Neuron

Neural mechanisms underlying paradoxical performance for monetary incentives are driven by loss aversion.

Publication Date: 2012 May 10 PMID: 22578508
Authors: Chib, V. S. - De Martino, B. - Shimojo, S. - O'Doherty, J. P.
Journal: Neuron

Employers often make payment contingent on performance in order to motivate workers. We used fMRI with a novel incentivized skill task to examine the neural processes underlying behavioral responses to performance-based pay. We found that individuals' performance increased with increasing incentives; however, very high incentive levels led to the paradoxical consequence of worse performance. Between initial incentive presentation and task execution, striatal activity rapidly switched between activation and deactivation in response to increasing incentives. Critically, decrements in performance and striatal deactivations were directly predicted by an independent measure of behavioral loss aversion. These results suggest that incentives associated with successful task performance are initially encoded as a potential gain; however, when actually performing a task, individuals encode the potential loss that would arise from failure.

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What makes a cell face selective? The importance of contrast.

Publication Date: 2012 May 10 PMID: 22578507
Authors: Ohayon, S. - Freiwald, W. A. - Tsao, D. Y.
Journal: Neuron

Faces are robustly detected by computer vision algorithms that search for characteristic coarse contrast features. Here, we investigated whether face-selective cells in the primate brain exploit contrast features as well. We recorded from face-selective neurons in macaque inferotemporal cortex, while presenting a face-like collage of regions whose luminances were changed randomly. Modulating contrast combinations between regions induced activity changes ranging from no response to a response greater than that to a real face in 50% of cells. The critical stimulus factor determining response magnitude was contrast polarity, for example, nose region brighter than left eye. Contrast polarity preferences were consistent across cells, suggesting a common computational strategy across the population, and matched features used by computer vision algorithms for face detection. Furthermore, most cells were tuned both for contrast polarity and for the geometry of facial features, suggesting cells encode information useful both for detection and recognition.

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Attentional modulations related to spatial gating but not to allocation of limited resources in primate v1.

Publication Date: 2012 May 10 PMID: 22578506
Authors: Chen, Y. - Seidemann, E.
Journal: Neuron

Attention can modulate neural responses in sensory cortical areas and improve behavioral performance in perceptual tasks. However, the nature and purpose of these modulations remain under debate. Here we used voltage-sensitive dye imaging (VSDI) to measure V1 population responses while monkeys performed a difficult detection task under focal or distributed attention. We found that V1 responses at attended locations are significantly elevated relative to actively ignored or irrelevant locations, consistent with the hypothesis that an important goal of attention in V1 is to highlight task-relevant information. Surprisingly, these modulations were indistinguishable under focal and distributed attention, suggesting a minor or no role for attention as a mechanism for allocating limited representational resources in V1. The response elevation at attended locations is additive, is widespread, and starts shortly before stimulus onset. This elevation could contribute to spatial gating by biasing competition in subsequent processing stages in favor of attended stimuli.

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The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults.

Publication Date: 2012 May 10 PMID: 22578505
Authors: Martel, M. A. - Ryan, T. J. - Bell, K. F. - Fowler, J. H. - McMahon, A. - Al-Mubarak, B. - Komiyama, N. H. - Horsburgh, K. - Kind, P. C. - Grant, S. G. - Wyllie, D. J. - Hardingham, G. E.
Journal: Neuron

It is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that the toxicity of NMDAR-mediated Ca(2+) influx is differentially controlled by the cytoplasmic C-terminal domains of GluN2B (CTD(2B)) and GluN2A (CTD(2A)). Studying the effects of acute expression of GluN2A/2B-based chimeric subunits with reciprocal exchanges of their CTDs revealed that CTD(2B) enhances NMDAR toxicity, compared to CTD(2A). Furthermore, the vulnerability of forebrain neurons in vitro and in vivo to NMDAR-dependent Ca(2+) influx is lowered by replacing the CTD of GluN2B with that of GluN2A by targeted exon exchange in a mouse knockin model. Mechanistically, CTD(2B) exhibits stronger physical/functional coupling to the PSD-95-nNOS pathway, which suppresses protective CREB activation. Dependence of NMDAR excitotoxicity on the GluN2 CTD subtype can be overcome by inducing high levels of NMDAR activity. Thus, the identity (2A versus 2B) of the GluN2 CTD controls the toxicity dose-response to episodes of NMDAR activity.

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Dopamine is required for learning and forgetting in Drosophila.

