The Role of a Specific Epigenetic Mechanism in Cocaine-induced Drug-seeking Behav

描述（由申请人提供）：本研究提案的重点是检查组蛋白去乙酰化酶3（HDAC 3）在体内作为背景药物相关记忆形成的潜在负调节剂的作用。先前的研究表明，HDAC 3在体外分别通过与NCoR 1和14-3-3蛋白相互作用与HDAC 4和5形成多蛋白复合物。我们假设，HDAC 3与HDAC 4和/或5在体内，在海马体和神经核（NAc），易位到细胞核和去乙酰化组蛋白，抑制转录必要的长期上下文记忆的形成与可卡因诱导的条件性位置偏爱（CPP）的收购。了解HDAC亚型参与情境药物相关记忆形成将有助于理解长期记忆形成和药物寻求行为的分子机制，并可能最终导致选择性药物治疗靶向染色质修饰酶治疗药物成瘾。具体目标1。检测Hdac 3缺失对其他HDAC表达和组蛋白乙酰化的影响。假设：HDAC 3在体内与HDAC 4和5形成复合物，以促进核定位和组蛋白脱乙酰化。具体目标2。研究HDAC 3在可卡因诱导的CPP获得中的作用。假设：HDAC 3功能的丧失将显著促进可卡因诱导的CPP的获得。具体目标3。研究HDAC 3是否作为可卡因诱导的CPP获得的关键负调节因子。假设：HDAC 3和/或NCoR 1的过表达将阻止可卡因诱导的CPP的获得。研究培训计划将设计为：1）为申请人提供行为药理学技术培训，使其能够有效地研究背景药物相关记忆形成的表观遗传机制; 2）将申请人培训为独立研究者，以便他将来能够精通实验室科学家，导师和学术界的首席研究员; 3）强调负责任的研究行为，包括人道对待实验室实验和伦理数据分析中使用的动物，指导研究生和本科生，与其他博士后研究员和主要研究者建立合作关系，以及熟练的实验设计和执行。这些技能将允许申请人在他作为学术研究教授的职业生涯的下一阶段进行自己的独立调查。

DESCRIPTION (provided by applicant): The focus of this research proposal is to examine the role of histone deacetylase 3 (HDAC3) in vivo as a potential negative regulator of context-drug associated memory formation. Previous studies have shown that HDAC3 forms multi-protein complexes with HDACs 4 and 5 in vitro, via interactions with NCoR1 and 14-3-3 protein, respectively. We hypothesize that HDAC3 associates with HDACs 4 and/or 5 in vivo, in the hippocampus and nucleus accumbens (NAc), to translocate to the nucleus and deacetylates histones, repressing transcription necessary for long-term contextual memory formation associated with the acquisition of cocaine-induced conditioned place preference (CPP). Understanding the HDAC isoforms involved in context-drug associated memory formation will contribute to an understanding of the molecular mechanisms of long-term memory formation and drug-seeking behaviors and may eventually lead to selective pharmacotherapies which target chromatin modifying enzymes to treat drug addiction. Specific Aim 1. To examine the effects of Hdac3 deletion on the expression of other HDACs and histone acetylation. Hypothesis: HDAC3 forms a complex with HDAC4 and 5 in vivo to facilitate nuclear localization and histone deacetylation. Specific Aim 2. To examine the role of HDAC3 in acquisition of cocaine-induced CPP. Hypothesis: Loss of HDAC3 function will significantly facilitate the acquisition of cocaine-induced CPP. Specific Aim 3. To examine whether HDAC3 serves as a critical negative regulator of cocaine- induced CPP acquisition. Hypothesis: Over-expression of HDAC3 and/or NCoR1 will prevent acquisition of cocaine-induced CPP. The research training program will be designed: 1) for the applicant to be trained in behavioral pharmacology techniques, allowing him to effectively study epigenetic mechanisms of context-drug associated memory formation; 2) to train the applicant to be an independent investigator so he may be proficient in the future as a laboratory scientist, mentor and lead investigator in academia; and 3) to emphasize responsible conduct of research, including the humane treatment of animals used in laboratory experiments and ethical data analysis, mentoring of graduate and undergraduate students, building collaborations with other post- doctoral fellows and principal investigators and proficient design and execution of experiments. Those skills will allow the applicant to carry on independent investigations of his own during the next phase of his career as an academic research professor.