Hot off the presses! Jun 23 Neuron

The Jun 23 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:

• Pushing the Envelope of Sound
  - Neuron 70(6):1021-1022 (2011)
  Normal hearing depends on the amplification of sound in the cochlea. In this issue of Neuron, Fettiplace and colleagues show that prestin-based amplification is a viable mechanism as it is not limited by the outer hair cell's membrane time constant as previously surmised.
• A Genetic Push to Understand Motion Detection
  - Neuron 70(6):1023-1025 (2011)
  Two articles in this issue of Neuron (Eichner et al. and Clark et al.) attack the problem of explaining how neuronal hardware in Drosophila implements the Reichardt motion detector, one of the most famous computational models in neuroscience, which has proven intractable up to now.
• Searching for the Neural Mechanisms of Feature-Based Attention in the Primate Brain
  - Neuron 70(6):1025-1028 (2011)
  In this issue, two studies, one by Zhou and Desimone and another by Cohen and Maunsell, provide new insights into the mechanisms of feature-based attention (FBA). The former demonstrates a new role of the frontal eye fields in the origins of FBA and the latter shows that FBA is coordinated across both hemispheres.
• Career Development for Women Scientists in Asia
  - Neuron 70(6):1029-1032 (2011)
  Previously, challenges faced by women scientists have made it difficult for them to realize their dreams. The remarkable growth of Asian bioscience over the past decade, however, has created opportunities for young women in their home countries. The time is ripe for women in Asia to pursue their scientific aspirations.
• Mitochondria: The Next (Neurode)Generation
  - Neuron 70(6):1033-1053 (2011)
  Adult-onset neurodegenerative disorders are disabling and often fatal diseases of the nervous system whose underlying mechanisms of cell death remain unknown. Defects in mitochondrial respiration had previously been proposed to contribute to the occurrence of many, if not all, of the most common neurodegenerative disorders. However, the discovery of genes mutated in hereditary forms of these enigmatic diseases has additionally suggested defects in mitochondrial dynamics. Such disturbances can lead to changes in mitochondrial trafficking, in interorganellar communication, and in mitochondrial quality control. These new mechanisms by which mitochondria may also be linked to neurodegeneration will likely have far-reaching implications for our understanding of the pathophysiology and treatment of adult-onset neurodegenerative disorders.
• Frontal Cortex and Reward-Guided Learning and Decision-Making
  - Neuron 70(6):1054-1069 (2011)
  Reward-guided decision-making and learning depends on distributed neural circuits with many components. Here we focus on recent evidence that suggests four frontal lobe regions make distinct contributions to reward-guided learning and decision-making: the lateral orbitofrontal cortex, the ventromedial prefrontal cortex and adjacent medial orbitofrontal cortex, anterior cingulate cortex, and the anterior lateral prefrontal cortex. We attempt to identify common themes in experiments with human participants and with animal models, which suggest roles that the areas play in learning about reward associations, selecting reward goals, choosing actions to obtain reward, and monitoring the potential value of switching to alternative courses of action.
• CTCF Regulates Ataxin-7 Expression through Promotion of a Convergently Transcribed, Antisense Noncoding RNA
  - Neuron 70(6):1071-1084 (2011)
  Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder caused by CAG/polyglutamine repeat expansions in the ataxin-7 gene. Ataxin-7 is a component of two different transcription coactivator complexes, and recent work indicates that disease protein normal function is altered in polyglutamine neurodegeneration. Given this, we studied how ataxin-7 gene expression is regulated. The ataxin-7 repeat and translation start site are flanked by binding sites for CTCF, a highly conserved multifunctional transcription regulator. When we analyzed this region, we discovered an adjacent alternative promoter and a convergently transcribed antisense noncoding RNA, SCAANT1. To understand how CTCF regulates ataxin-7 gene expression, we introduced ataxin-7 mini-genes into mice, and found that CTCF is required for SCAANT1 expression. Loss of SCAANT1 derepressed ataxin-7 sense transcription in a cis-dependent fashion and was accompanied by chromatin remodeling. Discovery of th! is pathway underscores the importance of altered epigenetic regulation for disease pathology at repeat loci exhibiting bidirectional transcription. 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 (14588 K)
• Isoform-Specific Dephosphorylation of Dynamin1 by Calcineurin Couples Neurotrophin Receptor Endocytosis to Axonal Growth
  - Neuron 70(6):1085-1099 (2011)
  Endocytic events are critical for neuronal survival in response to target-derived neurotrophic cues, but whether local axon growth is mediated by endocytosis-dependent signaling mechanisms remains unclear. Here, we report that Nerve Growth Factor (NGF) promotes endocytosis of its TrkA receptors and axon growth by calcineurin-mediated dephosphorylation of the endocytic GTPase dynamin1. Conditional deletion of calcineurin in sympathetic neurons disrupts NGF-dependent innervation of peripheral target tissues. Calcineurin signaling is required locally in sympathetic axons to support NGF-mediated growth in a manner independent of transcription. We show that calcineurin associates with dynamin1 via a PxIxIT interaction motif found only in specific dynamin1 splice variants. PxIxIT-containing dynamin1 isoforms colocalize with surface TrkA receptors, and their phosphoregulation is selectively required for NGF-dependent TrkA internalization and axon growth in sympathetic neurons! . Thus, NGF-dependent phosphoregulation of dynamin1 is a critical event coordinating neurotrophin receptor endocytosis and axonal growth.
