Wednesday, February 23, 2011

Hot off the presses! Feb 24 Neuron

The Feb 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:

  • Exciting Information for Inhibitory Neurons
    - Neuron (Cambridge Mass ) 69(4):585-587 (2011)
    One unsolved issue in brain development is how interneurons migrating tangentially into the cortex acquire their regional addresses and laminar positions. The study by Lodato et al. in this issue shows that projection neurons regulate the laminar fates of cortical interneurons.
  • An Arousing Discovery on Catalepsy: Orexin Regulates Vestibular Motor Functions
    - Neuron (Cambridge Mass ) 69(4):588-590 (2011)
    A study by Zhang et al. in this issue of Neuron reveals a novel mechanism of control of vestibular motor functions by the orexin (hypocretin) system in the perifornical/LH area through the lateral vestibular nucleus in the brainstem. This knowledge provides new insights into the understanding of brain circuitry that controls motor functions and diseases/conditions related to impairments in this circuitry.
  • The Doctor's Dilemma: Opiate Analgesics and Chronic Pain
    - Neuron (Cambridge Mass ) 69(4):591-594 (2011)
    Opiates are utilized routinely and effectively as a short-term analgesic treatment for a variety of acute pain conditions such as occur following trauma, and for patients with painful terminal diseases such as cancer. Because opiate analgesics are highly addictive substances, their use in the treatment of chronic nonmalignant pain remains controversial.
  • Cognitive Enhancement: Promises and Perils
    - Neuron (Cambridge Mass ) 69(4):595-598 (2011)
    The potential use of drugs to enhance cognition, emotion, and executive function has engendered controversy despite the fact that few such agents exist today. Here, I provide a context for discussions based on medical, regulatory, and ethical concerns that have been raised by the possibility that enhancers will emerge from current efforts to discover drugs for neuropsychiatric disorders.
  • Addiction: Pulling at the Neural Threads of Social Behaviors
    - Neuron (Cambridge Mass ) 69(4):599-602 (2011)
    Addiction coopts the brain's neuronal circuits necessary for insight, reward, motivation, and social behaviors. This functional overlap results in addicted individuals making poor choices despite awareness of the negative consequences; it explains why previously rewarding life situations and the threat of judicial punishment cannot stop drug taking and why a medical rather than a criminal approach is more effective in curtailing addiction.
  • Potential Vulnerabilities of Neuronal Reward, Risk, and Decision Mechanisms to Addictive Drugs
    - Neuron (Cambridge Mass ) 69(4):603-617 (2011)
    How do addictive drugs hijack the brain's reward system? This review speculates how normal, physiological reward processes may be affected by addictive drugs. Addictive drugs affect acute responses and plasticity in dopamine neurons and postsynaptic structures. These effects reduce reward discrimination, increase the effects of reward prediction error signals, and enhance neuronal responses to reward-predicting stimuli, which may contribute to compulsion. Addictive drugs steepen neuronal temporal reward discounting and create temporal myopia that impairs the control of drug taking. Tonically enhanced dopamine levels may disturb working memory mechanisms necessary for assessing background rewards and thus may generate inaccurate neuronal reward predictions. Drug-induced working memory deficits may impair neuronal risk signaling, promote risky behaviors, and facilitate preaddictive drug use. Malfunctioning adaptive reward coding may lead to overvaluation of drug rewards.! Many of these malfunctions may result in inadequate neuronal decision mechanisms and lead to choices biased toward drug rewards.
  • Genetic Vulnerability and Susceptibility to Substance Dependence
    - Neuron (Cambridge Mass ) 69(4):618-627 (2011)
    The development of substance dependence requires the initiation of substance use and the conversion from experimental use to established use before development of dependence. Numerous large twin studies have indicated a significant genetic contribution to this process. Genetic studies to date have been most successful at identifying genetic factors that influence the transition from regular use to dependence. The availability of large cohort samples for nicotine and alcohol dependence has resulted in significant progress being made in understanding at least some of the genetic contributions to these addictions. Fewer studies have replicated specific genetic contributions to illicit drug use, though it is clear that there is a strong genetic component involved here as well. Substance dependence can be thought of as a pharmacogenetic illness, and most likely hundreds and more probably thousands of genetic variants will be required to fully explain the genetic input to th! is disease.
