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

中脑边缘多巴胺（DA）系统由腹侧被盖区的DA能神经元组成 (VTA)投射到丘脑核（NAc）。它在强化学习中起着举足轻重的作用 通常被认为是大脑奖励系统的中心。滥用药物，如可卡因， 吗啡、尼古丁和安非他明具有不同的药理作用，但它们都 至少部分通过激活中边缘DA系统来显着影响奖励和动机。 在过去的十年中，一个重要的研究课题是阐明药物滥用如何诱导 腹侧被盖区DA能神经元的突触适应。这一系列工作导致了 被广泛接受的理论，即成瘾是一种学习和记忆的异常形式。 特别是，单次注射可卡因诱导强烈和持久的（> 3周） 兴奋性输入对投射到NAc内侧壳的DA神经元的增强。然而到目前为止 由于重大的技术限制，这些投入的来源仍然不明。近年来， 病毒追踪方法和光遗传学工具的最新组合使得有可能 完全描绘出中脑边缘回路的功能连接。由于这些努力， 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 对药物诱发的突触可塑性敏感。我们假设，不同的输入， VTA参与相关但独立的回路，这些回路被药物 虐待为了评估可卡因诱发的突触增强的输入特异性效应，我们将采用 结合突触电生理学，病毒追踪， 免疫组织化学和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有助于成瘾行为，我们还将研究， 特定VTA传入的光遗传学操作促进或抑制药物适应性行为 (e.g.,可卡因诱导的运动敏化、可卡因诱导的条件性位置偏爱）。 鉴于腹侧被盖区是成瘾性药物的主要作用部位， 内侧壳特别倾向于经历持久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 成瘾性药物引起的电路重塑的确切性质。这项研究的结果可能 为开发更有效的药物滥用治疗方法提供重要信息 和其他精神疾病。

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.