Publication Date: 2012 May 10 PMID: 22578504
Authors: Berry, J. A. - Cervantes-Sandoval, I. - Nicholas, E. P. - Davis, R. L.
Journal: Neuron

Psychological studies in humans and behavioral studies of model organisms suggest that forgetting is a common and biologically regulated process, but the molecular, cellular, and circuit mechanisms underlying forgetting are poorly understood. Here we show that the bidirectional modulation of a small subset of dopamine neurons (DANs) after olfactory learning regulates the rate of forgetting of both punishing (aversive) and rewarding (appetitive) memories. Two of these DANs, MP1 and MV1, exhibit synchronized ongoing activity in the mushroom body neuropil in alive and awake flies before and after learning, as revealed by functional cellular imaging. Furthermore, while the mushroom-body-expressed dDA1 dopamine receptor is essential for the acquisition of memory, we show that the dopamine receptor DAMB, also highly expressed in mushroom body neurons, is required for forgetting. We propose a dual role for dopamine: memory acquisition through dDA1 signaling and forgetting through DAMB signaling in the mushroom body neurons.

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Maturation of a PKG-Dependent Retrograde Mechanism for Exoendocytic Coupling of Synaptic Vesicles.

Publication Date: 2012 May 10 PMID: 22578503
Authors: Eguchi, K. - Nakanishi, S. - Takagi, H. - Taoufiq, Z. - Takahashi, T.
Journal: Neuron

At presynaptic terminals vesicular membranes are fused into plasma membrane upon exocytosis and retrieved by endocytosis. During a sustained high-frequency transmission, exoendocytic coupling is critical for the maintenance of synaptic transmission. Here, we show that this homeostatic coupling is supported by cGMP-dependent protein kinase (PKG) at the calyx of Held. This mechanism starts to operate after hearing onset during the second postnatal week, when PKG expression becomes upregulated in the brainstem. Pharmacological tests with capacitance measurements revealed that presynaptic PKG activity is supported by a retrograde signal cascade mediated by NO that is released by activation of postsynaptic NMDA receptors. Activation of PKG also upregulates phosphatidylinositol-4,5-bisphosphate, thereby accelerating endocytosis. Furthermore, presynaptic PKG activity upregulates synaptic fidelity during high-frequency transmission. We conclude that maturation of the PKG-dependent retrograde signal cascade strengthens the homeostatic plasticity for the maintenance of high-frequency synaptic transmission at the fast glutamatergic synapse.

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Relevance of exocytotic glutamate release from retinal glia.

Publication Date: 2012 May 10 PMID: 22578502
Authors: Slezak, M. - Grosche, A. - Niemiec, A. - Tanimoto, N. - Pannicke, T. - Munch, T. A. - Crocker, B. - Isope, P. - Hartig, W. - Beck, S. C. - Huber, G. - Ferracci, G. - Perraut, M. - Reber, M. - Miehe, M. - Demais, V. - Leveque, C. - Metzger, D. - Szklarczyk, K. - Przewlocki, R. - Seeliger, M. W. - Sage-Ciocca, D. - Hirrlinger, J. - Reichenbach, A. - Reibel, S. - Pfrieger, F. W.
Journal: Neuron

Glial cells release molecules that influence brain development, function, and disease. Calcium-dependent exocytosis has been proposed as potential release mechanism in astroglia, but the physiological relevance of "gliotransmission" in vivo remains controversial. We focused on the impact of glial exocytosis on sensory transduction in the retina. To this end, we generated transgenic mice to block exocytosis by Cre recombinase-dependent expression of the clostridial botulinum neurotoxin serotype B light chain, which cleaves vesicle-associated membrane protein 1-3. Ubiquitous and neuronal toxin expression caused perinatal lethality and a reduction of synaptic transmission thus validating transgene function. Toxin expression in Muller cells inhibited vesicular glutamate release and impaired glial volume regulation but left retinal histology and visual processing unaffected. Our model to study gliotransmission in vivo reveals specific functions of exocytotic glutamate release in retinal glia.

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Calcium and cAMP Levels Interact to Determine Attraction versus Repulsion in Axon Guidance.

Publication Date: 2012 May 10 PMID: 22578501
Authors: Forbes, E. M. - Thompson, A. W. - Yuan, J. - Goodhill, G. J.
Journal: Neuron

Correct guidance of axons to their targets depends on an intricate network of signaling molecules in the growth cone. Calcium and cAMP are two key regulators of whether axons are attracted or repelled by molecular gradients, but how these molecules interact to determine guidance responses remains unclear. Here, we constructed a mathematical model for the relevant signaling network, which explained a large range of previous biological data and made predictions for when axons will be attracted or repelled. We then confirmed these predictions experimentally, in particular showing that while small increases in cAMP levels promote attraction large increases do not, and that under some circumstances reducing cAMP levels promotes attraction. Together, these results show that a relatively simple mathematical model can quantitatively predict guidance decisions across a wide range of conditions, and that calcium and cAMP levels play a more complex role in these decisions than previously determined.

