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 消极的经历通过改变情绪状态、决策和行为来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， 具有临床相关性，因为它们通常被描述为复发的主要触发因素。同样，负面的经历 会引发或加重抑郁症等情绪障碍。为了制定办法， 这些负面经验的有害影响，关键是要了解神经机制， 厌恶性刺激影响动机。几十年的研究表明，核神经元（NAc）是一个关键， 情感过程影响行为的区域。因此，重要的是要了解负面经历如何 影响中脑边缘多巴胺信号传导以及对动机行为的影响。我们实验室的研究 表明，厌恶性刺激促进吸毒，也减少了脑桥核多巴胺。的 这个建议的中心假设是，负面的经历会减少中脑多巴胺， 这种减少导致我们在接触厌恶性物质后看到的动机行为增加， 刺激。 目的1将测试厌恶诱导的多巴胺变化改变逃避行为的必要性和充分性。 我们实验室的初步数据表明，大鼠会执行一个操作性反应，以终止一个厌恶的白色 噪声我将使用光遗传学来操纵多巴胺的释放，以模拟和抵消典型的白色 噪音引起的多巴胺减少目的2将检验厌恶诱发多巴胺的必要性和充分性 减少以改变吸毒行为。我们的初步数据表明，白色噪音既减少多巴胺， 增加吸毒。该实验将利用化学遗传学和光度学来操纵和测量细胞。 测量药物自我给药期间多巴胺的释放。目标3将检验既往慢性变量的影响 强调对厌恶刺激的敏感性。我会用光度法来描述自然产生的多巴胺 水平，然后测试慢性压力是否也会改变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的奖学金将扩大我的实验技能， 成功完成拟议的研究，以及获得专业技能，将装备我一个 博士后职位这个奖学金将帮助我实现我的最终目标，发展一个独立的 我在学术机构的一个研究项目，也允许我从事正常的教学责任。