical questions in biomedical research through studies of differential protein expression, protein-protein interactions, and posttranslational modifications. The complex structural and functional organization of the human brain warrants the application of high-throughput, systematic approaches to understand the functional alterations under normal physiological conditions and the perturbations of neurological diseases. This primer focuses on shotgun-proteomics-based tandem mass spectrometry for the identification of proteins in a complex mixture. It describes the basic concepts of protein differential expression analysis and posttranslational modification analysis and discusses several strategies to improve the coverage of the proteome.
• Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors
  - Neuron 63(1):27-39 (2009)
  Examining the behavioral consequences of selective CNS neuronal activation is a powerful tool for elucidating mammalian brain function in health and disease. Newly developed genetic, pharmacological, and optical tools allow activation of neurons with exquisite spatiotemporal resolution; however, the inaccessibility to light of widely distributed neuronal populations and the invasiveness required for activation by light or infused ligands limit the utility of these methods. To overcome these barriers, we created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacologically inert, orally bioavailable drug clozapine-N-oxide (CNO). Here, we expressed hM3Dq in forebrain principal neurons. Local field potential and single-neuron recordings revealed that peripheral administration of CNO activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased lo! comotion, stereotypy, and limbic seizures. These results demonstrate a powerful chemical-genetic tool for remotely controlling the activity of discrete populations of neurons in vivo.
• In Vivo Cocaine Experience Generates Silent Synapses
  - Neuron 63(1):40-47 (2009)
  Studies over the past decade have enunciated silent synapses as prominent cellular substrates for synaptic plasticity in the developing brain. However, little is known about whether silent synapses can be generated postdevelopmentally. Here, we demonstrate that highly salient in vivo experience, such as exposure to cocaine, generates silent synapses in the nucleus accumbens (NAc) shell, a key brain region mediating addiction-related learning and memory. Furthermore, this cocaine-induced generation of silent synapses is mediated by membrane insertions of new, NR2B-containing N-methyl-D-aspartic acid receptors (NMDARs). These results provide evidence that silent synapses can be generated de novo by in vivo experience and thus may act as highly efficient neural substrates for the subsequent experience-dependent synaptic plasticity underlying extremely long-lasting memory.
• Fgf10 Regulates Transition Period of Cortical Stem Cell Differentiation to Radial Glia Controlling Generation of Neurons and Basal Progenitors
  - Neuron 63(1):48-62 (2009)
  Radial glia (RG), the progenitors of cortical neurons and basal progenitors (BPs), differentiate from neuroepithelial cells (NCs) with stem cell properties. We show that the morphogen Fgf10 is transiently expressed by NCs coincident with the transition period of NC differentiation into RG. Targeted deletion of Fgf10 delays RG differentiation, whereas overexpression has opposing effects. Delayed RG differentiation in Fgf10 mutants occurs selectively in rostral cortex, paralleled by an extended period of symmetric NC divisions increasing progenitor number, coupled with delayed and initially diminished production of neurons and BPs. RG eventually differentiate in excess number and overproduce neurons and BPs rostrally resulting in tangential expansion of frontal areas and increased laminar thickness. Thus, transient Fgf10 expression regulates timely differentiation of RG, and through this function, determines both length of the early progenitor expansion phase and onset o! f neurogenesis and ultimately the number of progenitors and neurons fated to specific cortical areas.
• Myosin II Motors and F-Actin Dynamics Drive the Coordinated Movement of the Centrosome and Soma during CNS Glial-Guided Neuronal Migration
  - Neuron 63(1):63-80 (2009)
  Lamination of cortical regions of the vertebrate brain depends on glial-guided neuronal migration. The conserved polarity protein Par6α localizes to the centrosome and coordinates forward movement of the centrosome and soma in migrating neurons. The cytoskeletal components that produce this unique form of cell polarity and their relationship to polarity signaling cascades are unknown. We show that F-actin and Myosin II motors are enriched in the neuronal leading process and that Myosin II activity is necessary for leading process actin dynamics. Inhibition of Myosin II decreased the speed of centrosome and somal movement, whereas Myosin II activation increased coordinated movement. Ectopic expression or silencing of Par6α inhibited Myosin II motors by decreasing Myosin light-chain phosphorylation. These findings suggest leading-process Myosin II may function to "pull" the centrosome and soma forward during glial-guided migration by a mechanism involving the conse! rved polarity protein Par6α.
