Role of a medial habenula circuit and Nr4a2 in regulating cocaine action during reinstatement

内侧缰核回路和 Nr4a2 在恢复期间调节可卡因作用中的作用

• 批准号: 10231206
• 负责人: Alberto J Lopez
• 金额: $ 2.93万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-02-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231206
• 关键词: Abstinence; Address; Affect; American; Area; Automobile Driving; Behavior; Behavioral; Behavioral Model; Behavioral Paradigm; Biological Assay; California; Cells; ChIP-seq; Chronic; Cocaine; Collaborations; Complement; Cues; Data; Degree Completion; Development; Doctor of Philosophy; Dopamine; Drug Targeting; Educational process of instructing; Electrophysiology (science); Environment; Enzymes; Epigenetic Process; Exposure to; Faculty; Fellowship; Gene Expression; Gene Expression Regulation; Gene Targeting; Goals; HDAC3 gene; Habenula; Hand; Individual; Institution; Laboratories; Laboratory Study; Lead; Learning; Light; Link; Medial; Memory; Mentors; Mentorship; Methods; Modeling; Molecular; NR4A2 gene; Neurons; Nodal; Nuclear Orphan Receptor; Nucleus Accumbens; Pathway interactions; Periodicity; Pharmaceutical Preparations; Phase; Phenotype; Population; Positioning Attribute; Postdoctoral Fellow; Preparation; Process; Relapse; Research; Research Personnel; Resources; Rewards; Role; Running; Scanning; Self Administration; Signal Transduction; Substance Use Disorder; Synapses; Synaptic plasticity; Techniques; Testing; Training; Tyrosine 3-Monooxygenase; Universities; Viral Vector; Withdrawal; Work; addiction; career; cell type; cholinergic; cocaine relapse; design; designer receptors exclusively activated by designer drugs; dopamine transporter; drug of abuse; drug relapse; drug seeking behavior; epigenetic regulation; experimental study; in vivo; interest; long term memory; memory consolidation; neural circuit; neuromechanism; neuropsychiatric disorder; new therapeutic target; nicotine seeking behavior; novel; pedagogy; post-doctoral training; pre-doctoral; programs; response; reward circuitry; skills; substance use; substance use treatment; transcription factor; vector

Project Summary/Abstract Drugs of abuse are known to cause long-term changes in the synaptic plasticity of reward circuitry and, ultimately, persistent changes in behavior. Understanding the mechanisms underlying these changes is a key open question. As the reward circuitry and the learning and memory circuitry share key nodal points, new discoveries in the learning and memory field will have the potential to shed light on aspects of drug-seeking behavior. In particular, it is well established that gene expression is required for long-lasting forms of synaptic plasticity and long-term memory formation. Very recently, studies demonstrated that epigenetic regulation of gene expression during memory consolidation can modulate gene expression dynamics, resulting in surprising effects on memory formation. For example, inhibition or deletion of histone deacetylase 3 (HDAC3) in the nucleus accumbens leads to maintained expression of Nr4a2 (nuclear orphan receptor 2), correlating with cocaine- context associated memory formation. Nr4a2 is a transcription factor for tyrosine hydroxylase and the dopamine transporter, defining enzymes of dopaminergic signaling. The medial habenula (MHb), a region that highly expresses both HDAC3 and NR4A2, and its projections have recently been identified as main targets of drugs of abuse. I have already demonstrated that the MHb is engaged by cocaine-primed reinstatement of CPP and activation of the MHb induces a reinstatetement-like phenotype (Specific Aim 1). The F99 phase of this proposal will test whether Nr4a2 within the MHb is a key regulator of cocaine-primed reinstatement (Specific Aim 2.1). It will test whether epigenetic alterations induced by drugs of abuse lead to misregulation of Nr4a2 within the MHb (Specific Aim 2.2). Lastly, using a ChIP-seq approach, it will seek to identify alterations in Nr4a2 function that engage the reinstatement of drug-associated behavior (Specific Aim 2.2). The proposed project will also help the candidate, Mr. Alberto López, achieve his career goal of becoming an independent investigator at a research-focused institution. This project provides training in cutting-edge research skill, including FACS, ChIP-qPCR, and viral vectors to manipulate gene expression. Further, the proposed studies will provide professional and technical training to prepare the candidate to successfully transition to a postdoctoral position (K00) in a laboratory that studies the neural-circuitry driving drug-seeking behavior. The University of California, Irvine is an ideal environment for training towards achieving these goals. UCI is a university with 1) an intellectual environment that encourages cooperation and collaboration, 2) technical resources to perform cutting-edge research, and 3) renowned faculty that encourage pedagogical training, mentorship, and development of other necessary professional skills. The complete plan proposed here for both the F99 and K00 phases has been designed to develop an independent neurobiologist prepared for a transition to a successful postdoctoral position and, ultimately, independent tenured investigator.

项目总结/摘要 众所周知，滥用药物会导致奖赏回路突触可塑性的长期变化， 最终，行为的持续变化。理解这些变化背后的机制是一个关键 开放的问题。由于奖励回路和学习记忆回路共享关键节点， 在学习和记忆领域的发现将有可能阐明寻求毒品的各个方面， 行为特别是，已经确定的是，基因表达是突触的持久形式所必需的。 可塑性和长期记忆的形成。最近，研究表明，表观遗传调控， 记忆巩固过程中的基因表达可以调节基因表达动态，导致令人惊讶的结果。 对记忆形成的影响例如，抑制或缺失细胞核中的组蛋白脱乙酰酶3（HDAC 3）， 可卡因导致Nr 4a 2（核孤儿受体2）的表达维持，与可卡因相关。 上下文相关的记忆形成。NR 4a 2是酪氨酸羟化酶和多巴胺的转录因子， 转运蛋白，定义多巴胺能信号传导的酶。内侧缰核（MHb），一个高度 表达HDAC 3和NR 4A 2，其投射最近被确定为药物的主要靶点 虐待我已经证明，MHb通过可卡因引发的CPP恢复而参与， MHb的活化诱导恢复样表型（特异性目的1）。本提案的F99阶段 将测试MHb中的Nr 4a 2是否是可卡因引发的恢复的关键调节因子（具体目标2.1）。它 将测试滥用药物引起的表观遗传改变是否会导致MHb内Nr 4a 2的失调 （具体目标2.2）。最后，使用ChIP-seq方法，它将寻求鉴定Nr 4a 2功能的改变， 参与药物相关行为的恢复（具体目标2.2）。 拟议的项目还将帮助候选人Alberto López先生实现其职业目标， 一个研究机构的独立调查员该项目提供尖端技术培训， 研究技能，包括FACS，ChIP-qPCR和病毒载体，以操纵基因表达。此夕h 建议的研究将提供专业和技术培训，以准备候选人成功地 过渡到博士后职位（K 00），在实验室研究神经回路驱动药物寻求 行为加州大学欧文分校是实现这些目标的理想培训环境。 UCI是一所拥有1）鼓励合作与协作的智力环境，2）技术 进行尖端研究的资源，以及3）鼓励教学培训的知名教师， 指导和发展其他必要的专业技能。这里提出的完整计划， F99和K 00阶段的目的是培养一名独立的神经生物学家，为过渡做好准备 成为一名成功的博士后，最终成为一名独立的终身研究员。