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计划，旨在调查成瘾性疾病的基础病理生理学，并利用这些信息来指导新的治疗方法的开发。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、行为和神经生理学技术来确定潜在机制并确定候选治疗策略。本研究的直接目标是确定成瘾相关行为（如可卡因条件性位置偏爱和可卡因自我给药与线索诱导的恢复）中丘脑核GABA能中间神经元的生理放电模式和功能重要性。 为了补充我之前在动物行为和遗传方法方面的经验，以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。其中第一个包括成瘾的复杂行为模型和用于监测行为动物中特定中间神经元类型的神经元活动的体内神经生理学/光遗传学技术的正式培训。这些培训内容不仅是执行所提出的研究计划所必需的，而且也是在我自己的独立实验室进行未来研究所需的技能。这将通过旨在扩展我的一般神经生理学和成瘾神经生物学知识的培训目标来补充，以及旨在为实验室管理的实践方面做好准备的培训目标。研究项目描述：脑桥核（NAc）是已知的可卡因成瘾病理生理学的中心脑区，但其内部运作知之甚少。研究这些机制需要在其组成神经元亚型的水平上研究NAc。GABA能中间神经元（gIN）代表NAc中的神经元亚型，其在成瘾的背景下可能是最不了解的，尽管这些细胞在成瘾的其他部分中发挥关键的功能作用。 被认为是多种神经精神疾病的影响。我们首先提出测试的假设，即确定的gIN人群在NAc中发挥重要的功能作用，成瘾相关的行为，通过操纵活动在每个主要的gIN亚类，并测量对可卡因成瘾和复发的小鼠行为模型的影响。我们还建议通过记录成瘾相关行为期间gIN的神经元活动来进一步了解gIN的功能。这些研究将促进我们对NAc在成瘾中的功能的理解，并可能导致新的治疗靶点的鉴定。称号 建议：具体目的：目的1：检验在内侧核壳中鉴定的GABA能中间神经元亚群在情境依赖性可卡因成瘾相关行为中起功能作用的假设目的2：为了确定在可卡因自我给药、消退、和上下文诱导的恢复

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