  • How Addictive Drugs Disrupt Presynaptic Dopamine Neurotransmission
    - Neuron (Cambridge Mass ) 69(4):628-649 (2011)
    The fundamental principle that unites addictive drugs appears to be that each enhances synaptic dopamine by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. This occurs via the modulation of synaptic mechanisms that can be involved in learning, including enhanced excitation or disinhibition of dopamine neuron activity, blockade of dopamine reuptake, and altering the state of the presynaptic terminal to enhance evoked over basal transmission. Amphetamines offer an exception to such modulation in that they combine multiple effects to produce nonexocytic stimulation-independent release of neurotransmitter via reverse transport independent from normal presynaptic function. Questions about the molecular actions of addictive drugs, prominently including the actions of alcohol and solvents, remain unresolved, but their ability to co-opt normal presynaptic functions helps to explain why treatment for addiction has be! en challenging.
  • Drug-Evoked Synaptic Plasticity in Addiction: From Molecular Changes to Circuit Remodeling
    - Neuron (Cambridge Mass ) 69(4):650-663 (2011)
    Addictive drugs have in common that they target the mesocorticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here, we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and contribute to addictive behavior.
  • Reward Mechanisms in Obesity: New Insights and Future Directions
    - Neuron (Cambridge Mass ) 69(4):664-679 (2011)
    Food is consumed in order to maintain energy balance at homeostatic levels. In addition, palatable food is also consumed for its hedonic properties independent of energy status. Such reward-related consumption can result in caloric intake exceeding requirements and is considered a major culprit in the rapidly increasing rates of obesity in developed countries. Compared with homeostatic mechanisms of feeding, much less is known about how hedonic systems in brain influence food intake. Intriguingly, excessive consumption of palatable food can trigger neuroadaptive responses in brain reward circuitries similar to drugs of abuse. Furthermore, similar genetic vulnerabilities in brain reward systems can increase predisposition to drug addiction and obesity. Here, recent advances in our understanding of the brain circuitries that regulate hedonic aspects of feeding behavior will be reviewed. Also, emerging evidence suggesting that obesity and drug addiction may share common h! edonic mechanisms will also be considered.
  • Impulsivity, Compulsivity, and Top-Down Cognitive Control
    - Neuron (Cambridge Mass ) 69(4):680-694 (2011)
    Impulsivity is the tendency to act prematurely without foresight. Behavioral and neurobiological analysis of this construct, with evidence from both animal and human studies, defines several dissociable forms depending on distinct cortico-striatal substrates. One form of impulsivity depends on the temporal discounting of reward, another on motor or response disinhibition. Impulsivity is commonly associated with addiction to drugs from different pharmacological classes, but its causal role in human addiction is unclear. We characterize in neurobehavioral and neurochemical terms a rodent model of impulsivity based on premature responding in an attentional task. Evidence is surveyed that high impulsivity on this task precedes the escalation subsequently of cocaine self-administration behavior, and also a tendency toward compulsive cocaine-seeking and to relapse. These results indicate that the vulnerability to stimulant addiction may depend on an impulsivity endophenotype! . Implications of these findings for the etiology, development, and treatment of drug addiction are considered.
  • Neuroscience of Behavioral and Pharmacological Treatments for Addictions
    - Neuron (Cambridge Mass ) 69(4):695-712 (2011)
    Although substantial advances have been made in behavioral and pharmacological treatments for addictions, moving treatment development to the next stage may require novel ways of approaching addictions, particularly ways based on new findings regarding the neurobiological underpinnings of addictions that also assimilate and incorporate relevant information from earlier approaches. In this review, we first briefly review theoretical and biological models of addiction and then describe existing behavioral and pharmacologic therapies for the addictions within this framework. We then propose new directions for treatment development and targets that are informed by recent evidence regarding the heterogeneity of addictions and the neurobiological contributions to these disorders.
  • Differential Targeting of Optical Neuromodulators to Ganglion Cell Soma and Dendrites Allows Dynamic Control of Center-Surround Antagonism
    - Neuron (Cambridge Mass ) 69(4):713-720 (2011)
    Retinal degenerative diseases cause photoreceptor loss and often result in remodeling and deafferentation of the inner retina. Fortunately, ganglion cell morphology appears to remain intact long after photoreceptors and distal retinal circuitry have degenerated. We have introduced the optical neuromodulators channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR) differentially into the soma and dendrites of ganglion cells to recreate antagonistic center-surround receptive field interactions. We then reestablished the physiological receptive field dimensions of primate parafoveal ganglion cells by convolving Gaussian-blurred versions of the visual scene at the appropriate wavelength for each neuromodulator with the Gaussians inherent in the soma and dendrites. These Gaussian-modified ganglion cells responded with physiologically relevant antagonistic receptive field components and encoded edges with parafoveal resolution. This approach bypasses the degenerated areas of the ! distal retina and could provide a first step in restoring sight to individuals suffering from retinal disease.