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Von economo neurons in the anterior insula of the macaque monkey.

Publication Date: 2012 May 10 PMID: 22578500
Authors: Evrard, H. C. - Forro, T. - Logothetis, N. K.
Journal: Neuron

The anterior insular cortex (AIC) and its unique spindle-shaped von Economo neuron (VEN) emerged within the last decade as having a potentially major role in self-awareness and social cognition in humans. Invasive examination of the VEN has been precluded so far by the assumption that this neuron occurs among primates exclusively in humans and great apes. Here, we demonstrate the presence of the VEN in the agranular anterior insula of the macaque monkey. The morphology, size, laminar distribution, and proportional distribution of the monkey VEN suggest that it is at least a primal anatomical homolog of the human VEN. This finding sheds new light on the phylogeny of the VEN and AIC. Most importantly, it offers new and much-needed opportunities to investigate the primal connections and physiology of a neuron that could be crucial for human self-awareness, social cognition, and related neuropsychiatric disorders.

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Input to the lateral habenula from the Basal Ganglia is excitatory, aversive, and suppressed by serotonin.

Publication Date: 2012 May 10 PMID: 22578499
Authors: Shabel, S. J. - Proulx, C. D. - Trias, A. - Murphy, R. T. - Malinow, R.
Journal: Neuron

The lateral habenula (LHb) has recently been identified as a key regulator of the reward system by driving inhibition onto dopaminergic neurons. However, the nature and potential modulation of the major input to the LHb originating from the basal ganglia are poorly understood. Although the output of the basal ganglia is thought to be primarily inhibitory, here we show that transmission from the basal ganglia to the LHb is excitatory, glutamatergic, and suppressed by serotonin. Behaviorally, activation of this pathway is aversive, consistent with its role as an "antireward" signal. Our demonstration of an excitatory projection from the basal ganglia to the LHb explains how LHb-projecting basal ganglia neurons can have similar encoding properties as LHb neurons themselves. Our results also provide a link between antireward excitatory synapses and serotonin, a neuromodulator implicated in depression.

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Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment.

Publication Date: 2012 May 10 PMID: 22578498
Authors: Bakker, A. - Krauss, G. L. - Albert, M. S. - Speck, C. L. - Jones, L. R. - Stark, C. E. - Yassa, M. A. - Bassett, S. S. - Shelton, A. L. - Gallagher, M.
Journal: Neuron

Elevated hippocampal activation is observed in conditions that confer risk for Alzheimer's disease, including amnestic mild cognitive impairment (aMCI). Studies in relevant animal models have indicated that overactivity in selective hippocampal circuits contributes to cognitive impairment. Here, we tested the effect of reducing hippocampal activation in aMCI. Under placebo treatment, hippocampal activation in the dentate gyrus/CA3 was elevated in aMCI patients compared to a healthy control group. By using a low dose of the antiepileptic levetiracetam hippocampal activation in aMCI was reduced to a level that did not differ from the control group. Compared to aMCI memory performance under placebo, performance in the scanning task was significantly improved under drug treatment. Contrary to the view that greater hippocampal activation might serve a beneficial function, these results support the view that increased hippocampal activation in aMCI is a dysfunctional condition and that targeting excess hippocampal activity has therapeutic potential.

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The local transcriptome in the synaptic neuropil revealed by deep sequencing and high-resolution imaging.

Publication Date: 2012 May 10 PMID: 22578497
Authors: Cajigas, I. J. - Tushev, G. - Will, T. J. - Tom Dieck, S. - Fuerst, N. - Schuman, E. M.
Journal: Neuron

In neurons, dendritic protein synthesis is required for many forms of long-term synaptic plasticity. The population of mRNAs that are localized to dendrites, however, remains sparsely identified. Here, we use deep sequencing to identify the mRNAs resident in the synaptic neuropil in the hippocampus. Analysis of a neuropil data set yielded a list of 8,379 transcripts of which 2,550 are localized in dendrites and/or axons. Using a fluorescent barcode strategy to label individual mRNAs, we show that their relative abundance in the neuropil varies over 3 orders of magnitude. High-resolution in situ hybridization validated the presence of mRNAs in both cultured neurons and hippocampal slices. Among the many mRNAs identified, we observed a large fraction of known synaptic proteins including signaling molecules, scaffolds and receptors. These results reveal a previously unappreciated enormous potential for the local protein synthesis machinery to supply, maintain and modify the dendritic and synaptic proteome. VIDEO ABSTRACT:

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Harnessing the power of the endosome to regulate neural development.

