Input-specific mechanisms of drug-evoked synaptic plasticity in the ventral tegmental area

腹侧被盖区药物诱发突触可塑性的输入特异性机制

基本信息

批准号：
9902381
负责人：
Stephan Lammel
金额：
$ 34.35万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902381
关键词：
Adaptive Behaviors Addictive Behavior Address Affect Afferent Pathways Amphetamines Anatomy Behavior Behavioral Brain Cells Chemosensitization Chronic Cocaine Data Depressed mood Development Dopamine Dorsal Drug Addiction Drug Exposure Drug Targeting Drug usage Electrophysiology (science)Glutamates Health behavior Hour Hypothalamic structure Immunohistochemistry Injections Intervention Investigational Drugs Lateral Lead Learning Link Maps Medial Mediating Memory Mental disorders Methods Midbrain structure Modification Morphine Motivation Mus Nature Neurons Nicotine Nucleus Accumbens Outcome Study Pathologic Pathway interactions Persons Pharmaceutical Preparations Pharmacology Physiological Play Population Process Psychological reinforcement Research Rewards Role Signal Transduction Site Societies Synapses Synaptic Transmission Synaptic plasticity System Ventral Tegmental Area Viral addiction behavioral response conditioned place preference cost dopamine system dopaminergic neuron drug of abuse drug relapse effective therapy expectation experimental study in vivo interdisciplinary approach intraperitoneal mesolimbic system neural circuit novel optogenetics preference prevent substance abuse treatment synaptic depression theories tool transmission process treatment strategy

项目摘要

The mesolimbic dopamine (DA) system is composed of DA neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (NAc). It plays a pivotal role in reinforcement learning and is often considered the center of the brain's reward system. Drugs of abuse such as cocaine, morphine, nicotine and amphetamine have different pharmacological effects, yet they all significantly impact reward and motivation at least in part by activating the mesolimbic DA system. An important research topic over the last decade has been to elucidate how drugs of abuse induce synaptic adaptations of glutamatergic inputs on VTA DA neurons. This body of work has led to the well-accepted theory that addiction is an aberrant form of learning and memory. In particular, a single injection of cocaine induces a strong and long-lasting (> 3 weeks) potentiation of excitatory inputs on DA neurons projecting to NAc medial shell. However, so far the origin of these inputs remains unknown due to major technical limitations. In recent years, state-of-the-art combinations of viral tracing methods and optogenetic tools made it possible to fully map the functional connectivity of the mesolimbic circuitry. As the result of these efforts, the next important step in addiction research is to identify specific inputs to mesolimbic DA neurons that are susceptible to drug-evoked synaptic plasticity. We hypothesize that different inputs to the VTA participate in related but independent circuits that are differentially modulated by drugs of abuse. To assess input-specific effects of cocaine-evoked synaptic potentiation, we will employ a multidisciplinary approach combining synaptic electrophysiology, viral tracing, immunohistochemistry and in vivo and ex vivo optogenetic experiments in mice. Because drug- evoked synaptic plasticity may contribute to addictive behaviors we will also investigate if optogenetic manipulations of specific VTA afferents promote or suppress drug-adaptive behaviors (e.g., cocaine-induced locomotor sensitization, cocaine-induced conditioned place preference). Given that the VTA is a major site of action of addictive drugs, and DA neurons projecting to NAc medial shell are particularly prone to undergo long-lasting drug-evoked synaptic adaptations, selective manipulations of inputs to these cells will provide a more comprehensive understanding of the precise nature of circuit remodeling caused by addictive drugs. Outcomes of this study may reveal important information for the development of more effective treatments of substance abuse and other mental disorders.

中脑边缘多巴胺（DA）系统由腹侧被盖区的 DA 神经元组成（VTA）投射到伏隔核（NAc）。它在强化学习中发挥着关键作用通常被认为是大脑奖励系统的中心。滥用药物，例如可卡因、吗啡、尼古丁和安非他明的药理作用不同，但它们都至少部分通过激活中脑边缘 DA 系统来显着影响奖励和动机。过去十年的一个重要研究课题是阐明滥用药物如何诱发 VTA DA 神经元上谷氨酸能输入的突触适应。这项工作导致一种广为接受的理论，即成瘾是学习和记忆的一种异常形式。特别是，单次注射可卡因会产生强烈且持久的（> 3周）投射到 NAc 内侧壳的 DA 神经元的兴奋性输入增强。然而，到目前为止由于重大技术限制，这些投入的来源仍然未知。最近几年，病毒追踪方法和光遗传学工具的最先进组合使完全绘制中脑边缘电路的功能连接图。由于这些努力的结果，成瘾研究的下一个重要步骤是确定中脑边缘 DA 神经元的特定输入容易受到药物诱发的突触可塑性的影响。我们假设不同的输入 VTA 参与相关但独立的电路，并受到药物的差异调节虐待。为了评估可卡因引起的突触增强的输入特异性效应，我们将采用多学科方法结合突触电生理学、病毒追踪、免疫组织化学以及小鼠体内和离体光遗传学实验。因为毒品—— 诱发的突触可塑性可能会导致成瘾行为，我们还将研究是否特定 VTA 传入的光遗传学操作促进或抑制药物适应性行为（例如，可卡因诱导的运动敏化、可卡因诱导的条件性位置偏好）。鉴于 VTA 是成瘾药物的主要作用部位，而 DA 神经元投射到 NAc 内侧壳特别容易经历持久的药物诱发的突触适应，对这些细胞的输入进行选择性操作将提供更全面的理解成瘾药物引起的回路重塑的精确性质。这项研究的结果可能揭示开发更有效的药物滥用治疗方法的重要信息以及其他精神障碍。