Hot off the presses! Aug 25 Neuron

The Aug 25 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:

• What's in a Name?
  - Neuron 71(4):565 (2011)
  
• Cadherins as Matchmakers
  - Neuron 71(4):566-568 (2011)
  Cadherins implement afferent-target matching in invertebrates, but proof for this concept in mammalian circuits has remained elusive. Two new studies in this issue of Neuron show that cadherin-6 mediates retinal ganglion cell target selection and that cadherin-9 promotes synapse specificity in the hippocampus.
• The Nodal Origin of Intrinsic Bursting
  - Neuron 71(4):569-570 (2011)
  The output of cortical neurons in the form of bursts of action potentials was thought to be controlled solely by the dendrites. In this issue of Neuron, Maarten Kole reveals that axonal sodium channels at the first node of Ranvier are essential for neuronal burst firing.
• Memory Time
  - Neuron 71(4):571-573 (2011)
  In this issue of Neuron, MacDonald et al. describe hippocampal "time cells" that fire during specific delay periods as rats performed a memory task. Converging results in monkeys suggest that the hippocampus encodes episodes by signaling events in time.
• From Cradle to Grave: The Multiple Roles of Fibroblast Growth Factors in Neural Development
  - Neuron 71(4):574-588 (2011)
  The generation of a functional nervous system involves a multitude of steps that are controlled by just a few families of extracellular signaling molecules. Among these, the fibroblast growth factor (FGF) family is particularly prominent for the remarkable diversity of its functions. FGFs are best known for their roles in the early steps of patterning of the neural primordium and proliferation of neural progenitors. However, other equally important functions have emerged more recently, including in the later steps of neuronal migration, axon navigation, and synaptogenesis. We review here these diverse functions and discuss the mechanisms that account for this unusual range of activities. FGFs are essential components of most protocols devised to generate therapeutically important neuronal populations in vitro or to stimulate neuronal repair in vivo. How FGFs promote the development of the nervous system and maintain its integrity will thus remain an important focus of ! research in the future.
• Computational Models of Grid Cells
  - Neuron 71(4):589-603 (2011)
  Grid cells are space-modulated neurons with periodic firing fields. In moving animals, the multiple firing fields of an individual grid cell form a triangular pattern tiling the entire space available to the animal. Collectively, grid cells are thought to provide a context-independent metric representation of the local environment. Since the discovery of grid cells in 2005, a number of models have been proposed to explain the formation of spatially repetitive firing patterns as well as the conversion of these signals to place signals one synapse downstream in the hippocampus. The present article reviews the most recent developments in our understanding of how grid patterns are generated, maintained, and transformed, with particular emphasis on second-generation computational models that have emerged during the past 2-3 years in response to criticism and new data.
• A Transcriptomic Atlas of Mouse Neocortical Layers
  - Neuron 71(4):605-616 (2011)
  In the mammalian cortex, neurons and glia form a patterned structure across six layers whose complex cytoarchitectonic arrangement is likely to contribute to cognition. We sequenced transcriptomes from layers 1-6b of different areas (primary and secondary) of the adult (postnatal day 56) mouse somatosensory cortex to understand the transcriptional levels and functional repertoires of coding and noncoding loci for cells constituting these layers. A total of 5,835 protein-coding genes and 66 noncoding RNA loci are differentially expressed ("patterned") across the layers, on the basis of a machine-learning model (naive Bayes) approach. Layers 2-6b are each associated with specific functional and disease annotations that provide insights into their biological roles. This new resource (http://genserv.anat.ox.ac.uk/layers) greatly extends currently available resources, such as the Allen Mouse Brain Atlas and microarray data sets, by providing quantitative expression leve! ls, by being genome-wide, by including novel loci, and by identifying candidate alternatively spliced transcripts that are differentially expressed across layers.
• New Rabies Virus Variants for Monitoring and Manipulating Activity and Gene Expression in Defined Neural Circuits
  - Neuron 71(4):617-631 (2011)
  Glycoprotein-deleted (ΔG) rabies virus is a powerful tool for studies of neural circuit structure. Here, we describe the development and demonstrate the utility of new resources that allow experiments directly investigating relationships between the structure and function of neural circuits. New methods and reagents allowed efficient production of 12 novel ΔG rabies variants from plasmid DNA. These new rabies viruses express useful neuroscience tools, including the Ca2+ indicator GCaMP3 for monitoring activity; Channelrhodopsin-2 for photoactivation; allatostatin receptor for inactivation by ligand application; and rtTA, ERT2CreERT2, or FLPo, for control of gene expression. These new tools allow neurons targeted on the basis of their connectivity to have their function assayed or their activity or gene expression manipulated. Combining these tools with in vivo imaging and optogenetic methods and/or inducible gene expression in transgenic mice will facilitate experime! nts investigating neural circuit development, plasticity, and function that have not been possible with existing reagents.