Publication Date: 2012 May 10 PMID: 22578496
Authors: Yap, C. C. - Winckler, B.
Journal: Neuron

Endocytosis and endosomal trafficking play a multitude of roles in cellular function beyond regulating entry of essential nutrients. In this review, we discuss the cell biological principles of endosomal trafficking, the neuronal adaptations to endosomal organization, and the role of endosomal trafficking in neural development. In particular, we consider how cell fate decisions, polarity, migration, and axon outgrowth and guidance are influenced by five endosomal tricks: dynamic modulation of receptor levels by endocytosis and recycling, cargo-specific responses via cargo-specific endocytic regulators, cell-type-specific endocytic regulation, ligand-specific endocytic regulation, and endosomal regulation of ligand processing and trafficking.

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A-to-I RNA Editing: Effects on Proteins Key to Neural Excitability.

Publication Date: 2012 May 10 PMID: 22578495
Authors: Rosenthal, J. J. - Seeburg, P. H.
Journal: Neuron

RNA editing by adenosine deamination is a process used to diversify the proteome. The expression of ADARs, the editing enzymes, is ubiquitous among true metazoans, and so adenosine deamination is thought to be universal. By changing codons at the level of mRNA, protein function can be altered, perhaps in response to physiological demand. Although the number of editing sites identified in recent years has been rising exponentially, their effects on protein function, in general, are less well understood. This review assesses the state of the field and highlights particular cases where the biophysical alterations and functional effects caused by RNA editing have been studied in detail.

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Face selectivity properties of monkey temporal cortical neurons predicted by computer vision.

Publication Date: 2012 May 10 PMID: 22578494
Authors: Vogels, R.
Journal: Neuron

In this issue of Neuron, Ohayon et al. (2012) utilize fMRI-guided single-cell recordings to demonstrate the importance of contrast polarity features for face-selective responses in macaque temporal cortex, as predicted by a computer vision face detection algorithm.

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2B or Not 2B: A Tail of Two NMDA Receptor Subunits.

Publication Date: 2012 May 10 PMID: 22578493
Authors: Cepeda, C. - Levine, M. S.
Journal: Neuron

N-methyl-D-aspartate (NMDA) receptor activation can be neuroprotective or neurotoxic depending on receptor location. In this issue of Neuron, Martel et al. (2012) demonstrate that the C-terminal of NMDA receptor subunits also contributes critically to excitotoxicity. NMDA receptor subunits containing the GluN2B C-terminal are more lethal than those containing the GluN2A tails, regardless of location.

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Will studies of macaque insula reveal the neural mechanisms of self-awareness?

Publication Date: 2012 May 10 PMID: 22578492
Authors: Critchley, H. - Seth, A.
Journal: Neuron

The discovery of von Economo neurons within macaque insular cortex by Evrard et al. (2012) described in this issue of Neuron promises a valuable experimental model to characterize their functional roles. One hypothesis, now open to wider interrogation, is that these intriguing cells mediate self-referential processes underlying or dependent upon consciousness awareness.

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Effects of cue-triggered expectation on cortical processing of taste.

Publication Date: 2012 Apr 26 PMID: 22542192
Authors: Samuelsen, C. L. - Gardner, M. P. - Fontanini, A.
Journal: Neuron

Animals are not passive spectators of the sensory world in which they live. In natural conditions they often sense objects on the bases of expectations initiated by predictive cues. Expectation profoundly modulates neural activity by altering the background state of cortical networks and modulating sensory processing. The link between these two effects is not known. Here, we studied how cue-triggered expectation of stimulus availability influences processing of sensory stimuli in the gustatory cortex (GC). We found that expected tastants were coded more rapidly than unexpected stimuli. The faster onset of sensory coding related to anticipatory priming of GC by associative auditory cues. Simultaneous recordings and pharmacological manipulations of GC and basolateral amygdala revealed the role of top-down inputs in mediating the effects of anticipatory cues. Altogether, these data provide a model for how cue-triggered expectation changes the state of sensory cortices to achieve rapid processing of natural stimuli.

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Distinct cortical circuit mechanisms for complex forelimb movement and motor map topography.

Publication Date: 2012 Apr 26 PMID: 22542191
Authors: Harrison, T. C. - Ayling, O. G. - Murphy, T. H.
Journal: Neuron

Cortical motor maps are the basis of voluntary movement, but they have proven difficult to understand in the context of their underlying neuronal circuits. We applied light-based motor mapping of Channelrhodopsin-2 mice to reveal a functional subdivision of the forelimb motor cortex based on the direction of movement evoked by brief (10 ms) pulses. Prolonged trains of electrical or optogenetic stimulation (100-500 ms) targeted to anterior or posterior subregions of motor cortex evoked reproducible complex movements of the forelimb to distinct positions in space. Blocking excitatory cortical synaptic transmission did not abolish basic motor map topography, but the site-specific expression of complex movements was lost. Our data suggest that the topography of movement maps arises from their segregated output projections, whereas complex movements evoked by prolonged stimulation require intracortical synaptic transmission.

