Accumbens neuronal subtypes in addiction

描述（由申请人提供）：我的长期目标是建立一个独立的研究项目，旨在调查成瘾性疾病的潜在病理生理学，并利用这些信息指导新疗法的发展。为了实现这一目标，我计划在啮齿动物中建立可卡因成瘾模型，并结合遗传学、行为学和神经生理学技术来确定潜在的机制和确定候选的治疗策略。本研究计划的直接目标是确定伏隔核gaba能中间神经元在成瘾相关行为中的生理放电模式和功能重要性，如可卡因条件下的位置偏好和可卡因自我给药与线索诱导恢复。为了补充我之前在动物行为和遗传方法方面的经验，有针对性地操纵神经活动，训练计划包含几个主要组成部分。其中第一项包括成瘾复杂行为模型的正式训练，以及用于监测行为动物特定中间神经元类型神经元活动的体内神经生理学/光遗传学技术。这些训练内容不仅是执行所提出的研究计划所必需的，也是我未来在自己的独立实验室进行研究所需要的技能。作为补充，培训目标旨在扩展我在一般神经生理学和成瘾神经生物学方面的知识，以及为实验室管理的实际方面做好准备。研究项目描述：伏隔核（NAc）是一个已知对可卡因成瘾的病理生理起核心作用的大脑区域，但其内部运作机制尚不清楚。研究这些机制需要在每个组成神经元亚型的水平上研究NAc。gaba能中间神经元（gINs）代表了NAc中神经元的亚型，尽管这些细胞在NAc的其他部分起着关键的功能作用，但在成瘾的背景下，它可能是最不为人所知的

DESCRIPTION (provided by applicant): My long-term goal is to establish an independent research program aimed at investigating the underlying pathophysiology of addictive disorders and using this information to guide development of novel treatments. To accomplish this, I plan to model cocaine addiction in rodents and use a combination of genetic, behavioral, and neurophysiological techniques to determine underlying mechanisms and identify candidate therapeutic strategies. The immediate goal of this research proposal is to determine the physiological firing patterns and functional importance of GABAergic interneurons of the nucleus accumbens in addiction-related behaviors such as cocaine conditioned place preference and cocaine self-administration with cue-induced reinstatement. To complement my prior experience with animal behavior and genetic approaches for targeted manipulation of neural activity, the training plan contains several major components. The first of these includes formal training in complex behavioral models of addiction and in vivo neurophysiology/optogenetics techniques used to monitor neuronal activity of specific interneuron types in behaving animals. These training components are necessary not only to carry out the research plan as proposed, but also as skills required for future studies in my own independent laboratory. This will be complemented by training aims designed to expand my knowledge of general neurophysiology and the neurobiology of addiction, as well as a training aim designed to prepare me for practical aspects of laboratory management. Research Project Description: The nucleus accumbens (NAc) is a brain region known to be central to the pathophysiology of cocaine addiction, but its internal operations are poorly understood. Investigating these mechanisms requires studying the NAc at the level of each of its constituent neuronal subtypes. GABAergic interneurons (gINs) represent the subtype of neuron in the NAc that is perhaps most poorly understood in the context of addiction, despite the fact that these cells play key functional roles in other parts of the brain and are thought to be affected in multiple neuropsychiatric disorders. We first propose to test the hypothesis that identified gIN populations in the NAc play important functional roles i addiction-related behaviors by manipulating activity in each of the major gIN subclasses and measuring the effect on mouse behavioral models of cocaine addiction and relapse. We additionally propose to gain further understanding of gIN function by recording neuronal activity from gINs during addiction-related behaviors. These studies will advance our understanding of NAc function in addiction and may lead to the identification of novel therapeutic targets. Title of proposal: Functional roles of GABAergic interneurons of the nucleus accumbens in cocaine addiction Specific Aims: Aim 1: To test the hypothesis that identified GABAergic interneuron subpopulations in the medial nucleus accumbens shell play functional roles in context-dependent cocaine addiction-related behaviors Aim 2: To determine the physiological firing patterns of each GABAergic interneuron subpopulation in the nucleus accumbens during cocaine self-administration, extinction, and context-induced reinstatement