• Overlapping Role of Dynamin Isoforms in Synaptic Vesicle Endocytosis
  - Neuron 70(6):1100-1114 (2011)
  The existence of neuron-specific endocytic protein isoforms raises questions about their importance for specialized neuronal functions. Dynamin, a GTPase implicated in the fission reaction of endocytosis, is encoded by three genes, two of which, dynamin 1 and 3, are highly expressed in neurons. We show that dynamin 3, thought to play a predominantly postsynaptic role, has a major presynaptic function. Although lack of dynamin 3 does not produce an overt phenotype in mice, it worsens the dynamin 1 KO phenotype, leading to perinatal lethality and a more severe defect in activity-dependent synaptic vesicle endocytosis. Thus, dynamin 1 and 3, which together account for the overwhelming majority of brain dynamin, cooperate in supporting optimal rates of synaptic vesicle endocytosis. Persistence of synaptic transmission in their absence indicates that if dynamin plays essential functions in neurons, such functions can be achieved by the very low levels of dynamin 2.
• An Instructive Role for Patterned Spontaneous Retinal Activity in Mouse Visual Map Development
  - Neuron 70(6):1115-1127 (2011)
  Complex neural circuits in the mammalian brain develop through a combination of genetic instruction and activity-dependent refinement. The relative role of these factors and the form of neuronal activity responsible for circuit development is a matter of significant debate. In the mammalian visual system, retinal ganglion cell projections to the brain are mapped with respect to retinotopic location and eye of origin. We manipulated the pattern of spontaneous retinal waves present during development without changing overall activity levels through the transgenic expression of β2-nicotinic acetylcholine receptors in retinal ganglion cells of mice. We used this manipulation to demonstrate that spontaneous retinal activity is not just permissive, but instructive in the emergence of eye-specific segregation and retinotopic refinement in the mouse visual system. This suggests that specific patterns of spontaneous activity throughout the developing brain are essential in the! emergence of specific and distinct patterns of neuronal connectivity.
• Multiple Forms of Activity-Dependent Competition Refine Hippocampal Circuits In Vivo
  - Neuron 70(6):1128-1142 (2011)
  Efficient memory formation relies on the establishment of functional hippocampal circuits. It has been proposed that synaptic connections are refined by neural activity to form functional brain circuitry. However, it is not known whether and how hippocampal connections are refined by neural activity in vivo. Using a mouse genetic system in which restricted populations of neurons in the hippocampal circuit are inactivated, we show that inactive axons are eliminated after they develop through a competition with active axons. Remarkably, in the dentate gyrus, which undergoes neurogenesis throughout life, axon refinement is achieved by a competition between mature and young neurons. These results demonstrate that activity-dependent competition plays multiple roles in the establishment of functional memory circuits in vivo.
• Prestin-Driven Cochlear Amplification Is Not Limited by the Outer Hair Cell Membrane Time Constant
  - Neuron 70(6):1143-1154 (2011)
  Outer hair cells (OHCs) provide amplification in the mammalian cochlea using somatic force generation underpinned by voltage-dependent conformational changes of the motor protein prestin. However, prestin must be gated by changes in membrane potential on a cycle-by-cycle basis and the periodic component of the receptor potential may be greatly attenuated by low-pass filtering due to the OHC time constant (τm), questioning the functional relevance of this mechanism. Here, we measured τm from OHCs with a range of characteristic frequencies (CF) and found that, at physiological endolymphatic calcium concentrations, approximately half of the mechanotransducer (MT) channels are opened at rest, depolarizing the membrane potential to near −40 mV. The depolarized resting potential activates a voltage-dependent K+ conductance, thus minimizing τm and expanding the membrane filter so there is little receptor potential attenuation at the cell's CF. These data suggest that min! imal τm filtering in vivo ensures optimal activation of prestin.
• Internal Structure of the Fly Elementary Motion Detector
  - Neuron 70(6):1155-1164 (2011)
  Recent experiments have shown that motion detection in Drosophila starts with splitting the visual input into two parallel channels encoding brightness increments (ON) or decrements (OFF). This suggests the existence of either two (ON-ON, OFF-OFF) or four (for all pairwise interactions) separate motion detectors. To decide between these possibilities, we stimulated flies using sequences of ON and OFF brightness pulses while recording from motion-sensitive tangential cells. We found direction-selective responses to sequences of same sign (ON-ON, OFF-OFF), but not of opposite sign (ON-OFF, OFF-ON), refuting the existence of four separate detectors. Based on further measurements, we propose a model that reproduces a variety of additional experimental data sets, including ones that were previously interpreted as support for four separate detectors. Our experiments and the derived model mark an important step in guiding further dissection of the fly motion detection circuit.
