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 负面的经历通过改变情绪状态，决策和 动机行为。对于那些试图避免滥用毒品的人，这种经验 在临床上相关，因为它们通常被描述为复发的主要触发因素。同样，负面经历 可以触发或加剧情绪障碍，例如抑郁症。为了开发保护侵害的方法 这些负面经历的有害影响，了解神经机制至关重要 厌恶刺激会影响动机。数十年的研究表明，伏隔核（NAC）是关键 情感过程影响行为的区域。因此，重要的是要了解负面经历 影响中唇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 表明厌恶刺激会促进吸毒并减少伏伏核多巴胺。这 该提议中的中心假设是负面的经历减少了中兆胺的多巴胺，这是 这种减少导致我们在厌恶性厌恶后看到的动机行为增加 刺激。 AIM 1将测试厌恶引起的多巴胺变化的必要性和充分性，以改变逃生行为。 我们实验室的初步数据表明，大鼠将执行操作响应以终止厌恶的白色 噪音。我将使用光遗传学操纵多巴胺释放以模仿和抵消典型的白色 噪声引起的多巴胺减少。 AIM 2将测试厌恶引起的多巴胺的必要性和充分性 减少改变吸毒行为。我们的初步数据表明，白噪声既降低了多巴胺，又减少 增加吸毒。该实验将利用化学遗传学和光度法来操纵和 在药物自我给药过程中测量多巴胺释放。 AIM 3将测试先前慢性变量的影响 压力对厌恶刺激的敏感性。我将使用光度法来表征天然发生的多巴胺 慢性应激后的水平，然后测试慢性应激是否也改变了对A中厌恶刺激的敏感性 惩罚范式。 我相信博士的培训和指导。罗伯特·惠勒，玛丽克·吉尔马丁和约翰·曼茨 在整个研究和培训方面，该奖学金将扩大我的实验技能 成功完成拟议的研究，并获得专业技能，使我能够为 博士后位置。因此，该奖学金将帮助我实现建立独立的最终目标 学术机构的研究计划也使我能够从事定期的教学责任。