Aversion signals in the reward system

项目摘要 令人厌恶的环境事件通过改变人们的情绪状态、决策和行为， 和动机行为。对于那些试图留在美国的物质滥用障碍患者， 禁欲，这些不幸的事件是临床相关的，因为他们经常被引用为一个主要原因， 复发为了制定防止这一复发的重要决定因素的战略，必须 描述厌恶刺激影响动机神经回路的机制。为此目的， 几十年的研究已经将中脑核（NAc）确定为关键的边缘/运动界面， 受多巴胺的高度调节，其中情感和联想奖励信息直接影响行为 输出.不幸的是，厌恶性刺激调节多巴胺信号的方式仍然很差 这一点已经得到了理解，但有几项研究得出了相互矛盾的结果。我们发现了一个厌恶信号， 厌恶引起多巴胺浓度降低，这与纹状体活动增加有关， 药物寻求这个建议的目的是确定厌恶刺激如何调节NAc多巴胺 多巴胺减少改变NAc神经元活动的信号传导和机制， 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、体内电生理学和离体切片电生理学来检查 多巴胺信号减少和纹状体活动增加对厌恶的独立贡献- 相关行为，包括药物寻求，以及奖励和惩罚敏感性。在目标1中，我们将测试 假设厌恶刺激，通过减少NAc多巴胺激活厌恶反应的亚群， 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 厌恶性刺激增加腹侧被盖区促肾上腺皮质激素释放因子（CRF）的假说 (VTA)并通过CRFR 1和GABAB受体依赖性调节Girk来减少NAc中的多巴胺 VTA DA神经元上投射到NAc壳的通道。在目标3中，我们将研究上游途径， 介导厌恶刺激对NAc多巴胺和行为的影响，并将测试β-肾上腺素受体的假设。 肾上腺素能受体调节的途径，从腹床核的终纹的腹侧被盖区代表 一条这样的路。了解厌恶性刺激如何改变NAc多巴胺信号传导以及这种改变如何 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。 包括成瘾和抑郁症。

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.