The role of NPAS4 in drug addiction

物质使用障碍是一种以强迫性药物为特征的慢性复发性行为障碍。 不顾对个人的负面后果而寻求和使用。在吸毒过程中，有 发生在伏隔核(NAC)的持续性神经适应，这是一个与奖赏相关的大脑区域 和动力。该区域高度参与药物奖赏敏感性和学习，以及失调 会导致成瘾的多个阶段。例如，在戒除成瘾者中，复发可以通过以下方式触发 与以前的药物使用有关的环境线索，但潜在的分子和细胞机制 复发的诱因还没有被很好地理解。一种可能的机制是药物使用激活了特定的人群 负责强化行为和药物相关刺激之间联系的神经元。我们的 实验室之前已经证明，表观遗传酶，组蛋白脱乙酰基酶5(HDAC5)对可卡因至关重要 奖赏相关的学习和记忆。我们目前正在测试一种假设，即转录因子和 HDAC5的下游靶点神经元PAS结构域蛋白4(NPAS4)参与了可卡因的形成 奖赏-背景记忆通过其在NAC中特定神经元亚群中的功能来实现。NPAS4是 由谷氨酸能突触活性快速而短暂地诱导，并调节兴奋性/抑制性突触 平衡和突触传递。NPAS4还塑造神经元电路来编码学习信息，并且它 通过接触新的药物环境而强烈诱导。这份提案中列出的目标将决定细胞 NPAS4在可卡因奖赏-情境学习和记忆中的特定类型作用，以及NPAS4- 诱导NAC神经元在外部线索和可卡因奖赏体验之间的习得性联系。这些 实验采用转基因品系与尖端病毒载体构建的融合来阐明 NPAS4在药物成瘾背后的机制中。所有的分析都将在小鼠模型中进行 和非偶然药物奖励学习。南卡罗来纳医科大学是一家领先的研究中心 药物滥用领域，是进行这些实验的理想场所。另外，我的导师身份 在克里斯托弗·考恩博士的带领下，我将加强实验室技术、奖学金、职业发展方面的培训， 和道德，所有这些都是我博士前培训和后续学术研究取得成功所必需的 职业生涯。这些研究的综合实验设计和严谨的开创性应用 这些技术将提供有关NPAS4在药物学习和记忆中的作用的基本知识 奖励，并将提供重要的学习和发展机会，这将成为我的 未来在神经科学领域的职业。

Substance use disorder is a chronic, relapsing behavioral disorder that is characterized by compulsive drug seeking and use despite negative consequences to the individual. During the course of drug use, there are persistent neuroadaptations that occur in the nucleus accumbens (NAc), a brain region associated with reward and motivation. This region is highly involved in drug reward sensitivity and learning, and dysregulation contributes to multiple phases of addiction. For example, in abstinent addicts, relapse can be triggered by environmental cues associated with previous drug use, but the molecular and cellular mechanisms underlying relapse triggers are not well understood. One possible mechanism is that drug use activates specific populations of neurons that are responsible for the association between reinforced behavior and drug-associated stimuli. Our lab has previously shown that the epigenetic enzyme, histone deacetylase 5 (HDAC5), is critical for cocaine reward-related learning and memory. We are currently testing the hypothesis that a transcription factor and downstream target of HDAC5, neuronal PAS Domain Protein 4 (NPAS4), is involved in the formation of cocaine reward-context memories through its function in a specific subpopulation of neurons in the NAc. NPAS4 is induced rapidly and transiently by glutamatergic synaptic activity, and it regulates excitatory/inhibitory synapse balance and synaptic transmission. NPAS4 also shapes neuronal circuits to encode learned information, and it is induced strongly by exposure to novel drug contexts. The aims laid out in this proposal will determine the cell type-specific role of NPAS4 in cocaine reward-context learning and memory, as well as the role of NPAS4- inducing NAc neurons in the learned association between external cues and cocaine reward experiences. These experiments employ a fusion of transgenic lines with cutting edge viral vector constructs to elucidate the role of NPAS4 in the mechanisms behind drug addiction. All analyses will be performed in mouse models of contingent and non-contingent drug reward learning. The Medical University of South Carolina is a leading center in the substance abuse field and is an ideal location for performing these experiments. In addition, my mentorship under Dr. Christopher Cowan will bolster my training in laboratory techniques, scholarship, career development, and ethics, all of which are necessary for success in my predoctoral training and subsequent academic research career. The comprehensive experimental design of these studies and rigorous application of pioneering techniques will provide fundamental knowledge about the role of NPAS4 in the learning and memory of drug reward and will provide significant learning and development opportunities that will serve as a foundation for my future career in neuroscience.