  • Mir-17-3p Controls Spinal Neural Progenitor Patterning by Regulating Olig2/Irx3 Cross-Repressive Loop
    - Neuron (Cambridge Mass ) 69(4):721-735 (2011)
    Neural patterning relies on transcriptional cross-repressive interactions that ensure unequivocal assignment of neural progenitor identity to proliferating cells. Progenitors of spinal motor neurons (pMN) and V2 interneurons (p2) are specified by a pair of cross-repressive transcription factors, Olig2 and Irx3. Lineage tracing revealed that many p2 progenitors transiently express the pMN marker Olig2 during spinal cord development. Here we demonstrate that the repression of Olig2 in p2 domain is controlled by mir-17-3p microRNA-mediated silencing of Olig2 mRNA. Mice lacking all microRNAs or just the mir-1792 cluster manifest a dorsal shift in pMN/p2 boundary and impairment in the production of V2 interneurons. Our findings suggest that microRNA-mediated repression of Olig2 mRNA plays a critical role during the patterning of ventral spinal progenitor domains by shifting the balance of cross-repressive interactions between Olig2 and Irx3 transcription factors.
  • Synaptotagmin Increases the Dynamic Range of Synapses by Driving Ca2+-Evoked Release and by Clamping a Near-Linear Remaining Ca2+ Sensor
    - Neuron (Cambridge Mass ) 69(4):736-748 (2011)
    Ca2+-evoked transmitter release shows a high dynamic range over spontaneous release. We investigated the role of the Ca2+ sensor protein, Synaptotagmin2 (Syt2), in both spontaneous and Ca2+-evoked release under direct control of presynaptic [Ca2+]i, using an in vivo rescue approach at the calyx of Held. Re-expression of Syt2 rescued the highly Ca2+ cooperative release and suppressed the elevated spontaneous release seen in Syt2 KO synapses. This latter release clamping function was partially mediated by the poly-lysine motif of the C2B domain. Using an aspartate mutation in the C2B domain (D364N) in which Ca2+ triggering was abolished but release clamping remained intact, we show that Syt2 strongly suppresses the action of another, near-linear Ca2+ sensor that mediates release over a wide range of [Ca2+]i. Thus, Syt2 increases the dynamic range of synapses by driving release with a high Ca2+ cooperativity, as well as by suppressing a remaining, near-linear Ca2+ sensor.
  • Rab3-GAP Controls the Progression of Synaptic Homeostasis at a Late Stage of Vesicle Release
    - Neuron (Cambridge Mass ) 69(4):749-762 (2011)
    Homeostatic signaling systems stabilize neural function through the modulation of neurotransmitter receptor abundance, ion channel density, and presynaptic neurotransmitter release. Molecular mechanisms that drive these changes are being unveiled. In theory, molecular mechanisms may also exist to oppose the induction or expression of homeostatic plasticity, but these mechanisms have yet to be explored. In an ongoing electrophysiology-based genetic screen, we have tested 162 new mutations for genes involved in homeostatic signaling at the Drosophila NMJ. This screen identified a mutation in the rab3-GAP gene. We show that Rab3-GAP is necessary for the induction and expression of synaptic homeostasis. We then provide evidence that Rab3-GAP relieves an opposing influence on homeostasis that is catalyzed by Rab3 and which is independent of any change in NMJ anatomy. These data define roles for Rab3-GAP and Rab3 in synaptic homeostasis and uncover a mechanism, acting at a l! ate stage of vesicle release, that opposes the progression of homeostatic plasticity.
  • Excitatory Projection Neuron Subtypes Control the Distribution of Local Inhibitory Interneurons in the Cerebral Cortex
    - Neuron (Cambridge Mass ) 69(4):763-779 (2011)
    In the mammalian cerebral cortex, the developmental events governing the integration of excitatory projection neurons and inhibitory interneurons into balanced local circuitry are poorly understood. We report that different subtypes of projection neurons uniquely and differentially determine the laminar distribution of cortical interneurons. We find that in Fezf2−/− cortex, the exclusive absence of subcerebral projection neurons and their replacement by callosal projection neurons cause distinctly abnormal lamination of interneurons and altered GABAergic inhibition. In addition, experimental generation of either corticofugal neurons or callosal neurons below the cortex is sufficient to recruit cortical interneurons to these ectopic locations. Strikingly, the identity of the projection neurons generated, rather than strictly their birthdate, determines the specific types of interneurons recruited. These data demonstrate that in the neocortex individual populations o! f projection neurons cell-extrinsically control the laminar fate of interneurons and the assembly of local inhibitory circuitry.