• Cadherin-6 Mediates Axon-Target Matching in a Non-Image-Forming Visual Circuit
  - Neuron 71(4):632-639 (2011)
  Neural circuits consist of highly precise connections among specific types of neurons that serve a common functional goal. How neurons distinguish among different synaptic targets to form functionally precise circuits remains largely unknown. Here, we show that during development, the adhesion molecule cadherin-6 (Cdh6) is expressed by a subset of retinal ganglion cells (RGCs) and also by their targets in the brain. All of the Cdh6-expressing retinorecipient nuclei mediate non-image-forming visual functions. A screen of mice expressing GFP in specific subsets of RGCs revealed that Cdh3-RGCs which also express Cdh6 selectively innervate Cdh6-expressing retinorecipient targets. Moreover, in Cdh6-deficient mice, the axons of Cdh3-RGCs fail to properly innervate their targets and instead project to other visual nuclei. These findings provide functional evidence that classical cadherins promote mammalian CNS circuit development by ensuring that axons of specific cell types ! connect to their appropriate synaptic targets.
• Cadherin-9 Regulates Synapse-Specific Differentiation in the Developing Hippocampus
  - Neuron 71(4):640-655 (2011)
  Our understanding of mechanisms that regulate the differentiation of specific classes of synapses is limited. Here, we investigate the formation of synapses between hippocampal dentate gyrus (DG) neurons and their target CA3 neurons and find that DG neurons preferentially form synapses with CA3 rather than DG or CA1 neurons in culture, suggesting that specific interactions between DG and CA3 neurons drive synapse formation. Cadherin-9 is expressed selectively in DG and CA3 neurons, and downregulation of cadherin-9 in CA3 neurons leads to a selective decrease in the number and size of DG synapses onto CA3 neurons. In addition, loss of cadherin-9 from DG or CA3 neurons in vivo leads to striking defects in the formation and differentiation of the DG-CA3 mossy fiber synapse. These observations indicate that cadherin-9 bidirectionally regulates DG-CA3 synapse development and highlight the critical role of differentially expressed molecular cues in establishing specific conn! ections in the mammalian brain.
• A Role for Repressive Histone Methylation in Cocaine-Induced Vulnerability to Stress
  - Neuron 71(4):656-670 (2011)
  Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated coc! aine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression.
• First Node of Ranvier Facilitates High-Frequency Burst Encoding
  - Neuron 71(4):671-682 (2011)
  In central neurons the first node of Ranvier is located at the first axonal branchpoint, 100 μm from the axon initial segment where synaptic inputs are integrated and converted into action potentials (APs). Whether the first node contributes to this signal transformation is not well understood. Here it was found that in neocortical layer 5 axons, the first branchpoint is required for intrinsic high-frequency (≥100 Hz) AP bursts. Furthermore, block of nodal Na+ channels or axotomy of the first node in intrinsically bursting neurons depolarized the somatic AP voltage threshold (5 mV) and eliminated APs selectively within a high-frequency cluster in response to steady currents or simulated synaptic inputs. These results indicate that nodal persistent Na+ current exerts an anterograde influence on AP initiation in the axon initial segment, revealing a computational role of the first node of Ranvier beyond conduction of the propagating AP.
• Parallel Mechanisms Encode Direction in the Retina
  - Neuron 71(4):683-694 (2011)
  In the retina, presynaptic inhibitory mechanisms that shape directionally selective (DS) responses in output ganglion cells are well established. However, the nature of inhibition-independent forms of directional selectivity remains poorly defined. Here, we describe a genetically specified set of ON-OFF DS ganglion cells (DSGCs) that code anterior motion. This entire population of DSGCs exhibits asymmetric dendritic arborizations that orientate toward the preferred direction. We demonstrate that morphological asymmetries along with nonlinear dendritic conductances generate a centrifugal (soma-to-dendrite) preference that does not critically depend upon, but works in parallel with the GABAergic circuitry. We also show that in symmetrical DSGCs, such dendritic DS mechanisms are aligned with, or are in opposition to, the inhibitory DS circuitry in distinct dendritic subfields where they differentially interact to promote or weaken directional preferences. Thus, pre- and p! ostsynaptic DS mechanisms interact uniquely in distinct ganglion cell populations, enabling efficient DS coding under diverse conditions.
