Parvalbumin interneurons regulate nucleus accumbens synapses and behavior

小白蛋白中间神经元调节伏隔核突触和行为

基本信息

  • 批准号:
    10487428
  • 负责人:
  • 金额:
    $ 48.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Substance use disorders (SUDs) remain a medical and societal burden with a relative paucity of prevention and treatment options. The nucleus accumbens (NAc) is an essential hub integrating cognitive, contextual, sensory and affective information into behavioral outcomes. Changes in excitatory (glutamatergic) synaptic function in the NAc is a leading molecular mechanism by which illicit drug exposure leads to the behavioral manifestations represented by SUDs. However, a gap in the input specificity, temporal dynamic, mechanism(s) and consequences of plasticity and drug-induced plasticity onto parvalbumin expressing fast spiking interneurons (PV-FSIs) remains. The long-term goal is to understand the mechanisms by which NAc circuits mediate reinforced behaviors. The overall objective of this application is: (1) to define input-specific plasticity mechanisms controlling excitatory synaptic strength onto PV-FSIs, (2) to elucidate mechanistic contributions of these synapses to reinforcement behavior, and (3) to determine contribution of NAc PV-FSI AMPA receptors to cocaine-evoked plasticity of MSN excitatory synapses. The central hypothesis is that functionally-distinct corticolimbic and thalamic synapses onto PV-FSIs in the NAc support cocaine-evoked adaptations in reinforcement behavior and circuit function. Aim 1 is designed to determine mechanisms of stimulus and cocaine-evoked synaptic plasticity of specific excitatory inputs onto NAc PV-FSIs. Aim 2 will determine the role of glutamatergic signaling onto NAc PV-FSIs in modulating reinforcement behavior in an input specific manner. And, Aim 3 will elucidate the contribution of NAc PV-FSI AMPA receptors to cocaine-induced plasticity of MSNs. The rationale for the proposed studies is that they will provide a detailed understanding of the functional organization of NAc PV-FSI microcircuitry, revealing synaptic mechanisms by which PV-FSIs adapt to stimuli and support reinforcement behavior as well as influence cocaine-evoked reorganization of output circuits. To accomplish these aims a combination of whole-cell patch clamp electrophysiology, Drugs Acutely Restricted by Tethering (DART) pharmacology, optogenetics, reinforcement behavior and transgenic mice will be used. The proposed research is innovative because it represents a new and substantive departure from the status quo by shifting focus to the modulation of PV-FSI feedforward inhibition as a master regulator of NAc function and thus reward-related behavior. Completion of the work in this proposal will: (1) establish plasticity mechanisms at specific excitatory inputs onto PV-FSIs. (2) Establish a causal relationship between NAc PV-FSI AMPA receptors and reinforcement behavior and (3) demonstrate that NAc PV-FSI AMPA receptors are necessary for cocaine- evoked plasticity of MSN excitatory synapses. Completion of this work is expected to have a positive translational impact by examining an understudied but integral component of the reward system and will provide a launching point for the development of novel strategies to prevent and treat Substance Use Disorders.
项目摘要 物质使用障碍(SUD)仍然是一个医疗和社会负担,预防措施相对缺乏, 治疗方案。丘脑核(nucleus reverbens,NAc)是整合认知、语境、感觉和认知功能的重要中枢 和情感信息转化为行为结果。兴奋性(突触能)突触功能的变化, NAc是一种主要的分子机制,通过这种机制,非法药物暴露导致行为表现, 以SUD为代表。然而,在输入特异性、时间动态、机制和 可塑性和药物诱导的可塑性对表达小清蛋白的快速尖峰中间神经元的影响 (PV-FSI)仍然存在。长期目标是了解NAc回路介导的机制 强化行为。本申请的总体目标是:(1)定义输入特定的可塑性机制 控制PV-FSI的兴奋性突触强度,(2)阐明这些机制的贡献 突触对强化行为的影响,以及(3)确定NAc PV-FSI AMPA受体对 可卡因诱发的MSN兴奋性突触可塑性。核心假设是, 在NAc中PV-FSI上的皮质边缘和丘脑突触支持可卡因诱发的适应, 强化行为和回路功能。目的1旨在确定刺激机制, 可卡因诱发的特定兴奋性输入对NAc PV-FSI的突触可塑性。目标2将决定作用 在以输入特异性方式调节强化行为中, 目的3将阐明NAc PV-FSI AMPA受体对可卡因诱导的MSNs可塑性的贡献。 拟议研究的理由是,它们将提供对功能的详细了解, NAc PV-FSI微电路的组织,揭示PV-FSI适应刺激的突触机制 并支持强化行为以及影响可卡因诱发的输出回路重组。到 实现这些目标的组合全细胞膜片钳电生理学,药物急性限制, 将使用拴系(DART)药理学、光遗传学、强化行为和转基因小鼠。的 拟议的研究是创新的,因为它代表了一个新的和实质性的偏离现状, 将焦点转移到PV-FSI前馈抑制的调节上,作为NAc功能的主要调节剂, 与奖励有关的行为。完成本建议的工作将:(1)建立可塑性机制, 特异性兴奋性输入到PV-FSI上。(2)建立NAc PV-FSI AMPA受体之间的因果关系 和强化行为;(3)证明NAc PV-FSI AMPA受体是可卡因所必需的。 诱发MSN兴奋性突触的可塑性。这一工作的完成有望对翻译产生积极的影响 通过研究一个研究不足但不可或缺的组成部分的奖励制度,并将提供一个启动 为预防和治疗物质使用障碍的新策略的发展点。

项目成果

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Brad Alan Grueter其他文献

Brad Alan Grueter的其他文献

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{{ truncateString('Brad Alan Grueter', 18)}}的其他基金

Photoperiodic Programming of Monoamine Brain Circuits
单胺脑回路的光周期编程
  • 批准号:
    10735447
  • 财政年份:
    2023
  • 资助金额:
    $ 48.89万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小清蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    10298824
  • 财政年份:
    2016
  • 资助金额:
    $ 48.89万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小白蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    10161984
  • 财政年份:
    2016
  • 资助金额:
    $ 48.89万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小清蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    9923260
  • 财政年份:
    2016
  • 资助金额:
    $ 48.89万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小清蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    10675558
  • 财政年份:
    2016
  • 资助金额:
    $ 48.89万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小白蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    9698739
  • 财政年份:
    2016
  • 资助金额:
    $ 48.89万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小清蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    9174760
  • 财政年份:
    2016
  • 资助金额:
    $ 48.89万
  • 项目类别:
Synaptic Mechanisms of Addiction-Related Behaviors in the Nucleus Accumbens
伏核成瘾相关行为的突触机制
  • 批准号:
    8585390
  • 财政年份:
    2013
  • 资助金额:
    $ 48.89万
  • 项目类别:
Synaptic Mechanisms of Addiction-Related Behaviors in the Nucleus Accumbens
伏核成瘾相关行为的突触机制
  • 批准号:
    8637959
  • 财政年份:
    2013
  • 资助金额:
    $ 48.89万
  • 项目类别:
Synaptic Mechanisms of Addiction-Related Behaviors in the Nucleus Accumbens
伏核成瘾相关行为的突触机制
  • 批准号:
    8825475
  • 财政年份:
    2013
  • 资助金额:
    $ 48.89万
  • 项目类别:

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Neurobiological impact of acute digital media abstinence among drug using college students
吸毒大学生急性数字媒体戒断的神经生物学影响
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