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 由反复暴露导致的神经元可塑性变化导致持续变化 神经元功能，最终行为。一种可能是此基础的强大机制 持久性是表观遗传学。表观遗传学（即通过改变发生的基因表达的调节 染色质结构没有对DNA序列本身的根本变化）已证明可以建立 细胞功能的稳定变化。这些稳定的细胞功能变化会导致显着的变化 许多级别的观察（例如神经元可塑性，行为）。目前，我们对 可以建立寻求毒品行为的持久特征的表观遗传机制和 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的分子和细胞机制 复职。更具体地说，我们将重点关注内侧Habenula（MHB）在可卡因诱导的 恢复毒品的行为。大多数研究MHB的研究都集中在尼古丁上 由于整个内侧发现的烟碱乙酰胆碱受体的高浓度而寻求 Habenula插头核途径。最近的研究已经开始将MHB暗示可卡因 - 相关的行为，但MHB在调节可卡因的行为中的作用 仍然是未知的。实际上，MHB很少包含在奖励电路图中。我们最近 调查结果表明，MHB是由可卡因定位的恢复和胆碱活性参与的 在MHB中表达神经元的乙酰基转移酶（CHAT）足以驱动恢复原状（Lopez等，，。 2018）。这些结果表明，MHB是类似复发行为的强大调节者，它具有 了解与复发有关的大脑奖励途径的重要含义。我们也会 检查组蛋白脱乙酰基酶的作用，称为HDAC3，而Key HDAC3靶基因（称为NR4A2）在 MHB依赖于寻求药物的恢复。 HDAC3是内存形成的关键负调节器 和关联可塑性，通过抑制NR4A2的表达来起作用。 NR4A2是转录 调节发育过程中多巴胺信号的各个方面的因素。 HDAC3和NR4A2都是 在表达神经元的聊天中的MHB中高度表达，表明这些重要的调节剂 记忆过程在与MHB依赖性恢复相关的行为中具有核心作用。在这个 提案，我们将检验中心假设，即MHB是可卡因恢复的关键调节剂 寻求行为，并以HDAC3/NR4A2依赖性方式进行。这些成功完成 研究将证明MHB在恢复原处的关键性质，确定生理过程 MHB对可卡因做出反应，并确定MHB功能的关键表观遗传调节剂。