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

描述(由申请人提供)：本提案描述了一个有指导的研究项目，目的是为首席研究员(PI)提供进一步的培训，以实现成功过渡到神经科学领域的独立职业。研究人员帕斯卡尔·凯瑟尔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人员在一系列电生理实验中获得培训。所描述的研究利用了斯坦福神经创新和翻译神经科学研究所(SINTN)托马斯·C·S博士和罗伯特·C·马伦卡博士实验室的独特资源。这两位导师S博士和马伦卡博士是突触传递和可塑性分析方面的专家；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为研究人员创造了一个很好的环境，让他们学习研究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。毒品成瘾是一种对个人和社会都具有重大社会和经济后果的重要疾病。尽管在潜在回路的定义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方面的进展至关重要。RIM蛋白是突触前活动区的中心成分，它将神经递质的释放协调到一个连贯的过程中，并调节大多数形式的突触前可塑性。到目前为止，对突触前神经递质释放机制在基于奖赏的学习和成瘾中的参与知之甚少。伏隔核(NAC)是中脑边缘多巴胺系统中的关键脑区，参与奖赏和基于奖赏的学习。这项拨款的总体目标是描述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。推测NAC的RIMS对于正常的突触可塑性和可卡因诱导的行为是必要的。具体目标包括：1)确定RIM1和/或2亚型在NAC中的表达；2)检测RIM1和/或2在NAC中的突触前短期和长期可塑性；3)确定RIM1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；以及4)探索BES和CPP是否需要依赖RIM1和/或2的NAC中的突触前可塑性。S博士和马伦卡博士实验室充满活力的研究环境，这位研究人员在博士后培训期间开发的独特基因模型，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，学习电生理学，并最终成功过渡到独立的神经科学职业提供了理想的环境。 公共卫生相关性：了解成瘾的分子神经生物学对于改进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联系起来。总的来说，它们有助于理解滥用药物是如何利用大脑记忆机制来创造长期的奖励记忆的。

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.