Hot off the presses! Sep 24 Neuron

The Sep 24 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:

• How DISC1 Regulates Postnatal Brain Development: Girdin Gets In on the AKT
  - Neuron 63(6):711-713 (2009)
  In this issue of Neuron, Kim et al. and Enomoto et al. show that DISC1 plays a key role in regulating postnatal brain development though interaction with Girdin. Girdin in turn regulates AKT signaling. Thus, another facet of the role of DISC1 is established, shedding more light on fundamental brain processes and the developmental basis of major psychiatric disorders.
• MicroRNAs in Memory Processing
  - Neuron 63(6):714-716 (2009)
  MicroRNAs are a class of small RNA molecules that regulate the expression of a wide variety of genes. In this issue of Neuron, Rajasethupathy and colleagues identify 170 distinct microRNAs in Aplysia, including one, miR-124, that plays a critical role in the regulation of signaling molecules underlying synaptic plasticity and memory.
• Computational Sophistication at a Single GABAergic Connection
  - Neuron 63(6):716-718 (2009)
  Diverse computational roles of GABAergic inhibition are often assumed to reflect heterogeneity in the sources of GABA and in the receptors sensing the neurotransmitter. New data suggest that distinct effects on integration of excitatory inputs by cerebellar granule cells might result from different modes of signaling by individual interneurons.
• Resting Our Cortices by Going DOWN to Sleep
  - Neuron 63(6):719-721 (2009)
  In this issue of Neuron, Vyazovskiy et al. reports on progressive changes in cortical unit activity within extended wakefulness and within extended sleep paralleling changes in EEG slow-wave sleep activity. Sleep debt may be integrated at the level of individual cortical neurons, providing support for the synaptic homeostasis theory.
• Conceptual Representation and the Making of New Decisions
  - Neuron 63(6):721-723 (2009)
  A key feature of an adaptive decision making mechanism is its ability to guide behavior even in new situations. In this issue of Neuron, Kumaran et al. report that conceptual representations, which allow generalization from one situation to another through their shared features, can guide decisions even when new problems are encountered via the hippocampus.
• Confidence and Corrections: How We Make and Un-Make Up Our Minds
  - Neuron 63(6):724-726 (2009)
  Single neurons in several brain areas intervening between sensation and action signal the accumulation of sensory evidence favoring a particular behavioral response. Two new studies show that these same neurons encode decision confidence and that decision makers continue to process relevant sensory information even after a choice has been made.
• Cortical Enlightenment: Are Attentional Gamma Oscillations Driven by ING or PING?
  - Neuron 63(6):727-732 (2009)
  The response of a neuron to sensory stimuli can only give correlational support for functional hypotheses. To experimentally test causal function, the neural activity needs to be manipulated in a cell-type-specific as well as spatially and temporally precise way. We review recent optogenetic experiments on parvalbumin-positive cortical interneurons that link modeling studies of synchronization to experimental studies on attentional modulation of gamma oscillations in primates.
• The Neurobiology of Decision: Consensus and Controversy
  - Neuron 63(6):733-745 (2009)
  We review and synthesize recent neurophysiological studies of decision making in humans and nonhuman primates. From these studies, the basic outline of the neurobiological mechanism for primate choice is beginning to emerge. The identified mechanism is now known to include a multicomponent valuation stage, implemented in ventromedial prefrontal cortex and associated parts of striatum, and a choice stage, implemented in lateral prefrontal and parietal areas. Neurobiological studies of decision making are beginning to enhance our understanding of economic and social behavior as well as our understanding of significant health disorders where people's behavior plays a key role.