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GABAergic inhibition regulates developmental synapse elimination in the cerebellum.

Publication Date: 2012 Apr 26 PMID: 22542190
Authors: Nakayama, H. - Miyazaki, T. - Kitamura, K. - Hashimoto, K. - Yanagawa, Y. - Obata, K. - Sakimura, K. - Watanabe, M. - Kano, M.
Journal: Neuron

Functional neural circuit formation during development involves massive elimination of redundant synapses. In the cerebellum, one-to-one connection from excitatory climbing fiber (CF) to Purkinje cell (PC) is established by elimination of early-formed surplus CFs. This process depends on glutamatergic excitatory inputs, but contribution of GABAergic transmission remains unclear. Here, we demonstrate impaired CF synapse elimination in mouse models with diminished GABAergic transmission by mutation of a single allele for the GABA synthesizing enzyme GAD67, by conditional deletion of GAD67 from PCs and GABAergic interneurons or by pharmacological inhibition of cerebellar GAD activity. The impaired CF synapse elimination was rescued by enhancing GABA(A) receptor sensitivity in the cerebellum by locally applied diazepam. Our electrophysiological and Ca(2+) imaging data suggest that GABA(A) receptor-mediated inhibition onto the PC soma from molecular layer interneurons influences CF-induced Ca(2+) transients in the soma and regulates CF synapse elimination from postnatal day 10 (P10) to around P16.

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Elimination of inhibitory synapses is a major component of adult ocular dominance plasticity.

Publication Date: 2012 Apr 26 PMID: 22542189
Authors: van Versendaal, D. - Rajendran, R. - Saiepour, M. H. - Klooster, J. - Smit-Rigter, L. - Sommeijer, J. P. - De Zeeuw, C. I. - Hofer, S. B. - Heimel, J. A. - Levelt, C. N.
Journal: Neuron

During development, cortical plasticity is associated with the rearrangement of excitatory connections. While these connections become more stable with age, plasticity can still be induced in the adult cortex. Here we provide evidence that structural plasticity of inhibitory synapses onto pyramidal neurons is a major component of plasticity in the adult neocortex. In vivo two-photon imaging was used to monitor the formation and elimination of fluorescently labeled inhibitory structures on pyramidal neurons. We find that ocular dominance plasticity in the adult visual cortex is associated with rapid inhibitory synapse loss, especially of those present on dendritic spines. This occurs not only with monocular deprivation but also with subsequent restoration of binocular vision. We propose that in the adult visual cortex the experience-induced loss of inhibition may effectively strengthen specific visual inputs with limited need for rearranging the excitatory circuitry.

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Clustered dynamics of inhibitory synapses and dendritic spines in the adult neocortex.

Publication Date: 2012 Apr 26 PMID: 22542188
Authors: Chen, J. L. - Villa, K. L. - Cha, J. W. - So, P. T. - Kubota, Y. - Nedivi, E.
Journal: Neuron

A key feature of the mammalian brain is its capacity to adapt in response to experience, in part by remodeling of synaptic connections between neurons. Excitatory synapse rearrangements have been monitored in vivo by observation of dendritic spine dynamics, but lack of a vital marker for inhibitory synapses has precluded their observation. Here, we simultaneously monitor in vivo inhibitory synapse and dendritic spine dynamics across the entire dendritic arbor of pyramidal neurons in the adult mammalian cortex using large-volume, high-resolution dual-color two-photon microscopy. We find that inhibitory synapses on dendritic shafts and spines differ in their distribution across the arbor and in their remodeling kinetics during normal and altered sensory experience. Further, we find inhibitory synapse and dendritic spine remodeling to be spatially clustered and that clustering is influenced by sensory input. Our findings provide in vivo evidence for local coordination of inhibitory and excitatory synaptic rearrangements. VIDEO ABSTRACT:

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The p150(Glued) CAP-Gly Domain Regulates Initiation of Retrograde Transport at Synaptic Termini.