• Pioneer GABA Cells Comprise a Subpopulation of Hub Neurons in the Developing Hippocampus
  - Neuron 71(4):695-709 (2011)
  Connectivity in the developing hippocampus displays a functional organization particularly effective in supporting network synchronization, as it includes superconnected hub neurons. We have previously shown that hub network function is supported by a subpopulation of GABA neurons. However, it is unclear whether hub cells are only transiently present or later develop into distinctive subclasses of interneurons. These questions are difficult to assess given the heterogeneity of the GABA neurons and the poor early expression of markers. To circumvent this conundrum, we used "genetic fate mapping" that allows for the selective labeling of GABA neurons based on their place and time of origin. We show that early-generated GABA cells form a subpopulation of hub neurons, characterized by an exceptionally widespread axonal arborization and the ability to single-handedly impact network dynamics when stimulated. Pioneer hub neurons remain into adulthood, when they acquire th! e classical markers of long-range projecting GABA neurons. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (13747 K)
• A Synaptic Strategy for Consolidation of Convergent Visuotopic Maps
  - Neuron 71(4):710-724 (2011)
  The mechanisms by which experience guides refinement of converging afferent pathways are poorly understood. We describe a vision-driven refinement of corticocollicular inputs that determines the consolidation of retinal and visual cortical (VC) synapses on individual neurons in the superficial superior colliculus (sSC). Highly refined corticocollicular terminals form 1–2 days after eye-opening (EO), accompanied by VC-dependent filopodia sprouting on proximal dendrites, and PSD-95 and VC-dependent quadrupling of functional synapses. Delayed EO eliminates synapses, corticocollicular terminals, and spines on VC-recipient dendrites. Awake recordings after EO show that VC and retina cooperate to activate sSC neurons, and VC light responses precede sSC responses within intervals promoting potentiation. Eyelid closure is associated with more protracted cortical visual responses, causing the majority of VC spikes to follow those of the colliculus. These data implicate spike-! timing plasticity as a mechanism for cortical input survival, and support a cooperative strategy for retinal and cortical coinnervation of the sSC.
• Perceptual Classification in a Rapidly Changing Environment
  - Neuron 71(4):725-736 (2011)
  Humans and monkeys can learn to classify perceptual information in a statistically optimal fashion if the functional groupings remain stable over many hundreds of trials, but little is known about categorization when the environment changes rapidly. Here, we used a combination of computational modeling and functional neuroimaging to understand how humans classify visual stimuli drawn from categories whose mean and variance jumped unpredictably. Models based on optimal learning (Bayesian model) and a cognitive strategy (working memory model) both explained unique variance in choice, reaction time, and brain activity. However, the working memory model was the best predictor of performance in volatile environments, whereas statistically optimal performance emerged in periods of relative stability. Bayesian and working memory models predicted decision-related activity in distinct regions of the prefrontal cortex and midbrain. These findings suggest that perceptual category! judgments, like value-guided choices, may be guided by multiple controllers.
• Hippocampal "Time Cells" Bridge the Gap in Memory for Discontiguous Events
  - Neuron 71(4):737-749 (2011)
  The hippocampus is critical to remembering the flow of events in distinct experiences and, in doing so, bridges temporal gaps between discontiguous events. Here, we report a robust hippocampal representation of sequence memories, highlighted by "time cells" that encode successive moments during an empty temporal gap between the key events, while also encoding location and ongoing behavior. Furthermore, just as most place cells "remap" when a salient spatial cue is altered, most time cells form qualitatively different representations ("retime") when the main temporal parameter is altered. Hippocampal neurons also differentially encode the key events and disambiguate different event sequences to compose unique, temporally organized representations of specific experiences. These findings suggest that hippocampal neural ensembles segment temporally organized memories much the same as they represent locations of important events in spatially defined environments.
• Perceptual Learning Reduces Interneuronal Correlations in Macaque Visual Cortex
  - Neuron 71(4):750-761 (2011)
  Responses of neurons in early visual cortex change little with training and appear insufficient to account for perceptual learning. Behavioral performance, however, relies on population activity, and the accuracy of a population code is constrained by correlated noise among neurons. We tested whether training changes interneuronal correlations in the dorsal medial superior temporal area, which is involved in multisensory heading perception. Pairs of single units were recorded simultaneously in two groups of subjects: animals trained extensively in a heading discrimination task, and "naive" animals that performed a passive fixation task. Correlated noise was significantly weaker in trained versus naive animals, which might be expected to improve coding efficiency. However, we show that the observed uniform reduction in noise correlations leads to little change in population coding efficiency when all neurons are decoded. Thus, global changes in correlated noise amon! g sensory neurons may be insufficient to account for perceptual learning.