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
• 负责人: Brad Alan Grueter
• 金额: $ 47.8万
• 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/10675558
• 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; Learning; Long-Term Depression; Mediating; Medical; Memory; Mission; Molecular; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Opsin; Organizational Productivity; 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; 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.

项目总结 物质使用障碍(SODS)仍然是一个医疗和社会负担，预防和治疗相对匮乏 治疗方案。伏隔核(NAC)是整合认知、语境、感觉的重要中枢 并将情感信息转化为行为结果。大鼠兴奋性(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 以肥皂泡为代表。然而，在输入的特殊性、时间动态、机制(S)和 可塑性和药物诱导可塑性对小白蛋白表达快峰型中间神经元的影响 (PV-FSIS)仍然存在。长期目标是了解NAC电路的中介机制 强化的行为。该应用程序的总体目标是：(1)定义特定于输入的可塑性机制 控制Pv-FSIS的兴奋性突触强度，(2)阐明它们的作用机制 突触与强化行为，以及(3)确定NAC PV-FSI AMPA受体对 可卡因诱导的MSN兴奋性突触的可塑性。中心假设是功能不同的 NAC内皮质边缘和丘脑与PV-FSIS的突触支持可卡因诱导的适应 加固行为和电路功能。目标1旨在确定刺激和 可卡因诱发的NAC PV-FSIS上特定兴奋性输入的突触可塑性。目标2将决定角色 NAC PV-FSIS上的谷氨酸能信号以一种特定的输入方式调节增强行为。 并且，目标3将阐明NAC PV-FSI AMPA受体在可卡因诱导的MSN可塑性中的作用。 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-FSIS适应刺激的突触机制 并支持强化行为，并影响可卡因诱发的输出回路重组。至 要实现这些目标，结合全细胞膜片钳电生理学、药物的严格限制 将使用栓系(DART)药理学、光遗传学、强化行为和转基因小鼠。这个 拟议的研究是创新的，因为它代表了对现状的新的和实质性的偏离， 将焦点转移到作为NAC功能的主调节器的PV-FSI前馈抑制的调制上，从而 与奖励相关的行为。完成本提案中的工作将：(1)在 PV-FSIS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，以及(3)表明NAC PV-FSI AMPA受体是可卡因- 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翻译 通过审查奖励制度未得到充分研究但不可或缺的组成部分产生的影响，并将提供 为制定预防和治疗药物使用障碍的新战略指明了方向。