Aversion signals in the reward system

项目总结 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 以及有动机的行为。对于有药物滥用障碍的人来说，他们试图留下来 节制，这些不幸的事件是临床相关的，因为它们经常被认为是 旧病复发。为了制定防止复发的这一重要决定因素的战略，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)是边缘/运动的关键界面， 受多巴胺的严格调控，其中情感和关联的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的方式仍然很差。 理解，几项研究产生了相互矛盾的结果。我们发现了一个厌恶信号，由 厌恶引起的多巴胺浓度降低，这与纹状体活动增加和 寻找毒品。这项建议的目的是确定厌恶刺激如何调节NAC多巴胺 信号和多巴胺减少改变NAC中神经元活动以形成的机制 行为。为了实现这一目标，该提案汇集了一个多学科团队，将在体内使用 快速扫描循环伏安法、体内电生理学和体外切片电生理学检查 多巴胺信号减少和纹状体活动增加对厌恶情绪的独立贡献- 相关行为，包括寻求毒品，以及奖惩敏感性。在目标1中，我们将测试 厌恶刺激通过NAC多巴胺的减少激活厌恶反应亚群的假说 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CRFR1和GABAB受体依赖性调节GIRK减少NAc中的多巴胺 VTA DA神经元上的通道投射到NAC壳上。在目标3中，我们将研究上游路径 调节厌恶刺激对NAC、多巴胺和行为的影响，并将检验aβ 从终纹腹侧床核到VTA的肾上腺素能受体调节通路代表 一条这样的路径。了解厌恶刺激如何改变NAC多巴胺信号以及这种改变是如何发生的 编码行为对理解和治疗一系列与应激相关的神经精神疾病具有重要意义 包括上瘾和抑郁在内的情况。

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.