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: 10487428
• 负责人: Brad Alan Grueter
• 金额: $ 48.89万
• 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/10487428
• 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; 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.

项目摘要 药物使用障碍（SUD）仍然是医疗和社会负担，相对缺乏预防和 治疗选择。伏隔核（NAC）是一个集成认知，上下文，感觉的基本集线器 和情感信息中的行为结果。兴奋性（谷氨酸能）突触功能的变化 NAC是一种主要的分子机制，非法药物暴露导致行为表现 由泡沫代表。但是，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白细胞蛋白表达快速尖峰中间神经元的后果 （PV-FSIS）保留。长期目标是了解NAC电路介导的机制 加强行为。该应用的总体目的是：（1）定义特定的可塑性机制 控制PV-FSI的兴奋性突触强度，（2）阐明这些的机械贡献 突触的增强行为，（3）确定NAC PV-FSI AMPA受体对 可卡因诱发的MSN兴奋性突触的可塑性。中心假设是功能上的现行 NAC支持可卡因诱发的适应性的Corticolimbic和丘脑突触 增强行为和电路功能。 AIM 1旨在确定刺激的机制和 可卡因诱发的特定兴奋性输入对NAC PV-FSI的突触可塑性。 AIM 2将决定角色 谷氨酸能信号传导以输入特定方式调节加固行为，以调节加固行为。 并且，AIM 3将阐明NAC PV-FSI AMPA受体对可卡因诱导的MSN可塑性的贡献。 拟议的研究的理由是，他们将对功能提供详细的理解 NAC PV-FSI微电路的组织，揭示了PV-FSIS适应刺激的突触机制 并支持加强行为，并影响可卡因诱发的输出电路重组。到 完成这些目的是将全细胞贴片夹电生理学的组合，药物严重限制 将使用束缚（DART）药理学，光遗传学，增强行为和转基因小鼠。这 拟议的研究具有创新性，因为它代表了与现状的新事物， 将重点转移到PV-FSI进料抑制作用作为NAC功能的主要调节剂的调制，因此 与奖励相关的行为。该提案中的工作完成将：（1）在 对PV-FSI的特定兴奋性输入。 （2）在NAC PV-FSI AMPA受体之间建立因果关系 并（3）证明可卡因是必不可少的NAC PV-FSI AMPA受体，并且 MSN兴奋性突触的诱发可塑性。这项工作的完成预计将具有积极的翻译 通过检查奖励系统的研究不分之不可或缺的组成部分，并将提供启动 开发新型策略以预防和治疗药物使用障碍的目的。