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
• 负责人: Brad Alan Grueter
• 金额: $ 6.2万
• 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: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923260
• 关键词: Acute; Address; Affective; Animal Model; Animals; Behavior; Behavioral; Brain; Brain region; CNR1 gene; Cannabinoids; Characteristics; Cocaine; Cognitive; Communication; Complex; Data; Development; Disease; Dopamine D2 Receptor; Drug Addiction; Drug Exposure; Drug abuse; Electrophysiology (science); Emotional; Endocannabinoids; Equilibrium; Exposure to; Feedback; Frequencies; Gene Transfer; Glutamates; Goals; Grant; Hippocampus (Brain); Human; Illicit Drugs; Inhibitory Synapse; Interneurons; Knowledge; Learning; Mediating; Mediator of activation protein; Medical; Membrane; Mental Depression; Mission; Modification; Molecular; Motivation; Mus; National Institute of Drug Abuse; Negative Reinforcements; Neuromodulator; Neurons; Nucleus Accumbens; Output; Parvalbumins; Pattern; Pharmaceutical Preparations; Pharmacology; Play; Positive Reinforcements; Pre-Clinical Model; Predisposition; Preparation; Prevention; Process; Production; Property; Protocols documentation; Publishing; Receptor Signaling; Regulation; Research; Rewards; Role; Self Stimulation; Sensory; Shapes; Signal Transduction; Slice; Synapses; Synaptic Membranes; Synaptic Transmission; System; Techniques; Testing; Therapeutic; Time; Transgenic Mice; United States National Institutes of Health; Vanilloid; Viral; Work; addiction; awake; behavioral outcome; design; drug of abuse; endocannabinoid signaling; endogenous cannabinoid system; experience; improved; in vivo; insight; learned behavior; motivated behavior; neural circuit; neuronal excitability; novel strategies; optogenetics; prevent; receptor; recruit; synaptic function; therapeutic target; tool; translational impact

PROJECT SUMMARY Drug abuse and addiction 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 synaptic function in the NAc is a leading molecular mechanism by which illicit drug exposure leads to the behavioral manifestations represented by addiction. While excitatory synaptic connections drive NAc neuronal firing, inhibitory synaptic transmission is important for coordinating and constraining neuronal excitability. Our work focuses on mechanisms of communication between NAc parvalbumin expressing fast-spiking interneurons (PV-FSIs) and specific medium spiny neuron subtypes (MSNs; D1 or D2 dopamine receptor expressing) in the NAc core. PV-FSIs, although limited in number, make vast inhibitory connections to MSNs thereby greatly influencing NAc output. Thus, PV- FSI synaptic activity is a putative mediator of NAc circuit adaptations. Changes in NAc excitatory and inhibitory circuit dynamics or the balance between excitation and inhibition, likely underlie addiction behaviors. Indeed, we find that manipulation of these PV-FSIs in the NAc modulate drug-related behaviors. Our data suggests that the strength of PV-FSI to MSN inhibitory synapses can be suppressed by endocannabinoid (eCB) signaling through cannabinoid receptor 1 (CB1R) and transient receptor potential vanillod 1 (TRPV1). We hypothesize that NAc PV-FSIs and MSNs communicate bi-directionally via the eCB system to regulate inhibitory synaptic function on MSNs underlying NAc-related behaviors and exposure to drugs of abuse leads to dysregulation of this process. In this grant, we will characterize the precise mechanisms by which PV-FSIs and eCB signaling at PV-FSI to MSN synapses mediate these actions. We will identify signaling mechanisms that alter synaptic strength at synapses onto NAc D1 or D2 MSNs using rigorous electrophysiological, optogenetic, and behavioral approaches in combinations of transgenic mouse lines. In turn, we will apply these protocols used to identify mechanisms of plasticity ex vivo to awake/behaving animals to determine behavioral responding. Furthermore, we will determine if manipulation of this signaling can regulate behavioral responding to drugs of abuse. The contribution of the proposed research is expected to be advancement in our knowledge of mechanisms by which PV-FSIs and more specifically, eCB signaling at PV-FSIs to MSN synapses, remodel NAc excitatory and inhibitory synaptic activity patterns and membrane firing properties, and the contribution this process likely plays in addiction-related disorders. These studies will identify mechanisms which can be exploited for the development of improved therapeutic tools for treating addiction.

项目摘要 药物滥用和成瘾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。 NAC中兴奋性突触功能的变化是 非法药物暴露导致所代表的行为表现的主要分子机制 通过成瘾。兴奋性突触连接驱动NAC神经元射击，而抑制性突触传播 对于协调和约束神经元兴奋性很重要。我们的工作重点是 NAC白蛋白表达快速刺激性中间神经元（PV-FSI）与特定介质之间的通信 NAC核中的刺神经元亚型（MSN； D1或D2多巴胺受体表达）。 pv-fsis，不过 数量有限，与MSN建立巨大的抑制作用，从而极大地影响了NAC输出。因此，PV- FSI突触活动是NAC电路适应的推定介体。 NAC兴奋性和抑制性的变化 电路动力学或激发与抑制之间的平衡，可能是成瘾行为的基础。的确， 我们发现在NAC调制药物相关的行为中对这些PV-FSI的操纵。我们的数据建议 内源性大麻素（ECB）可以抑制PV-FSI对MSN抑制突触的强度 通过大麻素受体1（CB1R）和瞬态受体电位Vanillod 1（TRPV1）的信号传导。我们 假设NAC PV-FSI和MSN通过欧洲央行系统进行双向交流以调节 NAC相关行为的MSN抑制性突触功能和暴露于滥用铅的药物 为此过程失调。在这笔赠款中，我们将表征PV-FSI的精确机制 MSN突触的PV-FSI的欧洲央行信号传导介导了这些动作。我们将确定信号机制 通过严格的电生理学，会改变突触时突触上突触的突触强度， 转基因小鼠系组合中的光遗传学和行为方法。反过来，我们将应用这些 用于确定可塑性机制的协议，以清醒/行为动物以确定行为 回应。此外，我们将确定对该信号的操纵是否可以调节行为响应 滥用药物。拟议研究的贡献预计将是我们所知的进步 PV-FSI，更具体地说，PV-FSIS在MSN突触，重塑的机制，更具体地说的ECB信号传导 NAC兴奋性和抑制性突触活动模式和膜发射特性，以及贡献 这个过程可能会在与成瘾有关的疾病中发挥作用。这些研究将确定可以是 利用用于开发改进的治疗成瘾的治疗工具。