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，旨在调查成瘾障碍的潜在病理生理学，并使用这些信息来指导新疗法的开发。为了实现这一点，我计划建立啮齿动物的可卡因成瘾模型，并使用遗传、行为和神经生理学技术的组合来确定潜在的机制和确定候选的治疗策略。本研究的直接目的是确定伏隔核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，如可卡因条件性位置偏爱和线索诱导恢复的可卡因自我给药。为了补充我之前在动物行为和遗传方法方面的经验，以定向操纵神经活动，培训计划包含几个主要部分。其中第一项包括对成瘾的复杂行为模型的正式培训，以及用于监测行为动物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。这些培训部分不仅是执行拟议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学习所需的技能。与此相补充的是，旨在扩大我对一般神经生理学和成瘾神经生物学知识的培训目标，以及旨在使我为实验室管理的实际方面做好准备的培训目标。研究项目简介：伏隔核(NAC)是已知在可卡因成瘾的病理生理学中起中心作用的大脑区域，但对其内部操作知之甚少。研究这些机制需要在NAC的每个组成神经元亚型的水平上进行研究。GABA能中间神经元(GIN)代表NAC中的神经元亚型，在成瘾的背景下可能是最不被了解的，尽管这些细胞在NAC的其他部分起着关键的功能作用 大脑，并被认为受到多种神经精神障碍的影响。我们首先提出通过控制每一个主要杜松子酒亚类的活动，并测量可卡因成瘾和复发对小鼠行为模型的影响，来检验NAC中已识别的杜松子酒种群在成瘾相关行为中发挥重要作用的假设。此外，我们还建议通过记录成瘾相关行为中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在成瘾中的作用的理解，并可能导致新的治疗靶点的确定。标题为 提议：伏核GABA能中间神经元在可卡因成瘾中的功能作用特定目的：目的1：验证内侧伏核GABA能中间神经元亚群在上下文依赖性可卡因成瘾相关行为中起功能作用的假说目标2：确定伏隔内侧核GABA能中间神经元亚群在可卡因自身给药、消退和上下文诱导恢复过程中的生理放电模式

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