Defining the cell-type specific role of histone acetyltransferase KAT2a in nucleus accumbens D1 medium spiny neurons as a driver of cocaine use disorder

定义组蛋白乙酰转移酶 KAT2a 在伏隔核 D1 中型多棘神经元中作为可卡因使用障碍驱动因素的细胞类型特异性作用

• 批准号: 10679238
• 负责人: Soren D Emerson
• 金额: $ 4.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679238
• 关键词: Acetylation; Acetyltransferase; Acute; Address; Affect; Animals; Behavior; Bioinformatics; Brain; Cells; Chromatin; Cocaine; Cocaine use disorder; Complex; Consumption; Control Animal; Cues; DNA; DNA Packaging; DNA Structure; Data; Disease; Dopamine; Dose; Enzymes; Epigenetic Process; Event; Exposure to; FDA approved; Female; Fiber; Gene Expression; Gene Expression Regulation; Gene Transfer; Genes; Genetic Transcription; Goals; Histone Acetylation; Histone H3; Histones; Impairment; Individual; Knowledge; Link; Lysine; Maintenance; Measures; Mediating; Molecular; Motivation; Mus; Mutation; Neurons; Nuclear; Nucleosomes; Nucleus Accumbens; Output; Pharmaceutical Preparations; Pharmacotherapy; Photometry; Physiological; Play; Population; Proteins; Proteomics; Public Health; Regulation; Reinforcement Schedule; Rewards; Rodent Model; Role; Self Administration; Series; Stimulus; Substance Use Disorder; Syndrome; System; Tail; Testing; Training; Transcriptional Regulation; Viral; Withdrawal; Work; addiction; awake; behavioral economic analysis; behavioral response; cell type; cocaine exposure; cocaine related behaviors; cocaine reward; cocaine seeking; cocaine self-administration; drug induced behavior; drug of abuse; drug seeking behavior; epigenetic regulation; histone acetyltransferase; in vivo; loss of function; maladaptive behavior; male; molecular marker; mutant; neural; novel; optical imaging; overexpression; postmitotic; receptor; recruit; response; virtual

Cocaine use disorder (CUD) imposes a large burden on public health, particularly because there are no FDA- approved pharmacotherapies for the disorder. The onset and maintenance of CUD is driven by physiological and molecular changes within the brain that lead to maladaptive behavior associated with cocaine taking and seeking. A key neuronal population in this dysregulation is dopamine 1 receptor expressing medium spiny neurons (D1 MSNs) in the nucleus accumbens (NAc). These cells are activated by acute cocaine, undergo physiological and transcriptional plasticity following repeated cocaine exposure, and are recruited by cocaine- associated cues to drive drug seeking. While their causal role in drug-induced behavior has been identified, the molecular mechanisms underlying cocaine-induced dysregulation remains poorly understood. The goal of this proposal is to define how chromatin regulation – through a recently identified cocaine-induced chromatin modifying enzyme [lysine acetyltransferase 2a (KAT2a)] – is a key substrate involved in the motivation to take and seek cocaine. We present in our preliminary data a detailed series of proteomic bioinformatic studies through which we identified KAT2a as an upstream regulator of the wide-scale transcriptional dysregulation associated with cocaine exposure in the NAc of both males and females. We also show that mutations to KAT2a that impair its function only in D1 MSNs greatly impair cocaine self-administration and disrupt physiological responses in D1 MSNs. I hypothesize that KAT2a acts within NAc D1 MSNs to control cocaine self-administration and cue-induced seeking via regulating D1 MSN activity at baseline and in response to drug-associated stimuli. To address this question, I will combine cocaine self-administration in mice with viral-mediated gene transfer and optical imaging in awake and behaving animals. In Aim 1, I will define the role that KAT2a in D1 MSNs plays in motivation to consume cocaine, cocaine reward sensitivity, and cue-induced seeking. In Aim 2, I will use optical imaging to define how KAT2a alters D1 MSN activity at baseline and in response to cocaine. In Aim 3, I will define the role of KAT2a in D1 MSN responses to cocaine-associated cues in awake and behaving animals and determine how these neural dynamics relate to drug-seeking behavior. The training goals in this proposal will provide the technical and conceptual expertise necessary to investigate the transcriptional and epigenetic mechanisms underlying substance use disorder. Finally, the experimental findings will define a cell type-specific neuroepigenetic mechanism of CUD in males and females.

可卡因使用障碍 (CUD) 对公众健康造成巨大负担，特别是因为没有 FDA CUD 的发生和维持是由生理驱动的。 大脑内的分子变化导致与可卡因吸食相关的适应不良行为 这种失调中的一个关键神经元群体是表达中等刺的多巴胺 1 受体。 伏隔核 (NAc) 中的神经元 (D1 MSN) 这些细胞被急性可卡因激活，经历 重复接触可卡因后的生理和转录可塑性，并被可卡因招募 虽然它们在药物诱发行为中的因果作用已被确定， 可卡因引起的失调的分子机制仍然知之甚少。 该提案旨在定义染色质如何通过最近发现的可卡因诱导的染色质进行调节 修饰酶 [赖氨酸乙酰转移酶 2a (KAT2a)] – 是参与动机的关键底物 我们在初步数据中展示了一系列详细的蛋白质组生物信息学研究。 通过该研究，我们确定 KAT2a 是大规模转录失调的上游调节因子 我们还发现，与男性和女性 NAc 中的可卡因暴露有关。 仅在 D1 MSN 中损害其功能的 KAT2a 会极大地损害可卡因的自我给药并扰乱 D1 MSN 中的生理反应我敢说 KAT2a 在 NAc D1 MSN 中发挥作用来控制可卡因。 通过调节基线 D1 MSN 活动和响应来进行自我管理和提示诱导寻找 药物相关刺激。 为了解决这个问题，我将把小鼠的可卡因自我给药与病毒介导的基因转移结合起来 在目标 1 中，我将定义 KAT2a 在 D1 MSN 中的作用。 在目标 2 中，我将影响消费可卡因的动机、可卡因奖励敏感性和提示诱导的寻求。 使用光学成像来确定 KAT2a 如何改变基线时的 D1 MSN 活性以及对可卡因的反应。 3，我将定义 KAT2a 在 D1 MSN 对清醒和行为中可卡因相关线索的反应中的作用 动物并确定这些神经动力​​学如何与寻求药物的行为相关。 提案将提供必要的技术和概念专业知识来调查转录和 最后，实验结果将定义细胞。 男性和女性 CUD 的类型特异性神经表观遗传机制。