• Automated Analysis of Cellular Signals from Large-Scale Calcium Imaging Data
  - Neuron 63(6):747-760 (2009)
  Recent advances in fluorescence imaging permit studies of Ca2+ dynamics in large numbers of cells, in anesthetized and awake behaving animals. However, unlike for electrophysiological signals, standardized algorithms for assigning optically recorded signals to individual cells have not yet emerged. Here, we describe an automated sorting procedure that combines independent component analysis and image segmentation for extracting cells' locations and their dynamics with minimal human supervision. In validation studies using simulated data, automated sorting significantly improved estimation of cellular signals compared to conventional analysis based on image regions of interest. We used automated procedures to analyze data recorded by two-photon Ca2+ imaging in the cerebellar vermis of awake behaving mice. Our analysis yielded simultaneous Ca2+ activity traces for up to >100 Purkinje cells and Bergmann glia from single recordings. Using this approach, we found microzones of Purkinje cells that were stable across behavioral states and in which synchronous Ca2+ spiking rose significantly during locomotion.
• DISC1 Regulates New Neuron Development in the Adult Brain via Modulation of AKT-mTOR Signaling through KIAA1212
  - Neuron 63(6):761-773 (2009)
  Disrupted-in-schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here, we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to overactivated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies the AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibili ty genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.
• Roles of Disrupted-In-Schizophrenia 1-Interacting Protein Girdin in Postnatal Development of the Dentate Gyrus
  - Neuron 63(6):774-787 (2009)
  Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, regulates neuronal migration and differentiation during mammalian brain development. Although roles for DISC1 in postnatal neurogenesis in the dentate gyrus (DG) have recently emerged, it is not known how DISC1 and its interacting proteins govern the migration, positioning, and differentiation of dentate granule cells (DGCs). Here, we report that DISC1 interacts with the actin-binding protein girdin to regulate axonal development. DGCs in girdin-deficient neonatal mice exhibit deficits in axonal sprouting in the cornu ammonis 3 region of the hippocampus. Girdin deficiency, RNA interference-mediated knockdown, and inhibition of the DISC1/girdin interaction lead to overextended migration and mispositioning of the DGCs resulting in profound cytoarchitectural disorganization of the DG. These findings identify girdin as an intrinsic factor in postnatal development of the DG and provi de insights into the critical role of the DISC1/girdin interaction in postnatal neurogenesis in the DG.
• The microRNA bantam Functions in Epithelial Cells to Regulate Scaling Growth of Dendrite Arbors in Drosophila Sensory Neurons
  - Neuron 63(6):788-802 (2009)
  In addition to establishing dendritic coverage of the receptive field, neurons need to adjust their dendritic arbors to match changes of the receptive field. Here, we show that dendrite arborization (da) sensory neurons establish dendritic coverage of the body wall early in Drosophila larval development and then grow in precise proportion to their substrate, the underlying body wall epithelium, as the larva more than triples in length. This phenomenon, referred to as scaling growth of dendrites, requires the function of the microRNA (miRNA) bantam (ban) in the epithelial cells rather than the da neurons themselves. We further show that ban in epithelial cells dampens Akt kinase activity in adjacent neurons to influence dendrite growth. This signaling between epithelial cells and neurons receiving sensory input from the body wall synchronizes their growth to ensure proper dendritic coverage of the receptive field.
• Characterization of Small RNAs in Aplysia Reveals a Role for miR-124 in Constraining Synaptic Plasticity through CREB
  - Neuron 63(6):803-817 (2009)
  Memory storage and memory-related synaptic plasticity rely on precise spatiotemporal regulation of gene expression. To explore the role of small regulatory RNAs in learning-related synaptic plasticity, we carried out massive parallel sequencing to profile the small RNAs of Aplysia californica. We identified 170 distinct miRNAs, 13 of which were novel and specific to Aplysia. Nine miRNAs were brain enriched, and several of these were rapidly downregulated by transient exposure to serotonin, a modulatory neurotransmitter released during learning. Further characterization of the brain-enriched miRNAs revealed that miR-124, the most abundant and well-conserved brain-specific miRNA, was exclusively present presynaptically in a sensory-motor synapse where it constrains serotonin-induced synaptic facilitation through regulation of the transcriptional factor CREB. We therefore present direct evidence that a modulatory neurotransmitter important for learning can regulate the lev els of small RNAs and present a role for miR-124 in long-term plasticity of synapses in the mature nervous system.
