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Dopaminergic regulation of aversion-motivated behaviors

厌恶动机行为的多巴胺能调节

基本信息

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
项目类别：
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

项目摘要

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.

项目总结