Aversion signals in the reward system

奖励系统中的厌恶信号

基本信息

批准号：
10570985
负责人：
John R. Mantsch
金额：
$ 43.38万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570985
关键词：
Affect Affective Animal Model Aversive Stimulus Behavior Behavior Control Behavioral Clinical Clinical Data Cocaine Dependence Cognitive Corpus striatum structure Corticotropin-Releasing Hormone Decision Making Development Disease Dopamine Electrophysiology (science)Emotional Event Exposure to Human Individual Knowledge Life Experience Mediating Mental Depression Mental disorders Modeling Motivation Motor Neurons Norepinephrine Nucleus Accumbens Output Pathway interactions Periodicity Persons Pharmaceutical Preparations Pharmacotherapy Property Punishment Quinine Regulation Relapse Research Rewards Scanning Shapes Signal Transduction Slice Source Stress Structure of terminal stria nuclei of preoptic region Substance abuse problem Swimming System Taste Perception Testing Ventral Tegmental Area addiction behavior influence behavioral response beta-adrenergic receptor coping mechanism dopaminergic neuron drug seeking behavior effective therapy food restriction gamma-Aminobutyric Acid genetic manipulation in vivo inhibitor innovation motivated behavior multidisciplinary neural circuit neurobiological mechanism neuropsychiatry optogenetics pharmacologic prevent receptor release factor response social defeat stressor theories

项目摘要

PROJECT SUMMARY Aversive environmental events influence the daily lives of all people by altering their emotional states, decision making, and motivated behavior. For individuals with substance abuse disorders who are attempting to remain abstinent, these unfortunate events are clinically relevent, as they are frequently cited as a principle cause of relapse. In order to develop strategies to protect against this important determinant of relapse, it is essential to characterize the mechanisms through which aversive stimuli influence motivational neural circuitry. To this end, several decades of research have identified the nucleus accumbens (NAc) as a critical limbic/motor interface, heavily regulated by dopamine, where affective and associative reward information directly influence behavioral output. Unfortunately, the manner by which aversive stimuli regulate dopamine signaling remains poorly understood, with several studies producing conflicting results. We have identified an aversion signal, initiated by aversion-induced reductions in dopamine concentration, that is associated with increased striatal activity and drug seeking. The objective of this proposal is to determine how aversive stimuli regulate NAc dopamine signaling and the mechanisms through which reductions in dopamine alter neuronal activity in the NAc to shape behavior. To accomplish this objective, the proposal brings together a multi-disciplinary team that will use in vivo fast scan cyclic voltammetry, in vivo electrophysiology, and ex vivo slice electrophysiology to examine the independent contributions of reduced dopamine signaling and increased striatal activity to a panel of aversion- related behaviors, including drug seeking, and both reward and punishment sensitivity. In Aim 1 we will test the hypothesis that aversive stimuli, via reductions in NAc dopamine activate a subpopulation of aversion-responsive D2-like receptor-expressing NAc neurons to produce aversion-related behavioral responses. In Aim 2 we test the hypothesis that aversive stimuli increase corticotropin releasing factor (CRF) in the ventral tegmental area (VTA) and reduce dopamine in the NAc through a CRFR1- and GABAB receptor-dependent regulation of Girk channels on VTA DA neurons that project to the NAc shell. In Aim 3 we will examine upstream pathways that mediate the effects of aversive stimuli on NAc dopamine and behavior and will test the hypothesis that a beta adrenergic receptor-regulated pathway from the ventral bed nucleus of the stria terminalis to the VTA represents one such pathway. Understanding how aversive stimuli alter NAc dopamine signaling and how such alterations encode behavior has implications for understanding and treating a range of stress-related neuropsychiatric conditions including addiction and depression.

项目概要令人厌恶的环境事件通过改变人们的情绪状态、决策来影响所有人的日常生活和动机行为。对于患有药物滥用障碍并试图继续留在戒酒后，这些不幸的事件在临床上是相关的，因为它们经常被认为是导致戒酒的主要原因。复发。为了制定策略来防止这一重要的复发决定因素，至关重要的是描述厌恶刺激影响动机神经回路的机制。为此，几十年的研究已经确定伏隔核（NAc）是一个关键的边缘/运动界面，受到多巴胺的严格调节，情感和联想奖励信息直接影响行为输出。不幸的是，厌恶刺激调节多巴胺信号传导的方式仍然很差理解，但多项研究得出了相互矛盾的结果。我们已经识别出厌恶信号，由厌恶引起的多巴胺浓度降低，这与纹状体活动增加有关寻求药物。该提案的目的是确定厌恶刺激如何调节 NAc 多巴胺信号传导以及多巴胺减少改变 NAc 中神经元活动的机制行为。为了实现这一目标，该提案汇集了一个多学科团队，将使用体内快速扫描循环伏安法、体内电生理学和离体切片电生理学来检查多巴胺信号传导减少和纹状体活动增加对一组厌恶的独立贡献相关行为，包括寻求毒品，以及奖励和惩罚的敏感性。在目标 1 中，我们将测试假设厌恶刺激通过 NAc 多巴胺的减少激活厌恶反应亚群表达 D2 样受体的 NAc 神经元产生厌恶相关的行为反应。在目标 2 中我们测试厌恶刺激会增加腹侧被盖区促肾上腺皮质激素释放因子（CRF）的假设 (VTA) 并通过 Girk 的 CRFR1 和 GABAB 受体依赖性调节减少 NAc 中的多巴胺 VTA DA 神经元上的通道投射到 NAc 壳。在目标 3 中，我们将检查上游路径介导厌恶刺激对 NAc 多巴胺和行为的影响，并将检验 β 的假设从终纹腹侧床核到 VTA 的肾上腺素受体调节通路代表一条这样的途径。了解厌恶刺激如何改变 NAc 多巴胺信号传导以及这种改变是如何发生的编码行为对于理解和治疗一系列与压力相关的神经精神疾病具有重要意义包括成瘾和抑郁等情况。