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

描述（由申请人提供）：该提案描述了一个指导的研究项目，其目标是为首席研究员（PI）提供进一步的培训，以成功过渡到神经科学领域的独立职业。研究人员Pascal Kaeser博士在分子和细胞神经科学方面有很强的记录，使用了各种方法。这里描述的实验将允许研究者在一系列电生理实验中获得训练。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·霍夫博士和罗伯特·c·马伦卡博士实验室的独特资源。两位导师，S¿dhof博士和Malenka博士，是分析突触传递和可塑性的专家；此外，马伦卡博士是一位经验丰富的成瘾研究人员。他们的两个实验室共同创造了一个良好的环境，为研究者学习生理学方法，研究RIM蛋白在突触可塑性和成瘾相关行为中的作用。药物成瘾是一种对个人和社会造成重大社会和经济后果的重要疾病。尽管在对潜在回路的定义方面取得了很大进展，但更好地了解药物成瘾的神经生物学和潜在的突触变化对预防和治疗的进展至关重要。RIM蛋白是突触前活跃区的核心成分，它将神经递质释放协调到一个连贯的过程中，并介导大多数（如果不是全部）形式的突触前可塑性。迄今为止，我们对突触前神经递质释放机制在基于奖励的学习和成瘾中的作用知之甚少。伏隔核（NAc）是大脑中边缘多巴胺系统的关键区域，参与奖励和基于奖励的学习。这项拨款的总体目标是表征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，在NAc中，rim对于正常的突触可塑性和可卡因诱导的行为是必要的。具体目的是利用研究者产生的多种构成型和条件型KO小鼠，包括：1)确定哪些RIM1和/或2亚型在NAc中表达；2)：研究RIM1和/或2在NAc突触前短期和长期可塑性中的作用，3)确定RIM1和/或2在可卡因诱导的行为致敏（BeS）和条件位置偏好（CPP）中的作用，以及4)探索RIM1依赖的NAc突触前可塑性是否为BeS和CPP所必需。S¿dhof博士和Malenka博士的实验室充满活力的研究环境，在博士后培训期间由研究者开发的独特遗传模型，以及斯坦福大学的特殊资源，为研究者提供了理想的环境，可以进行这些令人兴奋的实验，学习电生理学，并最终成功过渡到神经科学的独立职业。

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.