Dopaminergic regulation of aversion-motivated behaviors

厌恶动机行为的多巴胺能调节

• 批准号: 10680079
• 负责人: Elaine Grafelman
• 金额: $ 3.26万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-28 至 2026-08-27
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680079
• 关键词: Acute; Adult; Affect; Affective; American; Animals; Aversive Stimulus; Behavior; Behavioral; Brain; Cells; Chronic; Chronic stress; Cocaine; Consumption; Data; Decision Making; Disease; Dopamine; Drug Addiction; Drug Use Disorder; Educational process of instructing; Emotional; Exposure to; Fellowship; Fiber; Genetic; Goals; In Vitro; Institution; Knowledge; Learning; Link; Measurement; Measures; Mediating; Mental Depression; Mentorship; Mood Disorders; Motivation; Negative Reinforcements; Neurons; Noise; Nucleus Accumbens; Outcome; Pattern; Pharmaceutical Preparations; Photometry; Positioning Attribute; Postdoctoral Fellow; Process; Property; Punishment; Rattus; Regulation; Relapse; Research; Rewards; Role; Self Administration; Signal Pathway; Signal Transduction; Stimulus; Stress; Substance abuse problem; Technology; Testing; Training; Ventral Tegmental Area; acute stress; behavioral response; clinically relevant; cocaine seeking; experience; experimental study; illicit drug use; in vivo; motivated behavior; neurobiological mechanism; neuromechanism; optogenetics; programs; response; skills; stressor

Project Summary Negative experiences influence everyone's daily lives by altering emotional states, decision making, and motivated behavior. For those with substance abuse disorders attempting to remain abstinent, such experiences are clinically relevant as they are often described as a primary trigger to relapse. Similarly, negative experiences can trigger or exacerbate mood disorders such as depression. In order to develop ways to protect against the detrimental impact of these negative experiences, it is critical to understand the neural mechanisms by which aversive stimuli affect motivation. Decades of research has shown the nucleus accumbens (NAc) to be a key region for affective processes to impact behavior. Thus, it is important to understand how negative experiences affect mesolimbic dopamine signaling and the impact that has on motivated behaviors. Research from our lab suggests that aversive stimuli promote drug-taking and also decrease nucleus accumbens dopamine. The central hypothesis in this proposal is that negative experiences reduce mesoaccumbens dopamine and that it is this reduction which causes the increased motivated behavior we have seen following exposure to aversive stimuli. Aim 1 will test the necessity and sufficiency of aversion-induced dopamine changes to alter escape behavior. Preliminary data from our lab show that rats will perform an operant response to terminate an aversive white noise. I will use optogenetics to manipulate dopamine release to both mimic and counteract the typical white noise-induced reduction in dopamine. Aim 2 will test the necessity and sufficiency of aversion-induced dopamine reductions to alter drug-taking behavior. Our preliminary data show that white noise both reduces dopamine and increases drug-taking. This experiment will leverage chemogenetics and photometry to both manipulate and measure dopamine release during drug self-administration. Aim 3 will test the impact of prior chronic variable stress on the sensitivity to aversive stimuli. I will use photometry to characterize naturally occurring dopamine levels following chronic stress, then test if chronic stress also changes the sensitivity to aversive stimuli in a punishment paradigm. I am confident that the training and mentorship of Drs. Robert Wheeler, Marieke Gilmartin, and John Mantsch throughout the research and training aspects of this fellowship will expand on my experimental skills to successfully complete the proposed research, as well as gain professional skills that will equip me for a postdoctoral position. This fellowship will thus help me achieve my ultimate goal to develop an independent research program at an academic institution that also permits me to engage in regular teaching responsibilities.

项目摘要 负面经历通过改变情绪状态、决策和行为，影响每个人的日常生活 动机行为。对于那些试图保持禁欲的药物滥用障碍患者来说，这样的经历 在临床上是相关的，因为它们经常被描述为复发的主要触发因素。同样，消极的经历 会引发或加剧情绪障碍，如抑郁症。为了开发方法来防止 这些负面体验的有害影响，关键是要了解 令人厌恶的刺激会影响动机。数十年的研究表明，伏隔核(NAC)是 情感过程影响行为的区域。因此，重要的是要了解负面经历是如何 影响中脑边缘多巴胺信号，以及对动机行为的影响。来自我们实验室的研究 这表明，厌恶刺激促进了吸毒，也减少了伏隔核多巴胺。这个 这一提议的中心假设是，负面经历会减少中隔伏核的多巴胺，而且它是 这种减少导致了我们在接触厌恶情绪后看到的动机行为的增加 刺激物。 目标1将测试厌恶诱导的多巴胺改变改变逃避行为的必要性和充分性。 来自我们实验室的初步数据显示，老鼠将进行操作性反应，以终止厌恶的白色 噪音。我将使用光遗传学来操控多巴胺的释放，以模仿和抵消典型的白色 噪音引起的多巴胺减少。目标2将测试厌恶诱导的多巴胺的必要性和充分性。 减少以改变吸毒行为。我们的初步数据显示，白噪音可以减少多巴胺和 会增加吸毒率。这项实验将利用化学遗传学和光度学来操纵和 测量药物自我给药过程中的多巴胺释放。目标3将测试先前慢性变量的影响 强调对厌恶刺激的敏感性。我将用光度学来表征自然产生的多巴胺 慢性应激后的水平，然后测试慢性应激是否也改变了对厌恶刺激的敏感性 惩罚范式。 我相信罗伯特·惠勒博士、玛丽克·吉尔马丁博士和约翰·曼奇博士的培训和指导 在整个研究和培训方面，该奖学金将扩展我的实验技能，以 成功完成建议的研究，并获得专业技能，使我能够 博士后职位。因此，这笔奖学金将帮助我实现我的最终目标，即发展一种独立的 在一家学术机构的研究计划，也允许我从事常规的教学职责。