Function of RIM-dependent Synaptic Plasticity in Cocaine-induced Behaviors

描述（由申请人提供）：本提案描述了一个指导研究项目，其目标是为主要研究者（PI）提供进一步培训，以成功过渡到神经科学的独立职业生涯。研究人员Pascal Kaeser博士在使用各种方法的分子和细胞神经科学方面有着良好的记录。这里描述的实验将允许研究者获得一系列电生理学实验的培训。所描述的研究利用了斯坦福大学神经创新和转化神经科学研究所（SINTN）托马斯C. S？dhof和Robert C.玛伦卡两位导师S údhof博士和Malenka博士是突触传递和可塑性分析方面的专家;此外，Malenka博士是一位经验丰富的成瘾研究人员。他们的两个实验室一起为研究人员创造了一个良好的环境，以学习研究RIM蛋白在突触可塑性和成瘾相关行为中的作用的生理学方法。药物成瘾是一种对个人和社会具有重大社会和经济后果的重要疾病。虽然在定义潜在回路方面取得了很大进展，但更好地理解药物成瘾的神经生物学和潜在的突触变化对于预防和治疗的进展至关重要。RIM蛋白是突触前活动区的核心成分，其将神经递质释放协调成连贯的过程，并介导大多数（如果不是所有）形式的突触前可塑性。到目前为止，很少有人知道突触前神经递质释放机制在奖励为基础的学习和成瘾的参与。中脑边缘核（NAc）是中脑边缘多巴胺系统的一个关键区域，参与奖励和基于奖励的学习。这项资助的总体目标是描述NAc中突触传递的RIM依赖性，并评估RIM对成瘾相关行为的贡献。据推测，RIM是必要的NAC正常突触可塑性和可卡因诱导的行为。利用研究者产生的多个组成型和条件性KO小鼠的具体目的包括：1）确定哪些RIM 1和/或2亚型在NAc中表达，2）：检查RIM 1和/或2在NAc中突触前短期和长期可塑性中的参与，3）确定RIM 1和/或2在可卡因诱导的行为敏化（BeS）和条件性位置偏爱（CPP）中的参与，（4）探讨BeS和CPP是否需要RIM依赖的NAc突触前可塑性。Malenka博士的实验室充满活力的研究环境，研究人员在博士后培训期间开发的独特遗传模型，以及斯坦福大学的特殊资源，为研究人员进行这些令人兴奋的实验提供了理想的环境，学习电生理学，并最终成功过渡到神经科学的独立职业生涯。 公共卫生相关性：了解成瘾的分子神经生物学对于改善这种疾病的预防和治疗至关重要。这项拨款提案中概述的实验将允许将成瘾的关键大脑区域中特定形式的突触可塑性与可卡因诱导的行为相关联。总的来说，它们有助于理解滥用药物如何利用大脑记忆机制来创造持久的奖励记忆。

DESCRIPTION (provided by applicant): This proposal describes a mentored research project with the goal of providing further training to the principal investigator (PI) to achieve a successful transition into an independent career in Neuroscience. The investigator, Dr. Pascal Kaeser, has a strong track record in molecular and cellular neuroscience using a variety of approaches. The experiments described here will allow the investigator to obtain training in an array of electrophysiological experiments. The research described makes use the unique resources at the Stanford Institute for Neuro-Innovation and Translational Neuroscience (SINTN) in the laboratories of Dr. Thomas C. S¿dhof and Dr. Robert C. Malenka. The two mentors, Dr. S¿dhof and Dr. Malenka, are experts in the analysis of synaptic transmission and plasticity; moreover, Dr. Malenka is an experienced addiction researcher. Together, their two laboratories create an excellent environment for the investigator to learn physiological approaches for studying the role of RIM proteins in synaptic plasticity and addiction-related behaviors. Drug addiction is an important disease with major social and economical consequences for the individual and the society. Although much progress was made in the definition of the underlying circuits, a better understanding of the neurobiology of drug addiction and the underlying synaptic changes is critical to progress in prevention and treatment. RIM proteins are central components of presynaptic active zones that orchestrate neurotransmitter release into a coherent process and mediate most if not all forms of presynaptic plasticity. To date very little is known about the participation of the presynaptic neurotransmitter release machinery in reward-based learning and addiction. The nucleus accumbens (NAc) is a key brain area in the mesolimbic dopamine system that is involved in reward and reward-based learning. The overall goal of this grant is to characterize the RIM-dependence of synaptic transmission in the NAc, and to assess RIM's contribution to addiction-related behaviors. It is hypothesized that RIMs are necessary in the NAc for normal synaptic plasticity and cocaine-induced behaviors. The specific aims, which make use of multiple constitutive and conditional KO mice generated by the investigator, include: 1) Determining which RIM1 and/or 2 isoforms are expressed in the NAc, 2): examining the involvement of RIM1 and/or 2 in presynaptic short-term and long-term plasticity in the NAc, 3) determining the participation of RIM1 and/or 2 in cocaine-induced behavioral sensitization (BeS) and conditioned place preference (CPP), and 4) exploring whether RIM-dependent presynaptic plasticity in the NAc is required for BeS and CPP. The vibrant research environment in the laboratories of Dr. S¿dhof and Dr. Malenka, the unique genetic models that were developed by the investigator during his postdoctoral training, and the exceptional resources at Stanford University form an ideal setting for the investigator to perform these exciting experiments, to learn electrophysiology and, ultimately, for a successful transition into an independent career in Neuroscience. PUBLIC HEALTH RELEVANCE: Understanding the molecular neurobiology of addiction is crucial for improving prevention and treatment of this disease. The experiments outlined in this grant proposal will allow correlating specific forms of synaptic plasticity in a key brain area of addiction with cocaine-induced behaviors. At large, they help understanding how drugs of abuse utilize the brains memory mechanisms to create long-lasting memories of reward.