Epigenetic mechanisms in the medial habenula governing drug-seeking behavior

内侧缰核的表观遗传机制控制药物寻求行为

• 批准号: 10210374
• 负责人: GARY S LYNCH
• 金额: $ 63.75万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210374
• 关键词: Abstinence; Adult; Affect; Animals; Behavior; Binding; Brain; Brain region; Cell physiology; ChIP-seq; Characteristics; Choline O-Acetyltransferase; Chromatin Structure; Chronic; Cocaine; Cues; DNA Sequence; Data; Deacetylase; Development; Disease; Dominant-Negative Mutation; Dopamine; Drug Exposure; Drug Targeting; Epigenetic Process; Exposure to; Gene Expression; Gene Expression Regulation; Genes; HDAC3 gene; HDAC4 gene; Habenula; Histone Acetylation; Human; Knowledge; Learning; Light; Medial; Mediating; Memory; Methods; Midbrain structure; Molecular; Mus; NR4A2 gene; Nature; Neuronal Plasticity; Neurons; Nicotine Withdrawal; Nicotinic Receptors; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Physiological Processes; Physiology; Preparation; Publishing; RNA Splicing; Relapse; Rewards; Role; Signal Transduction; Slice; Social Impacts; Substance Use Disorder; Synapses; Synaptic Transmission; Testing; United States; Variant; Work; addiction; cell type; cholinergic neuron; designer receptors exclusively activated by designer drugs; drug of abuse; drug seeking behavior; drug use behavior; economic impact; epigenetic regulation; interpeduncular nucleus; memory consolidation; memory process; mutant; neuropsychiatric disorder; nicotine seeking behavior; novel; promoter; response; reward circuitry; substance use treatment; targeted treatment; transcription factor; transcriptome sequencing

Project Summary As a chronic neuropsychiatric disease, addiction is associated with specific molecular and functional neuronal plasticity changes that are triggered by repeated drug exposure leading to persistent changes in neuronal function and ultimately behavior. One powerful mechanism that may underlie aspects of this persistence is epigenetics. Epigenetics (i.e. modulation of gene expression that occurs through altered chromatin structure without fundamental changes to the DNA sequence itself) has been shown to establish stable changes in cell function. These stable changes in cell function can give rise to remarkable changes at many levels of observation (e.g. neuronal plasticity, behavior). Currently, we still know very little about the epigenetic mechanisms that could establish the persistence characteristic of drug-seeking behavior and whether such mechanisms may also be involved in reinstatement, or other relapse-like behaviors. This proposal is focused on examining the molecular and cellular mechanisms that may be involved in reinstatement. More specifically, we will focus on the role of the medial habenula (MHb) in cocaine-induced reinstatement of drug-seeking behavior. Most studies investigating the MHb have focused on nicotine seeking due to the high concentration of nicotinic acetylcholine receptors found throughout the medial habenula-interpeduncular nucleus pathway. Recent studies have begun to implicate the MHb in cocaine- associated behaviors, yet the role of the MHb in regulating reinstatement of cocaine-seeking behavior remains largely unknown. In fact, the MHb is rarely included in reward circuitry diagrams. Our recent findings demonstrate that the MHb is engaged by cocaine-primed reinstatement and the activity of choline acetyltransferase (ChAT) expressing neurons in the MHb is sufficient to drive reinstatement (Lopez et al., 2018). These results suggest that the MHb is a powerful regulator of relapse-like behaviors, which has important implications for understanding the reward pathways in the brain related to relapse. We will also examine the role of a histone deacetylase, called HDAC3, and a key HDAC3 target gene, called Nr4a2, in MHb-dependent reinstatement of drug-seeking. HDAC3 is a key negative regulator of memory formation and associative plasticity, which functions by repressing the expression of Nr4a2. NR4A2 is a transcription factor that regulates aspects of dopamine signaling during development. Both HDAC3 and NR4A2 are highly expressed in the MHb within ChAT expressing neurons, indicating these important regulators of memory processes have a central role in behaviors associated with MHb-dependent reinstatement. In this proposal, we will test the central hypothesis that the MHb is a key regulator of reinstatement of cocaine- seeking behavior, and does so in an HDAC3/NR4A2-dependent manner. Successful completion of these studies will demonstrate the key nature of the MHb in reinstatement, identify the physiological processes in the MHb responding to cocaine, and identify key epigenetic regulators of MHb function.

项目摘要 作为一种慢性神经精神疾病，成瘾与特定的分子和功能有关。 反复接触药物引发的神经元可塑性变化导致脑组织持续改变 神经元的功能和最终的行为。一种强大的机制可能是这方面的基础 持之以恒是表观遗传学。表观遗传学(即通过改变基因表达来调节基因表达 染色质结构而不对DNA序列本身进行根本改变)已被证明 细胞功能的稳定变化。细胞功能的这些稳定变化可以引起显著的变化 多层次的观察(如神经元可塑性、行为)。目前，我们仍然对此知之甚少 表观遗传机制可以建立寻求毒品行为的持续性特征和 这种机制是否也可能参与恢复或其他类似复发的行为。这 提案的重点是检查可能涉及到的分子和细胞机制 复职。更具体地说，我们将关注内侧缰核(MHB)在可卡因诱导中的作用 恢复吸毒行为。大多数调查MHB的研究都集中在尼古丁上 由于在内侧发现高浓度的烟碱型乙酰胆碱受体而寻找 缰核-脚间核通路。最近的研究已经开始证明MHB与可卡因有关- 相关行为，但MHB在调节恢复寻求可卡因行为中的作用 在很大程度上仍不为人所知。事实上，MHB很少包含在奖励电路图中。我们最近 研究结果表明，MHB通过可卡因诱导的恢复和胆碱的活性来参与 MHB中表达乙酰转移酶(ChAT)的神经元足以驱动恢复(Lopez等人， 2018年)。这些结果表明，MHB是复发类行为的强大调节器，它具有 这对于理解大脑中与复发相关的奖赏通路具有重要意义。我们还将 检验组蛋白去乙酰基酶HDAC3和关键的HDAC3靶基因Nr4a2在 依赖MHB的毒品寻觅的恢复。HDAC3是记忆形成的关键负性调节因子 以及联合可塑性，它通过抑制Nr4a2的表达发挥作用。NR4A2是一种转录 在发育过程中调节多巴胺信号的因素。HDAC3和NR4A2都是 在MHb中高表达ChAT表达的神经元，表明这些重要的调控因子 记忆过程在与MHB依赖恢复相关的行为中起着核心作用。在这 提案中，我们将检验MHB是恢复可卡因的关键调节器的中心假设- 寻找行为，并且以依赖HDAC3/NR4A2的方式进行。成功完成这些任务 研究将展示MHB在恢复过程中的关键性质，确定MHB在 MHb对可卡因的反应，并确定MHb功能的关键表观遗传调节因子。