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
• 负责人: Brad Alan Grueter
• 金额: $ 51.23万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10298824
• 关键词: AMPA Receptors; Abstinence; Acute; Affect; Affective; Automobile Driving; Behavior; Behavioral; Cells; Chemosensitization; Cocaine; Cognitive; Data; Development; Drug Exposure; Drug Receptors; Electrophysiology (science); Excitatory Synapse; Exhibits; Generations; Glutamates; Goals; Illicit Drugs; Interneurons; Knowledge; Lead; Learning; Long-Term Depression; Mediating; Medical; Memory; Mission; Molecular; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Opsin; Output; Parvalbumins; Pathology; Pharmaceutical Preparations; Pharmacology; Prevention; Property; Psychological reinforcement; Research; Rewards; Role; Self Stimulation; Sensory; Specificity; Stimulus; Substance Use Disorder; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Thalamic structure; Transgenic Mice; United States National Institutes of Health; Work; addiction; behavioral outcome; cell type; combinatorial; design; drug of abuse; excitatory neuron; experience; glutamatergic signaling; in vivo; inhibitor/antagonist; innovation; novel strategies; optogenetics; patch clamp; prevent; recruit; reinforced behavior; reward processing; synaptic function; translational impact; transmission process

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.

项目概要 物质使用障碍 (SUD) 仍然是一种医疗和社会负担，且预防和治疗相对缺乏。 治疗方案。伏隔核 (NAc) 是整合认知、情境、感觉的重要枢纽 并将情感信息转化为行为结果。兴奋性（谷氨酸）突触功能的变化 NAc 是非法药物暴露导致行为表现的主要分子机制 以 SUD 为代表。然而，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快速尖峰中间神经元的小白蛋白的影响 （PV-FSI）仍然存在。长期目标是了解 NAc 回路的介导机制 强化行为。该应用的总体目标是：（1）定义输入特定的可塑性机制 控制 PV-FSIs 上的兴奋性突触强度，(2) 阐明这些的机制贡献 突触对强化行为的影响，以及 (3) 确定 NAc PV-FSI AMPA 受体对强化行为的贡献 可卡因诱发 MSN 兴奋性突触的可塑性。中心假设是功能上不同的 皮质边缘和丘脑突触在 NAc 中的 PV-FSI 上支持可卡因诱发的适应 强化行为和电路功能。目标 1 旨在确定刺激机制和 可卡因诱发 NAc PV-FSIs 上特定兴奋性输入的突触可塑性。目标 2 将确定角色 NAc PV-FSIs 上的谷氨酸信号传导以输入特定方式调节强化行为。 并且，目标 3 将阐明 NAc PV-FSI AMPA 受体对可卡因诱导的 MSN 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理解 NAc PV-FSI 微电路的组织，揭示了 PV-FSI 适应刺激的突触机制 支持强化行为以及影响可卡因引起的输出电路重组。到 结合全细胞膜片钳电生理学、急性限制药物来实现这些目标 将使用束缚（DART）药理学、光遗传学、强化行为和转基因小鼠。这 拟议的研究具有创新性，因为它代表了对现状的新的实质性偏离 将重点转移到 PV-FSI 前馈抑制的调节上，作为 NAc 功能的主调节器，从而 与奖励相关的行为。完成本提案中的工作将：（1）建立可塑性机制 PV-FSI 上的特定兴奋性输入。 (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 受体对于可卡因- MSN 兴奋性突触的诱发可塑性。这项工作的完成预计将产生积极的转化 通过检查奖励系统中未被充分研究但不可或缺的组成部分来评估影响，并将提供启动 制定预防和治疗药物滥用障碍的新策略的要点。