• High-Affinity Kainate Receptor Subunits Are Necessary for Ionotropic but Not Metabotropic Signaling
  - Neuron 63(6):818-829 (2009)
  Kainate receptors signal through both ionotropic and metabotropic pathways. The high-affinity subunits, GluK4 and GluK5, are unique among the five receptor subunits, as they do not form homomeric receptors but modify the properties of heteromeric assemblies. Disruption of the Grik4 gene locus resulted in a significant reduction in synaptic kainate receptor currents. Moreover, ablation of GluK4 and GluK5 caused complete loss of synaptic ionotropic kainate receptor function. The principal subunits were distributed away from postsynaptic densities and presynaptic active zones. There was also a profound alteration in the activation properties of the remaining kainate receptors. Despite this, kainate receptor-mediated inhibition of the slow afterhyperpolarization current (IsAHP), which is dependent on metabotropic pathways, was intact in GluK4/GluK5 knockout mice. These results uncover a previously unknown obligatory role for the high-affinity subunits for ionotropic kainate receptor function and further demonstrate that kainate receptor participation in metabotropic signaling pathways does not require their classic role as ion channels.
• Precise Subcellular Input Retinotopy and Its Computational Consequences in an Identified Visual Interneuron
  - Neuron 63(6):830-842 (2009)
  The Lobula Giant Movement Detector (LGMD) is a higher-order visual interneuron of Orthopteran insects that responds preferentially to objects approaching on a collision course. It receives excitatory input from an entire visual hemifield that anatomical evidence suggests is retinotopic. We show that this excitatory projection activates calcium-permeable nicotinic acetylcholine receptors. In vivo calcium imaging reveals that the excitatory projection preserves retinotopy down to the level of a single ommatidium. Examining the impact of retinotopy on the LGMD's computational properties, we show that sublinear synaptic summation can explain orientation preference in this cell. Exploring retinotopy's impact on directional selectivity leads us to infer that the excitatory input to the LGMD is intrinsically directionally selective. Our results show that precise retinotopy has implications for the dendritic integration of visual information in a single neuron.
• Dynamics of Fast and Slow Inhibition from Cerebellar Golgi Cells Allow Flexible Control of Synaptic Integration
  - Neuron 63(6):843-853 (2009)
  Throughout the brain, multiple interneuron types influence distinct aspects of synaptic processing. Interneuron diversity can thereby promote differential firing from neurons receiving common excitation. In contrast, Golgi cells are the sole interneurons regulating granule cell spiking evoked by mossy fibers, thereby gating inputs to the cerebellar cortex. Here, we examine how this single interneuron class modifies activity in its targets. We find that GABAA-mediated transmission at unitary Golgi cell → granule cell synapses consists of varying contributions of fast synaptic currents and sustained inhibition. Fast IPSCs depress and slow IPSCs gradually build during high-frequency Golgi cell activity. Consequently, fast and slow inhibition differentially influence granule cell spike timing during persistent mossy fiber input. Furthermore, slow inhibition reduces the gain of the mossy fiber → granule cell input-output curve, while fast inhibition increases the thresho ld. Thus, a lack of interneuron diversity need not prevent flexible inhibitory control of synaptic processing.
• Representations of Odor in the Piriform Cortex
  - Neuron 63(6):854-864 (2009)
  Olfactory perception is initiated by the recognition of odorants by a large repertoire of receptors in the sensory epithelium. A dispersed pattern of neural activity in the nose is converted into a segregated map in the olfactory bulb. How is this representation transformed at the next processing center for olfactory information, the piriform cortex? Optical imaging of odorant responses in the cortex reveals that the piriform discards spatial segregation as well as chemotopy and returns to a highly distributed organization in which different odorants activate unique but dispersed ensembles of cortical neurons. Neurons in piriform cortex, responsive to a given odorant, are not only distributed without apparent spatial preference but exhibit discontinuous receptive fields. This representation suggests organizational principles that differ from those in neocortical sensory areas where cells responsive to similar stimulus features are clustered and response properties vary smoothly across the cortex.