  • Serotonin Mediates Cross-Modal Reorganization of Cortical Circuits
    - Neuron (Cambridge Mass ) 69(4):780-792 (2011)
    Loss of one type of sensory input can cause improved functionality of other sensory systems. Whereas this form of plasticity, cross-modal plasticity, is well established, the molecular and cellular mechanisms underlying it are still unclear. Here, we show that visual deprivation (VD) increases extracellular serotonin in the juvenile rat barrel cortex. This increase in serotonin levels facilitates synaptic strengthening at layer 4 to layer 2/3 synapses within the barrel cortex. Upon VD, whisker experience leads to trafficking of the AMPA-type glutamate receptors (AMPARs) into these synapses through the activation of ERK and increased phosphorylation of AMPAR subunit GluR1 at the juvenile age when natural whisker experience no longer induces synaptic GluR1 delivery. VD thereby leads to sharpening of the functional whisker-barrel map at layer 2/3. Thus, sensory deprivation of one modality leads to serotonin release in remaining modalities, facilitates GluR1-dependent syna! ptic strengthening, and refines cortical organization.
  • A Role for Orexin in Central Vestibular Motor Control
    - Neuron (Cambridge Mass ) 69(4):793-804 (2011)
    The absence of orexin results in narcolepsy-cataplexy. While the function of the central orexinergic system in sleep regulation has been well studied, the role of orexin in motor control is largely unknown. Here, we show that orexin-A acts via OX1 and OX2 receptors to directly depolarize neurons in the rat lateral vestibular nucleus (LVN), a subcortical motor center, and enhance their sensitivity. A dual ionic mechanism involving both Na+-Ca2+ exchangers and inward rectifier K+ channels underlies these effects. Furthermore, orexin-A regulates central vestibular-mediated posture, motor balance and negative geotaxis. Orexin is critical when an animal is facing a major motor challenge as opposed to during rest and general movements. Therefore, orexin participates not only in sleep and emotion (nonsomatic) but also in motor (somatic) regulation, suggesting that the central orexinergic system plays an important role in somatic-nonsomatic integration. These findings may acco! unt for why the absence of orexin results in narcolepsy-cataplexy.
  • Dual Mechanism of Neuronal Ensemble Inhibition in Primary Auditory Cortex
    - Neuron (Cambridge Mass ) 69(4):805-817 (2011)
    Inhibition plays an essential role in shaping and refining the brain's representation of sensory stimulus attributes. In primary auditory cortex (A1), so-called "sideband" inhibition helps to sharpen the tuning of local neuronal responses. Several distinct types of anatomical circuitry could underlie sideband inhibition, including direct thalamocortical (TC) afferents, as well as indirect intracortical mechanisms. The goal of the present study was to characterize sideband inhibition in A1 and to determine its mechanism by analyzing laminar profiles of neuronal ensemble activity. Our results indicate that both lemniscal and nonlemniscal TC afferents play a role in inhibitory responses via feedforward inhibition and oscillatory phase reset, respectively. We propose that the dynamic modulation of excitability in A1 due to the phase reset of ongoing oscillations may alter the tuning of local neuronal ensembles and can be regarded as a flexible overlay on the more oblig! atory system of lemniscal feedforward type responses.
  • Variance as a Signature of Neural Computations during Decision Making
    - Neuron (Cambridge Mass ) 69(4):818-831 (2011)
    Traditionally, insights into neural computation have been furnished by averaged firing rates from many stimulus repetitions or trials. We pursue an analysis of neural response variance to unveil neural computations that cannot be discerned from measures of average firing rate. We analyzed single-neuron recordings from the lateral intraparietal area (LIP), during a perceptual decision-making task. Spike count variance was divided into two components using the law of total variance for doubly stochastic processes: (1) variance of counts that would be produced by a stochastic point process with a given rate, and loosely (2) the variance of the rates that would produce those counts (i.e., "conditional expectation"). The variance and correlation of the conditional expectation exposed several neural mechanisms: mixtures of firing rate states preceding the decision, accumulation of stochastic "evidence" during decision formation, and a stereotyped response at decision! end. These analyses help to differentiate among several alternative decision-making models. 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 (29323 K)

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