The role of NPAS4 in drug addiction

物质使用障碍是一种慢性、复发性的行为障碍，其特征是强迫性药物依赖， 寻求和使用，尽管对个人的负面影响。在吸毒过程中，有 持续的神经适应发生在脑桥核（NAc），这是一个与奖励相关的大脑区域 和动机。该区域高度参与药物奖赏敏感性和学习，以及调节障碍 会导致成瘾的多个阶段例如，在戒断成瘾者中， 环境线索与以前的药物使用，但分子和细胞机制的基础 复发的诱因还不太清楚。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 一个实验室先前已经证明，表观遗传酶，组蛋白脱乙酰酶5（HDAC 5），是可卡因的关键 奖励相关的学习和记忆。我们目前正在验证一个假设，即转录因子和 HDAC 5的下游靶点神经元PAS结构域蛋白4（NPAS 4）参与可卡因的形成 通过其在NAc中特定神经元亚群中的功能来实现奖励背景记忆。NPAS 4是 由突触能活动迅速和短暂地诱导，并调节兴奋性/抑制性突触 平衡和突触传递。NPAS 4还可以塑造神经元回路，对学习信息进行编码， 是由暴露于新的药物环境强烈诱导的。该提案中提出的目标将决定该小组 NPAS 4在可卡因奖励背景学习和记忆中的类型特异性作用，以及NPAS 4- 诱导NAc神经元在外部线索和可卡因奖励经验之间的学习关联。这些 实验采用转基因系与最新病毒载体构建体的融合来阐明 NPAS 4在药物成瘾背后的机制。所有分析均将在偶然的小鼠模型中进行。 和非偶然的药物奖励学习。南卡罗来纳州的医科大学是一个领先的中心， 药物滥用领域，是进行这些实验的理想场所。此外，我的导师 在克里斯托弗科万博士的领导下，我将在实验室技术、学术、职业发展 和道德，所有这些都是必要的成功，在我的博士前培训和随后的学术研究 事业这些研究的综合性实验设计和严谨性应用具有开创性 这些技术将提供关于NPAS 4在药物治疗的学习和记忆中的作用的基础知识。 奖励并将提供重要的学习和发展机会，这将成为我的基础 神经科学的未来

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.