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: 10612113
• 负责人: GARY S LYNCH
• 金额: $ 62.6万
• 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/10612113
• 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; 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; Repression; Rewards; Role; Signal Transduction; Slice; Social Impacts; Substance Use Disorder; Synapses; Synaptic Transmission; Testing; United States; Variant; Work; addiction; cell type; cholinergic neuron; cocaine related behaviors; cocaine seeking; 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.

项目概要 作为一种慢性神经精神疾病，成瘾与特定的分子和功能相关。 重复药物暴露引发的神经元可塑性变化导致神经元可塑性的持续变化 神经元功能和最终行为。一个强大的机制可能是这方面的基础 持久性是表观遗传学。表观遗传学（即通过改变基因表达来调节基因表达） 染色质结构没有对 DNA 序列本身进行根本改变）已被证明可以建立 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着的变化 多层次的观察（例如神经元可塑性、行为）。目前我们对它还知之甚少 表观遗传机制可以建立寻药行为的持久性特征 这些机制是否也可能涉及恢复或其他类似复发的行为。这 该提案的重点是检查可能涉及的分子和细胞机制 复职。更具体地说，我们将重点关注内侧缰核 (MHb) 在可卡因诱导的 恢复寻求毒品的行为。大多数调查 MHb 的研究都集中在尼古丁上 由于整个内侧发现了高浓度的烟碱乙酰胆碱受体 缰核-脚间核通路。最近的研究开始表明 MHb 与可卡因有关 相关行为，但 MHb 在调节可卡因寻求行为恢复中的作用 仍然很大程度上未知。事实上，MHb 很少包含在奖励电路图中。我们最近的 研究结果表明 MHb 与可卡因引发的恢复和胆碱的活性有关 MHb 中表达乙酰转移酶 (ChAT) 的神经元足以驱动恢复（Lopez 等人， 2018）。这些结果表明 MHb 是复发样行为的强大调节器， 对于理解与复发相关的大脑奖励通路具有重要意义。我们还将 检查组蛋白脱乙酰酶（称为 HDAC3）和关键 HDAC3 靶基因（称为 Nr4a2）在 MHb 依赖性药物寻求恢复。 HDAC3 是记忆形成的关键负调节因子 关联可塑性，通过抑制 Nr4a2 的表达发挥作用。 NR4A2 是一个转录 在发育过程中调节多巴胺信号传导的因素。 HDAC3 和 NR4A2 都是 在 ChAT 表达神经元内的 MHb 中高度表达，表明这些重要的调节因子 记忆过程在与 MHb 依赖性恢复相关的行为中起着核心作用。在这个 提案中，我们将检验中心假设，即 MHb 是恢复可卡因的关键调节器 - 寻找行为，并以 HDAC3/NR4A2 依赖的方式进行。顺利完成这些 研究将证明 MHb 在恢复中的关键性质，确定 MHb 的生理过程 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。