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

RIM 依赖性突触可塑性在可卡因诱发行为中的作用

• 批准号: 8442946
• 负责人: Pascal Simon Kaeser
• 金额: $ 14.5万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442946
• 关键词: Antibodies; Applications Grants; Area; Behavior; Behavioral; Brain; Cocaine; Dependence; Disease; Dopamine; Drug Addiction; Electrophysiology (science); Endocannabinoids; Environment; Excitatory Synapse; Genes; Genetic Models; Goals; Grant; Individual; Injection of therapeutic agent; Institutes; Laboratories; Learning; Long-Term Depression; Measures; Mediating; Memory; Mentors; Molecular; Molecular Neurobiology; Mus; Neurobiology; Neurosciences; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Physiological; Presynaptic Terminals; Prevention; Principal Investigator; Process; Protein Isoforms; Proteins; Research; Research Personnel; Research Project Grants; Resources; Rewards; Role; Societies; Staining method; Stains; Subfamily lentivirinae; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Training; Universities; Ventral Striatum; Western Blotting; addiction; base; behavioral sensitization; career; drug of abuse; experience; improved; innovation; intraperitoneal; mesolimbic system; neurotransmitter release; post-doctoral training; postsynaptic; preference; presynaptic; public health relevance; recombinase; research study; social; translational neuroscience

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.

描述（由应用程序提供）：该提案描述了一个研究项目，目的是向主要研究者（PI）提供进一步的培训，以成功地过渡到神经科学领域的独立职业。研究者Pascal Kaeser博士使用各种方法在分子和细胞神经科学方面具有良好的记录。此处描述的实验将使研究人员可以在一系列电生理实验中获得训练。该研究描述的研究利用了斯坦福大学神经创新与翻译神经科学研究所（SINTN）的独特资源，托马斯·C·萨夫（Thomas C.Sâof）和罗伯特·C·马伦卡（Robert C. Malenka）博士的实验室中。两位导师SâDhof博士和Malenka博士是突触传播和可塑性分析的专家。此外，马伦卡博士是一位经验丰富的成瘾研究员。他们的两个实验室共同为研究人员创造了一个极好的环境，以学习研究轮辋蛋白在突触可塑性和成瘾相关行为中的作用的物理方法。吸毒成瘾是一种重要的疾病，对个人和社会产生了重大的社会和经济影响。尽管在基础电路的定义中取得了很多进展，但对药物成瘾的神经生物学和潜在的突触变化的更好理解对于预防和治疗的进展至关重要。边缘蛋白是突触前活性区域的中心成分，它们将神经递质释放到连贯的过程中，并介导大多数甚至所有形式的突触前可塑性。迄今为止，关于突触前神经递质释放机械在基于奖励的学习和成瘾中的参与知之甚少。伏隔核（NAC）是中断多巴胺系统中涉及奖励和基于奖励的学习的关键大脑区域。该赠款的总体目标是表征NAC中突触传播的边缘依赖性，并评估RIM对与成瘾相关的行为的贡献。假设在NAC中需要轮辋，以实现正常的突触可塑性和可卡因诱导的行为。使用研究者产生的多个组成型和条件的KO小鼠的具体目的包括：1）确定在NAC中表达了哪些RIM1和/或2个同工型，2）：检查RIM1和/或2的参与，在NAC前的短期短期和长期可塑性中，NAC中的长期可塑性，3）确定RIM1和/或2）2）或2） - 或2） - 或2）2）或2）或2）或2）或/或2） - （BES）和条件的位置偏好（CPP），以及4）探索BES和CPP是否需要NAC中的RIM依赖性突触前可塑性。 STO DHOF博士和Malenka博士实验室中充满活力的研究环境，这是研究人员在他的博士后培训期间开发的独特遗传模型，而斯坦福大学的非凡资源构成了研究人员的理想场所，是进行这些令人兴奋的实验的理想场所，以成功地向独立职业发展为独立的Neursoscience，以实现这些令人兴奋的实验。