• Cortical Firing and Sleep Homeostasis
  - Neuron 63(6):865-878 (2009)
  The need to sleep grows with the duration of wakefulness and dissipates with time spent asleep, a process called sleep homeostasis. What are the consequences of staying awake on brain cells, and why is sleep needed? Surprisingly, we do not know whether the firing of cortical neurons is affected by how long an animal has been awake or asleep. Here, we found that after sustained wakefulness cortical neurons fire at higher frequencies in all behavioral states. During early NREM sleep after sustained wakefulness, periods of population activity (ON) are short, frequent, and associated with synchronous firing, while periods of neuronal silence are long and frequent. After sustained sleep, firing rates and synchrony decrease, while the duration of ON periods increases. Changes in firing patterns in NREM sleep correlate with changes in slow-wave activity, a marker of sleep homeostasis. Thus, the systematic increase of firing during wakefulness is counterbalanced by staying asle ep.
• Spatial Attention Decorrelates Intrinsic Activity Fluctuations in Macaque Area V4
  - Neuron 63(6):879-888 (2009)
  Attention typically amplifies neuronal responses evoked by task-relevant stimuli while attenuating responses to task-irrelevant distracters. In this context, visual distracters constitute an external source of noise that is diminished to improve attended signal quality. Activity that is internal to the cortex itself, stimulus-independent ongoing correlated fluctuations in firing, might also act as task-irrelevant noise. To examine this, we recorded from area V4 of macaques performing an attention-demanding task. The firing of neurons to identically repeated stimuli was highly variable. Much of this variability originates from ongoing low-frequency (<5 Hz) fluctuations in rate correlated across the neuronal population. When attention is directed to a stimulus inside a neuron's receptive field, these correlated fluctuations in rate are reduced. This attention-dependent reduction of ongoing cortical activity improves the signal-to-noise ratio of pooled neural signals subst antially more than attention-dependent increases in firing rate.
• Tracking the Emergence of Conceptual Knowledge during Human Decision Making
  - Neuron 63(6):889-901 (2009)
  Concepts lie at the very heart of intelligence, providing organizing principles with which to comprehend the world. Surprisingly little, however, is understood about how we acquire and deploy concepts. Here, we show that a functionally coupled circuit involving the hippocampus and ventromedial prefrontal cortex (vMPFC) underpins the emergence of conceptual knowledge and its effect on choice behavior. Critically, the hippocampus alone supported the efficient transfer of knowledge to a perceptually novel setting. These findings provide compelling evidence that the hippocampus supports conceptual learning through the networking of discrete memories and reveal the nature of its interaction with downstream valuation modules such as the vMPFC. Our study offers neurobiological insights into the remarkable capacity of humans to discover the conceptual structure of related experiences and use this knowledge to solve exacting decision problems.
• Bayesian Reconstruction of Natural Images from Human Brain Activity
  - Neuron 63(6):902-915 (2009)
  Recent studies have used fMRI signals from early visual areas to reconstruct simple geometric patterns. Here, we demonstrate a new Bayesian decoder that uses fMRI signals from early and anterior visual areas to reconstruct complex natural images. Our decoder combines three elements: a structural encoding model that characterizes responses in early visual areas, a semantic encoding model that characterizes responses in anterior visual areas, and prior information about the structure and semantic content of natural images. By combining all these elements, the decoder produces reconstructions that accurately reflect both the spatial structure and semantic category of the objects contained in the observed natural image. Our results show that prior information has a substantial effect on the quality of natural image reconstructions. We also demonstrate that much of the variance in the responses of anterior visual areas to complex natural images is explained by the semantic c ategory of the image alone.