Publication Date: 2012 Apr 26 PMID: 22542187
Authors: Lloyd, T. E. - Machamer, J. - O'Hara, K. - Kim, J. H. - Collins, S. E. - Wong, M. Y. - Sahin, B. - Imlach, W. - Yang, Y. - Levitan, E. S. - McCabe, B. D. - Kolodkin, A. L.
Journal: Neuron

p150(Glued) is the major subunit of dynactin, a complex that functions with dynein in minus-end-directed microtubule transport. Mutations within the p150(Glued) CAP-Gly microtubule-binding domain cause neurodegenerative diseases through an unclear mechanism. A p150(Glued) motor neuron degenerative disease-associated mutation introduced into the Drosophila Glued locus generates a partial loss-of-function allele (Gl(G38S)) with impaired neurotransmitter release and adult-onset locomotor dysfunction. Disruption of the p150(Glued) CAP-Gly domain in neurons causes a specific disruption of vesicle trafficking at terminal boutons (TBs), the distal-most ends of synapses. Gl(G38S) larvae accumulate endosomes along with dynein and kinesin motor proteins within swollen TBs, and genetic analyses show that kinesin and p150(Glued) function cooperatively at TBs to coordinate transport. Therefore, the p150(Glued) CAP-Gly domain regulates dynein-mediated retrograde transport at synaptic termini, and this function of dynactin is disrupted by a mutation that causes motor neuron disease.

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Dynactin is required for transport initiation from the distal axon.

Publication Date: 2012 Apr 26 PMID: 22542186
Authors: Moughamian, A. J. - Holzbaur, E. L.
Journal: Neuron

Dynactin is a required cofactor for the minus-end-directed microtubule motor cytoplasmic dynein. Mutations within the highly conserved CAP-Gly domain of dynactin cause neurodegenerative disease. Here, we show that the CAP-Gly domain is necessary to enrich dynactin at the distal end of primary neurons. While the CAP-Gly domain is not required for sustained transport along the axon, we find that the distal accumulation facilitates the efficient initiation of retrograde vesicular transport from the neurite tip. Neurodegenerative disease mutations in the CAP-Gly domain prevent the distal enrichment of dynactin thereby inhibiting the initiation of retrograde transport. Thus, we propose a model in which distal dynactin is a key mediator in promoting the interaction among the microtubule, dynein motor, and cargo for the efficient initiation of transport. Mutations in the CAP-Gly domain disrupt the formation of the motor-cargo complex, highlighting the specific defects in axonal transport that may lead to neurodegeneration.

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Foxp-mediated suppression of N-cadherin regulates neuroepithelial character and progenitor maintenance in the CNS.

Publication Date: 2012 Apr 26 PMID: 22542185
Authors: Rousso, D. L. - Pearson, C. A. - Gaber, Z. B. - Miquelajauregui, A. - Li, S. - Portera-Cailliau, C. - Morrisey, E. E. - Novitch, B. G.
Journal: Neuron

Neuroepithelial attachments at adherens junctions are essential for the self-renewal of neural stem and progenitor cells and the polarized organization of the developing central nervous system. The balance between stem cell maintenance and differentiation depends on the precise assembly and disassembly of these adhesive contacts, but the gene regulatory mechanisms orchestrating this process are not known. Here, we demonstrate that two Forkhead transcription factors, Foxp2 and Foxp4, are progressively expressed upon neural differentiation in the spinal cord. Elevated expression of either Foxp represses the expression of a key component of adherens junctions, N-cadherin, and promotes the detachment of differentiating neurons from the neuroepithelium. Conversely, inactivation of Foxp2 and Foxp4 function in both chick and mouse results in a spectrum of neural tube defects associated with neuroepithelial disorganization and enhanced progenitor maintenance. Together, these data reveal a Foxp-based transcriptional mechanism that regulates the integrity and cytoarchitecture of neuroepithelial progenitors.

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Mutant PrP Suppresses Glutamatergic Neurotransmission in Cerebellar Granule Neurons by Impairing Membrane Delivery of VGCC alpha(2)delta-1 Subunit.

Publication Date: 2012 Apr 26 PMID: 22542184
Authors: Senatore, A. - Colleoni, S. - Verderio, C. - Restelli, E. - Morini, R. - Condliffe, S. B. - Bertani, I. - Mantovani, S. - Canovi, M. - Micotti, E. - Forloni, G. - Dolphin, A. C. - Matteoli, M. - Gobbi, M. - Chiesa, R.
Journal: Neuron

How mutant prion protein (PrP) leads to neurological dysfunction in genetic prion diseases is unknown. Tg(PG14) mice synthesize a misfolded mutant PrP which is partially retained in the neuronal endoplasmic reticulum (ER). As these mice age, they develop ataxia and massive degeneration of cerebellar granule neurons (CGNs). Here, we report that motor behavioral deficits in Tg(PG14) mice emerge before neurodegeneration and are associated with defective glutamate exocytosis from granule neurons due to impaired calcium dynamics. We found that mutant PrP interacts with the voltage-gated calcium channel alpha(2)delta-1 subunit, which promotes the anterograde trafficking of the channel. Owing to ER retention of mutant PrP, alpha(2)delta-1 accumulates intracellularly, impairing delivery of the channel complex to the cell surface. Thus, mutant PrP disrupts cerebellar glutamatergic neurotransmission by reducing the number of functional channels in CGNs. These results link intracellular PrP retention to synaptic dysfunction, indicating new modalities of neurotoxicity and potential therapeutic strategies.

