Sex differences in cholinergic regulation of nicotinic acetylcholine receptor modulation of local nucleus accumbens circuitry underlying motivation

项目概要/摘要 候选人：我的长期目标是成为一名独立调查员，经营一个跨学科和 合作研究团队了解药物和药物影响的机制 滥用内部/互连的大脑回路。具体来说，我的兴趣在于了解胆碱能如何 中间神经元 (ChAT) 调节局部神经回路中烟碱乙酰胆碱受体 (nAChR) 的活性 伏隔核（NAc），因此与奖励相关的多巴胺信号传导存在性别差异 和动机行为。我在电生理学和药理学方面有很强的背景，并建议成为 我接受了光遗传学、行为药理学和体内光纤光度测定方面的培训，以完善我的培训。这将 为我提供制作高影响力出版物和成功提交 R01 的技能。我收到了我的 2017年4月获得博士学位，目前是我博士后研究训练的第三年。 培训：除了 Calipari 博士之外，我还有一个由学术研究专家组成的咨询委员会，他们将 提供必要的培训和指导来完成该提案。 Barnett 博士，副主席兼 药理学系教授，博士后办公室主任McCabe博士 事务。在委员会之外，我们还确定了课程、研讨会和会议，以提供进一步的帮助 技术培训、演讲经验、负责任的研究行为以及必要的技能 （谈判、任期、实验室管理等）过渡到独立。 研究：物质使用障碍 (SUD) 是一种慢性、复发性脑部疾病，其特征是显着的 寻求奖励行为的功能障碍。大量的工作集中在理解神经网络 大脑奖励回路的机制，但这些研究绝大多数集中在男性受试者上。 流行病学证据表明，女性是 SUD 特别易感的人群，但 奖励和动机方面存在性别差异的大脑机制在很大程度上尚不清楚。神经元 奖赏的控制取决于 NAc 中多巴胺的释放，而 NAc 受到 ChAT 的强烈调节 通过 nAChR 发出信号；对环境奖励信息进行编码至关重要的过程 预测线索。我的初步数据显示了多巴胺释放调节的根本性别差异 通过nAChRs，迄今为止，尚不清楚这一过程是如何发生的，哪些因素影响了这种效应，以及这种效应是如何发生的 与动机行为有关。该提案的总体目标是定义基于性别的特定电路 奖励处理中性别差异的机制。通过使用伏安法技术 药理学、行为分析和体内多巴胺记录，我预计能够扩展我们的研究 了解 ChAT 调节 nAChR 调节多巴胺释放的性别差异 奖励学习。该拟议项目的成功完成有可能为发展提供信息 更好、更有效的药物疗法来对抗女性的神经系统疾病状态。

Project Summary/Abstract Candidate: My long term goal is to become an independent investigator running an interdisciplinary and collaborative research team to understand the mechanisms underlying the effects of medications and drugs of abuse on intra/interconnected brain circuits . Specifically, my interests surround understanding how cholinergic interneurons (ChAT) regulate the activity of nicotinic acetylcholine receptors (nAChRs) in the local circuitry of the nucleus accumbens (NAc), thereby underlying sex differences in dopamine signaling associated with reward and motivated behavior. I have a strong background in electrophysiology and pharmacology, and propose to be trained in optogenetics, behavioral pharmacology, and in vivo fiber photometry to round out my training. This will provide me with the skills to produce high impact publications and successful R01 submissions. I received my PhD in April of 2017 and this is currently my third year of postdoctoral research training. Training: In addition to Dr. Calipari, I have an advisory committee of experts in academic research who will provide the necessary training and guidance to accomplish this proposal. Dr. Barnett, is the Vice-chair of and a Professor in the Department of Pharmacology and Dr. McCabe is the Director of the Office of Postdoctoral Affairs. Outside of the committee, we have identified, courses, seminars, and meetings to provide further technical training, presentation experience, responsible conduct in research, and the necessary skills (negotiations, tenure, laboratory management, etc.) to transition to independence. Research: Substance use disorder (SUD) is a chronic, recurring brain disease characterized by significant dysfunction in reward-seeking behavior. A large body of work has focused on understanding the neural mechanisms in the brain’s reward circuitry, yet these studies have overwhelmingly focused on male subjects. Epidemiological evidence shows that women represent a particularly susceptible population to SUD, yet the mechanisms in the brain that underlie sex differences in reward and motivation are largely unknown. The neural control of reward is dependent on dopamine release in the NAc that is subject to heavy modulation by ChAT signaling through nAChRs; a process that is essential to encoding information about environmental reward predictive cues. My preliminary data show fundamental sex differences in the regulation of dopamine release via nAChRs, yet to date, it is not known how this process occurs, what factors influence this effect, and how this relates to motivated behavior. The overall goal of this proposal is to define sex-specific circuit-based mechanisms governing sex differences in reward processing. By using voltammetry techniques along with pharmacology, behavioral analysis, and in vivo dopamine recording, I anticipate being able to expand our understanding of the sex differences in ChAT regulation of nAChR modulation of dopamine release underlying reward learning. The successful completion of this proposed project has the potential to inform the development of better and more effective pharmacotherapies to counter neurological disease states in women.