Role of a medial habenula circuit and Nr4a2 in cocaine-induced reinstatement

内侧缰核回路和 Nr4a2 在可卡因诱导的恢复中的作用

• 批准号: 9261173
• 负责人: Alberto J Lopez
• 金额: $ 1.89万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2017-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261173
• 关键词: Abstinence; Acetylation; Address; Adult; Affect; Alpha Cell; Animals; Automobile Driving; Behavior; Behavioral; Clozapine; Cocaine; Data; Dominant-Negative Mutation; Drug Addiction; Drug Targeting; Engineering; Enzymes; Epigenetic Process; Exposure to; Gene Expression; Gene Expression Regulation; HDAC3 gene; Habenula; Histone H4; Impairment; Lead; Learning; Ligands; Light; Lysine; Medial; Mediating; Memory; Modeling; Molecular Genetics; Mus; Neurons; Nicotine; Nodal; Nuclear Orphan Receptor; Nucleus Accumbens; Oxides; Pathway interactions; Pharmaceutical Preparations; Process; RNA Splicing; Relapse; Rewards; Role; Signal Transduction; Synaptic plasticity; Testing; Time; Training; Tyrosine 3-Monooxygenase; Variant; Viral; Work; addiction; cell type; cocaine use; designer receptors exclusively activated by designer drugs; dopamine transporter; drug of abuse; drug relapse; drug seeking behavior; epigenetic regulation; experimental study; insight; long term memory; memory consolidation; memory process; neural circuit; overexpression; preference; promoter; receptor; response; reward circuitry; transcription factor

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. Recent work has shown that the MHb is implicated in both the acquisition and reinstatement of drug-seeking behavior. Furthermore, my preliminary data has shown that the MHb is active during the reinstatement of cocaine- associated memories. Yet, the effects that drugs of abuse have on the circuitry of the MHb and the epigenetic mechanisms that regulate its gene expression remain largely unstudied. The experiments in this proposal will address the overall hypothesis that the MHb is necessary and sufficient for reinstatement of cocaine-context memory (Specific Aim 1 and 2) in an Nr4a2-dependent manner (Specific Aim 3).

项目摘要/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， 归根结底，是行为的持续变化。理解这些变化背后的机制是 一个关键的未决问题。由于奖赏电路和学习记忆电路共享关键节点 点，学习和记忆领域的新发现将有可能阐明各方面 毒品寻觅行为的证据。特别是，众所周知，基因表达是长期需要的。 持久形式的突触可塑性和长期记忆形成。最近，研究表明， 记忆巩固过程中基因表达的表观遗传调控可以调节基因 表情动力学，对记忆的形成产生了惊人的影响。例如，抑制或 伏隔核组蛋白脱乙酰基酶3(HDAC3)的缺失导致维持表达 Nr4a2(核孤儿受体2)，与可卡因相关的记忆形成相关。Nr4a2 是酪氨酸羟化酶和多巴胺转运蛋白的转录因子，定义了 多巴胺能信号。内侧缰核(MHB)，一个高表达HDAC3和 NR4A2及其预测最近被确定为滥用药物的主要目标。近期工作 已经表明，MHB与获得和恢复寻求毒品的行为有关。 此外，我的初步数据显示，在可卡因恢复期间，MHB处于活跃状态- 相关的记忆。然而，滥用药物对MHB和MHB电路的影响 调控其基因表达的表观遗传机制在很大程度上仍未得到研究。在中国的实验 这项建议将解决总体假设，即MHB对以下方面是必要和充分的 以Nr4a2依赖的方式恢复可卡因背景记忆(特定目标1和2)(特定 目标3)。