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De novo gene disruptions in children on the autistic spectrum.

Publication Date: 2012 Apr 26 PMID: 22542183
Authors: Iossifov, I. - Ronemus, M. - Levy, D. - Wang, Z. - Hakker, I. - Rosenbaum, J. - Yamrom, B. - Lee, Y. H. - Narzisi, G. - Leotta, A. - Kendall, J. - Grabowska, E. - Ma, B. - Marks, S. - Rodgers, L. - Stepansky, A. - Troge, J. - Andrews, P. - Bekritsky, M. - Pradhan, K. - Ghiban, E. - Kramer, M. - Parla, J. - Demeter, R. - Fulton, L. L. - Fulton, R. S. - Magrini, V. J. - Ye, K. - Darnell, J. C. - Darnell, R. B. - Mardis, E. R. - Wilson, R. K. - Schatz, M. C. - McCombie, W. R. - Wigler, M.
Journal: Neuron

Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.

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Regulation of presynaptic neurotransmission by macroautophagy.

Publication Date: 2012 Apr 26 PMID: 22542182
Authors: Hernandez, D. - Torres, C. A. - Setlik, W. - Cebrian, C. - Mosharov, E. V. - Tang, G. - Cheng, H. C. - Kholodilov, N. - Yarygina, O. - Burke, R. E. - Gershon, M. - Sulzer, D.
Journal: Neuron

mTOR is a regulator of cell growth and survival, protein synthesis-dependent synaptic plasticity, and autophagic degradation of cellular components. When triggered by mTOR inactivation, macroautophagy degrades long-lived proteins and organelles via sequestration into autophagic vacuoles. mTOR further regulates synaptic plasticity, and neurodegeneration occurs when macroautophagy is deficient. It is nevertheless unknown whether macroautophagy modulates presynaptic function. We find that the mTOR inhibitor rapamycin induces formation of autophagic vacuoles in prejunctional dopaminergic axons with associated decreased axonal profile volumes, synaptic vesicle numbers, and evoked dopamine release. Evoked dopamine secretion was enhanced and recovery was accelerated in transgenic mice in which macroautophagy deficiency was restricted to dopaminergic neurons; rapamycin failed to decrease evoked dopamine release in the striatum of these mice. Macroautophagy that follows mTOR inhibition in presynaptic terminals, therefore, rapidly alters presynaptic structure and neurotransmission.

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gamma-Protocadherins Control Cortical Dendrite Arborization by Regulating the Activity of a FAK/PKC/MARCKS Signaling Pathway.

Publication Date: 2012 Apr 26 PMID: 22542181
Authors: Garrett, A. M. - Schreiner, D. - Lobas, M. A. - Weiner, J. A.
Journal: Neuron

The 22 gamma-protocadherins (gamma-Pcdhs) potentially specify thousands of distinct homophilic adhesive interactions in the brain. Neonatal lethality of mice lacking the Pcdh-gamma gene cluster has, however, precluded analysis of many brain regions. Here, we use a conditional Pcdh-gamma allele to restrict mutation to the cerebral cortex and find that, in contrast to other central nervous system phenotypes, loss of gamma-Pcdhs in cortical neurons does not affect their survival or result in reduced synaptic density. Instead, mutant cortical neurons exhibit severely reduced dendritic arborization. Mutant cortices have aberrantly high levels of protein kinase C (PKC) activity and of phosphorylated (inactive) myristoylated alanine-rich C-kinase substrate, a PKC target that promotes arborization. Dendrite complexity can be rescued in Pcdh-gamma mutant neurons by inhibiting PKC, its upstream activator phospholipase C, or the gamma-Pcdh binding partner focal adhesion kinase. Our results reveal a distinct role for the gamma-Pcdhs in cortical development and identify a signaling pathway through which they play this role.

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Complementary chimeric isoforms reveal dscam1 binding specificity in vivo.

Publication Date: 2012 Apr 26 PMID: 22542180
Authors: Wu, W. - Ahlsen, G. - Baker, D. - Shapiro, L. - Zipursky, S. L.
Journal: Neuron

Dscam1 potentially encodes 19,008 ectodomains of a cell recognition molecule of the immunoglobulin (Ig) superfamily through alternative splicing. Each ectodomain, comprising a unique combination of three variable (Ig) domains, exhibits isoform-specific homophilic binding in vitro. Although we have proposed that the ability of Dscam1 isoforms to distinguish between one another is crucial for neural circuit assembly, via a process called self-avoidance, whether recognition specificity is essential in vivo has not been addressed. Here we tackle this issue by assessing the function of Dscam1 isoforms with altered binding specificities. We generated pairs of chimeric isoforms that bind to each other (heterophilic) but not to themselves (homophilic). These isoforms failed to support self-avoidance or did so poorly. By contrast, coexpression of complementary isoforms within the same neuron restored self-avoidance. These data establish that recognition between Dscam1 isoforms on neurites of the same cell provides the molecular basis for self-avoidance.