• Defining the Computational Structure of the Motion Detector in Drosophila
  - Neuron 70(6):1165-1177 (2011)
  Many animals rely on visual motion detection for survival. Motion information is extracted from spatiotemporal intensity patterns on the retina, a paradigmatic neural computation. A phenomenological model, the Hassenstein-Reichardt correlator (HRC), relates visual inputs to neural activity and behavioral responses to motion, but the circuits that implement this computation remain unknown. By using cell-type specific genetic silencing, minimal motion stimuli, and in vivo calcium imaging, we examine two critical HRC inputs. These two pathways respond preferentially to light and dark moving edges. We demonstrate that these pathways perform overlapping but complementary subsets of the computations underlying the HRC. A numerical model implementing differential weighting of these operations displays the observed edge preferences. Intriguingly, these pathways are distinguished by their sensitivities to a stimulus correlation that corresponds to an illusory percept, "revers! e phi," that affects many species. Thus, this computational architecture may be widely used to achieve edge selectivity in motion detection.
• Contrast Gain Control in Auditory Cortex
  - Neuron 70(6):1178-1191 (2011)
  The auditory system must represent sounds with a wide range of statistical properties. One important property is the spectrotemporal contrast in the acoustic environment: the variation in sound pressure in each frequency band, relative to the mean pressure. We show that neurons in ferret auditory cortex rescale their gain to partially compensate for the spectrotemporal contrast of recent stimulation. When contrast is low, neurons increase their gain, becoming more sensitive to small changes in the stimulus, although the effectiveness of contrast gain control is reduced at low mean levels. Gain is primarily determined by contrast near each neuron's preferred frequency, but there is also a contribution from contrast in more distant frequency bands. Neural responses are modulated by contrast over timescales of 100 ms. By using contrast gain control to expand or compress the representation of its inputs, the auditory system may be seeking an efficient coding of natural sou! nds.
• Using Neuronal Populations to Study the Mechanisms Underlying Spatial and Feature Attention
  - Neuron 70(6):1192-1204 (2011)
  Visual attention affects both perception and neuronal responses. Whether the same neuronal mechanisms mediate spatial attention, which improves perception of attended locations, and nonspatial forms of attention has been a subject of considerable debate. Spatial and feature attention have similar effects on individual neurons. Because visual cortex is retinotopically organized, however, spatial attention can comodulate local neuronal populations, whereas feature attention generally requires more selective modulation. We compared the effects of feature and spatial attention on local and spatially separated populations by recording simultaneously from dozens of neurons in both hemispheres of V4. Feature and spatial attention affect the activity of local populations similarly, modulating both firing rates and correlations between pairs of nearby neurons. However, whereas spatial attention appears to act on local populations, feature attention is coordinated across hemisph! eres. Our results are consistent with a unified attentional mechanism that can modulate the responses of arbitrary subgroups of neurons.
• Feature-Based Attention in the Frontal Eye Field and Area V4 during Visual Search
  - Neuron 70(6):1205-1217 (2011)
  When we search for a target in a crowded visual scene, we often use the distinguishing features of the target, such as color or shape, to guide our attention and eye movements. To investigate the neural mechanisms of feature-based attention, we simultaneously recorded neural responses in the frontal eye field (FEF) and area V4 while monkeys performed a visual search task. The responses of cells in both areas were modulated by feature attention, independent of spatial attention, and the magnitude of response enhancement was inversely correlated with the number of saccades needed to find the target. However, an analysis of the latency of sensory and attentional influences on responses suggested that V4 provides bottom-up sensory information about stimulus features, whereas the FEF provides a top-down attentional bias toward target features that modulates sensory processing in V4 and that could be used to guide the eyes to a searched-for target.
• Disrupted Neural Synchronization in Toddlers with Autism
  - Neuron 70(6):1218-1225 (2011)
  Autism is often described as a disorder of neural synchronization. However, it is unknown how early in development synchronization abnormalities emerge and whether they are related to the development of early autistic behavioral symptoms. Here, we show that disrupted synchronization is evident in the spontaneous cortical activity of naturally sleeping toddlers with autism, but not in toddlers with language delay or typical development. Toddlers with autism exhibited significantly weaker interhemispheric synchronization (i.e., weak "functional connectivity" across the two hemispheres) in putative language areas. The strength of synchronization was positively correlated with verbal ability and negatively correlated with autism severity, and it enabled identification of the majority of autistic toddlers (72%) with high accuracy (84%). Disrupted cortical synchronization, therefore, appears to be a notable characteristic of autism neurophysiology that is evident at very! early stages of autism development.