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

烟碱乙酰胆碱受体调节局部伏隔核回路潜在动机的胆碱能调节的性别差异

• 批准号: 10337248
• 负责人: Lillian J. Brady
• 金额: $ 10万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337248
• 关键词: Acetylcholine; Advisory Committees; Behavior; Behavioral; Biological Factors; Brain; Brain Diseases; Cells; Chronic; Consumption; Cues; Data; Development; Doctor of Philosophy; Dopamine; Electrophysiology (science); Epidemiology; Exhibits; Female; Fiber; Functional disorder; Goals; Human; Interneurons; Intervention; Laboratories; Learning; Link; Mediating; Mediation; Mediator of activation protein; Motivation; Mus; Nicotinic Receptors; Nucleus Accumbens; Optics; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Photometry; Physiology; Play; Population; Process; Psychological reinforcement; Publications; Regulation; Research; Research Personnel; Research Training; Rewards; Rodent; Role; Running; Scanning; Self Administration; Sex Differences; Signal Transduction; Site; Slice; Substance Use Disorder; Sucrose; Synaptic Transmission; Syndrome; Techniques; Testing; Training; Ventral Tegmental Area; Vulnerable Populations; Woman; Work; base; behavioral pharmacology; behavioral response; cell type; cholinergic; drug of abuse; efficacious treatment; experience; gamma-Aminobutyric Acid; high risk; in vivo; interest; male; meetings; men; mesolimbic system; motivated behavior; nervous system disorder; neural circuit; neuromechanism; neuroregulation; neurotransmission; optogenetics; postsynaptic; preclinical study; presynaptic; professor; receptor; response; reward circuitry; reward processing; sensor; sex; skills; substance use treatment

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.

项目总结/摘要 候选人：我的长期目标是成为一名独立的调查员， 合作研究团队了解药物和药物作用的机制 滥用内部/相互连接的大脑回路。具体来说，我的兴趣是了解胆碱能 中间神经元（ChAT）调节烟碱乙酰胆碱受体（nAChRs）在局部回路中的活性。 丘脑核（NAc），从而在与奖励相关的多巴胺信号中存在性别差异 和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 光遗传学、行为药理学和体内纤维光度学的训练，使我的训练更加充实。这将 为我提供制作高影响力出版物和成功提交R 01的技能。我收到我 2017年4月获得博士学位，这是我目前博士后研究培训的第三年。 培训：除了卡利帕里博士，我还有一个学术研究专家咨询委员会，他们将 提供必要的培训和指导，以完成此提案。巴内特博士是一个 药理学系教授，McCabe博士是博士后办公室主任 按照政事在委员会之外，我们还确定了课程、研讨会和会议， 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 寻求奖励行为的障碍。大量的工作都集中在理解神经系统 大脑奖赏回路的机制，但这些研究绝大多数集中在男性受试者身上。 流行病学证据表明，妇女是特别易受SUD影响的人群， 大脑中的机制是奖励和动机的性别差异的基础，这在很大程度上是未知的。神经 奖赏的控制依赖于NAc中多巴胺的释放，而NAc受到ChAT的强烈调节 通过nAChRs发出信号;这是一个编码环境奖励信息的过程 预测线索我的初步数据显示，在调节多巴胺释放方面， 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电路 奖励处理中的性别差异机制。通过使用伏安法技术沿着 药理学、行为分析和体内多巴胺记录，我期望能够扩大我们的研究范围， 了解ChAT调节nAChR调节多巴胺释放的性别差异 奖励学习。成功完成这一拟议项目有可能告知发展 更好和更有效的药物治疗来对抗女性的神经疾病状态。