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Timing to perfection: the biology of central and peripheral circadian clocks.

Publication Date: 2012 Apr 26 PMID: 22542179
Authors: Albrecht, U.
Journal: Neuron

The mammalian circadian system, which is comprised of multiple cellular clocks located in the organs and tissues, orchestrates their regulation in a hierarchical manner throughout the 24 hr of the day. At the top of the hierarchy are the suprachiasmatic nuclei, which synchronize subordinate organ and tissue clocks using electrical, endocrine, and metabolic signaling pathways that impact the molecular mechanisms of cellular clocks. The interplay between the central neural and peripheral tissue clocks is not fully understood and remains a major challenge in determining how neurological and metabolic homeostasis is achieved across the sleep-wake cycle. Disturbances in the communication between the plethora of body clocks can desynchronize the circadian system, which is believed to contribute to the development of diseases such as obesity and neuropsychiatric disorders. This review will highlight the relationship between clocks and metabolism, and describe how cues such as light, food, and reward mediate entrainment of the circadian system.

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On the perception of probable things: neural substrates of associative memory, imagery, and perception.

Publication Date: 2012 Apr 26 PMID: 22542178
Authors: Albright, T. D.
Journal: Neuron

Perception is influenced both by the immediate pattern of sensory inputs and by memories acquired through prior experiences with the world. Throughout much of its illustrious history, however, study of the cellular basis of perception has focused on neuronal structures and events that underlie the detection and discrimination of sensory stimuli. Relatively little attention has been paid to the means by which memories interact with incoming sensory signals. Building upon recent neurophysiological/behavioral studies of the cortical substrates of visual associative memory, I propose a specific functional process by which stored information about the world supplements sensory inputs to yield neuronal signals that can account for visual perceptual experience. This perspective represents a significant shift in the way we think about the cellular bases of perception.

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Neuroscience in the public sphere.

Publication Date: 2012 Apr 26 PMID: 22542177
Authors: O'Connor, C. - Rees, G. - Joffe, H.
Journal: Neuron

The media are increasingly fascinated by neuroscience. Here, we consider how neuroscientific discoveries are thematically represented in the popular press and the implications this has for society. In communicating research, neuroscientists should be sensitive to the social consequences neuroscientific information may have once it enters the public sphere.

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A taste of what to expect: top-down modulation of neural coding in rodent gustatory cortex.

Publication Date: 2012 Apr 26 PMID: 22542176
Authors: Zelano, C. - Gottfried, J. A.
Journal: Neuron

A central aspect of sensory perception is the anticipation of forthcoming stimuli, allowing for a faster and more accurate assessment of the surrounding environment. A new study by Samuelsen et al. (2012) in this issue of Neuron highlights the neural mechanisms underlying the expectation of an imminent taste.

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Synapses Let Loose for a Change: Inhibitory Synapse Pruning throughout Experience-Dependent Cortical Plasticity.

Publication Date: 2012 Apr 26 PMID: 22542175
Authors: Gambino, F. - Holtmaat, A.
Journal: Neuron

In this issue of Neuron, Chen et al. (2012) and van Versendaal et al. (2012) used fluorescently tagged gephyrin to track inhibitory synapses in the mouse visual cortex in vivo. Their studies show that visual experience-dependent plasticity is associated with clustered and location-specific pruning of inhibitory synapses.

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The CAP-Gly of p150: One Domain, Two Diseases, and a Function at the End.

Publication Date: 2012 Apr 26 PMID: 22542174
Authors: Cronin, M. A. - Schwarz, T. L.
Journal: Neuron

In this issue of Neuron, work from Moughamian and Holzbaur (2012) and Lloyd et al. (2012) reveals a role for p150 in initiation of retrograde transport at synaptic terminals. These studies also suggest how mutations of p150's CAP-Gly domain lead to both Perry syndrome and HMN7B disease.

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Crucial first steps: the transcriptional control of neuron delamination.

Publication Date: 2012 Apr 26 PMID: 22542173
Authors: Pacary, E. - Martynoga, B. - Guillemot, F.
Journal: Neuron

A crucial event in the birth of a neuron is the detachment of its apical process from the neuroepithelium. In this issue of Neuron, Rousso et al. (2012) show that repression of N-cadherin by Foxp transcription factors disrupts apical adherens junctions and triggers neurogenesis.

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