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）给公共卫生带来了巨大的负担，特别是因为没有FDA- 批准的药物治疗CUD的发生和维持是由生理学驱动的。 以及大脑中的分子变化，导致与可卡因服用相关的适应不良行为， 寻找在这种失调中，一个关键的神经元群体是多巴胺1受体表达的中等多刺 D1神经元（D1 MSNs）位于中脑腹外侧核（NAc）。这些细胞被急性可卡因激活， 重复可卡因暴露后的生理和转录可塑性，并被可卡因招募， 相关线索来驱动药物寻求。虽然它们在药物诱导行为中的因果作用已经确定， 可卡因诱导的失调的分子机制仍然知之甚少。的目标 这个建议是为了定义染色质调节-通过最近发现的可卡因诱导的染色质 修饰酶[赖氨酸乙酰转移酶2a（KAT 2a）] -是参与以下动机的关键底物： 寻找可卡因。在我们的初步数据中，我们提出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KAT 2a是大规模转录失调的上游调节因子， 与男性和女性NAc中的可卡因暴露相关。我们还表明，突变， 仅在D1 MSN中损害其功能的KAT 2a极大地损害可卡因自我给药，并破坏了D1 MSN中的KAT 2a。 D1 MSN中的生理反应。我假设KAT 2a在NAc D1 MSN中起作用以控制可卡因 自我管理和线索诱导的寻求通过调节D1 MSN活动在基线和响应 药物相关刺激 为了解决这个问题，我将把联合收割机可卡因自我给药与病毒介导的基因转移结合起来 和光学成像。在目标1中，我将定义KAT 2a在D1 MSN中的角色 在可卡因消费动机、可卡因奖赏敏感性和线索诱导寻求中起作用。在目标2中，我将 使用光学成像来定义KAT 2a如何改变基线处和对可卡因的响应中的D1 MSN活性。在Aim中 3、明确KAT 2a在清醒和行为状态下对可卡因相关线索的D1 MSN反应中的作用 并确定这些神经动力学如何与药物寻求行为相关。培训目标在此 建议将提供必要的技术和概念的专门知识，以调查转录和 物质使用障碍的表观遗传机制最后，实验结果将定义一个细胞 在男性和女性中CUD的类型特异性神经表观遗传机制。