• GOSPEL: A Neuroprotective Protein that Binds to GAPDH upon S-Nitrosylation
  - Neuron 63(1):81-91 (2009)
  We recently reported a cell death cascade whereby cellular stressors activate nitric oxide formation leading to S-nitrosylation of GAPDH that binds to Siah and translocates to the nucleus. The nuclear GAPDH/Siah complex augments p300/CBP-associated acetylation of nuclear proteins, including p53, which mediate cell death. We report a 52 kDa cytosolic protein, GOSPEL, which physiologically binds GAPDH, in competition with Siah, retaining GAPDH in the cytosol and preventing its nuclear translocation. GOSPEL is neuroprotective, as its overexpression prevents NMDA-glutamate excitotoxicity while its depletion enhances death in primary neuron cultures. S-nitrosylation of GOSPEL at cysteine 47 enhances GAPDH-GOSPEL binding and the neuroprotective actions of GOSPEL. In intact mice, virally delivered GOSPEL selectively diminishes NMDA neurotoxicity. Thus, GOSPEL may physiologically regulate the viability of neurons and other cells.
• Endocytic Trafficking and Recycling Maintain a Pool of Mobile Surface AMPA Receptors Required for Synaptic Potentiation
  - Neuron 63(1):92-105 (2009)
  At excitatory glutamatergic synapses, postsynaptic endocytic zones (EZs), which are adjacent to the postsynaptic density (PSD), mediate clathrin-dependent endocytosis of surface AMPA receptors (AMPAR) as a first step to receptor recycling or degradation. However, it remains unknown whether receptor recycling influences AMPAR lateral diffusion and whether EZs are important for the expression of synaptic potentiation. Here, we demonstrate that the presence of both EZs and AMPAR recycling maintain a large pool of mobile AMPARs at synapses. In addition, we find that synaptic potentiation is accompanied by an accumulation and immobilization of AMPARs at synapses resulting from both their exocytosis and stabilization at the PSD. Displacement of EZs from the postsynaptic region impairs the expression of synaptic potentiation by blocking AMPAR recycling. Thus, receptor recycling is crucial for maintaining a mobile population of surface AMPARs that can be delivered to synapses ! for increases in synaptic strength.
• Translocation of a "Winner" Climbing Fiber to the Purkinje Cell Dendrite and Subsequent Elimination of "Losers" from the Soma in Developing Cerebellum
  - Neuron 63(1):106-118 (2009)
  Functional neural circuits are formed by eliminating early-formed redundant synapses and strengthening necessary connections during development. In newborn mouse cerebellum, each Purkinje cell (PC) is innervated by multiple climbing fibers (CFs) with similar strengths. Subsequently, a single CF is selectively strengthened by postnatal day 7 (P7). We find that this competition among multiple CFs occurs on the soma before CFs form synapses along dendrites. Notably, in most PCs, the single CF that has been functionally strengthened (the "winner" CF) undergoes translocation to dendrites while keeping its synapses on the soma. Synapses of the weaker CFs (the "loser" CFs) remain around the soma and form "pericellular nests" with synapses of the winner CFs. Then most perisomatic synapses are eliminated nonselectively by P15. Thus, our results suggest that the selective translocation of the winner CF to dendrites in each PC determines the single CF that survives su! bsequent synapse elimination and persistently innervates the PC.
• Midbrain Dopamine Neurons Signal Preference for Advance Information about Upcoming Rewards
  - Neuron 63(1):119-126 (2009)
  The desire to know what the future holds is a powerful motivator in everyday life, but it is unknown how this desire is created by neurons in the brain. Here we show that when macaque monkeys are offered a water reward of variable magnitude, they seek advance information about its size. Furthermore, the same midbrain dopamine neurons that signal the expected amount of water also signal the expectation of information, in a manner that is correlated with the strength of the animal's preference. Our data show that single dopamine neurons process both primitive and cognitive rewards, and suggest that current theories of reward-seeking must be revised to include information-seeking.
• Training Improves Multitasking Performance by Increasing the Speed of Information Processing in Human Prefrontal Cortex
  - Neuron 63(1):127-138 (2009)
  Our ability to multitask is severely limited: task performance deteriorates when we attempt to undertake two or more tasks simultaneously. Remarkably, extensive training can greatly reduce such multitasking costs. While it is not known how training alters the brain to solve the multitasking problem, it likely involves the prefrontal cortex given this brain region's purported role in limiting multitasking performance. Here, we show that the reduction of multitasking interference with training is not achieved by diverting the flow of information processing away from the prefrontal cortex or by segregating prefrontal cells into independent task-specific neuronal ensembles, but rather by increasing the speed of information processing in this brain region, thereby allowing multiple tasks to be processed in rapid succession. These results not only reveal how training leads to efficient multitasking, they also provide a mechanistic account of multitasking limitations, namely ! the poor speed of information processing in human prefrontal cortex.
• Reading the Book of Memory: Sparse Sampling versus Dense Mapping of Connectomes
  - Neuron 63(1):139 (2009)