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

项目摘要/摘要 候选人：我的长期目标是成为一名独立的调查员，运行一项跨学科和 合作研究小组了解药物和药物作用的潜在机制 虐待内部/相互连接的大脑回路。具体地说，我的兴趣围绕着理解胆碱能 中间神经元(ChAT)调节中枢局部回路中烟碱型乙酰胆碱受体(NAChRs)的活性 伏核(NAC)，从而导致与奖赏相关的多巴胺信号的性别差异 有动机的行为。我在电生理学和药理学方面有很强的背景，并建议成为 接受了光遗传学、行为药理学和体内纤维光度学方面的培训，以完善我的培训。这将是 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，这是我目前第三年进行博士后研究培训。 培训：除了卡利帕里博士，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，以完成此建议。巴尼特博士是该组织的副主席和 药理学系教授，麦凯布博士是博士后办公室主任 婚外情。在委员会之外，我们已经确定了课程、研讨会和会议，以提供进一步的 技术培训、演讲经验、负责任的研究行为和必要的技能 (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、反复发作的脑部疾病，其特征是 寻求奖赏行为功能障碍。大量的工作都集中在了解神经 尽管这些研究主要集中在男性受试者身上，但这些研究并未涉及大脑奖赏回路的机制。 流行病学证据表明，妇女是特别容易患上sud的人群，然而 大脑中导致性别奖励和动机差异的机制在很大程度上是未知的。神经学 奖赏的控制依赖于NAC中受ChAT强烈调制的多巴胺的释放 通过nAChRs发出信号；这是对环境奖励信息进行编码的关键过程 可预测的线索。我的初步数据显示，在调节多巴胺释放方面存在根本的性别差异 通过nAChRs，到目前为止，还不知道这个过程是如何发生的，什么因素影响了这个效果，以及这是如何发生的 与有动机的行为有关。这项提案的总体目标是定义基于性别的电路 奖励加工中性别差异的控制机制。通过使用伏安技术以及 药理学、行为分析和活体多巴胺记录，我预计能够扩大我们的 了解ChAT对nAChR调节多巴胺释放的性别差异 奖励学习。这一拟议项目的成功完成有可能为发展提供信息 更好和更有效的药物疗法来对抗女性的神经疾病状态。

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.