Experience-Dependent Regulation of Reward Learning and Addiction Vulnerability

项目摘要 紧张的生活事件会增加上瘾和其他精神疾病的风险，而日常锻炼可能会 帮助减少对上瘾的敏感性，减轻压力的影响。激励的非适应性归因 人们认为，对与奖励相关的环境线索的重视，比如上瘾的药物或美味的食物 驾驶提示诱导的渴望和复发，这是成瘾障碍的核心症状之一。然而，压力和压力 练习不同地调节激励价值分配的奖励学习过程 环境刺激仍然知之甚少。因此，当前项目的目标是确定 压力和日常锻炼对线索-奖赏学习机制和规则的影响。 腹侧被盖区(VTA)的多巴胺神经元在基于奖赏的学习中起着关键作用。这些 在重复的线索-奖励配对过程中，神经元获得对奖励预测线索的瞬时爆发反应， 从而为这些提示分配激励值。我们之前已经描述了NMDA的Hebbian可塑性 受体介导的谷氨酸能传递到多巴胺神经元，这可能在一定程度上有助于 获得条件性爆发反应。在老鼠身上，这项提议将检验压力和压力 日常锻炼会对NMDA的可塑性和药物/食物相关线索的学习产生相反的影响， 从而使日常锻炼能够缓冲压力的影响。在目标1中，我们将询问压力暴露是如何调节的 线索-奖赏学习的大小、速度和时间依赖性。在目标2中，我们将确定差值 促肾上腺皮质激素释放因子和去甲肾上腺素在应激反应中的作用 反应，在调节线索-奖赏学习和NMDA可塑性。在这两个目标中，我们还将调查 精神刺激剂苯丙胺的影响，它会导致大脑中强烈的NE释放，是一种很好的- 已知的并发非药物成瘾的危险因素。在目标3中，我们将询问如何每天 跑步经验会影响学习和可塑性，这种影响可以抵消压力和 安非他明在前两个目标中进行了检查。去甲肾上腺素能活性的化学遗传调控 投射到VTA的神经元，连同用微透析测量VTA中去甲肾上腺素的水平，将被 进一步探讨去甲肾上腺素能信号转导的作用。该项目将允许确定 压力和运动对成瘾产生相反影响的可塑性机制 这可能会导致针对高危人群成瘾的新的预防策略。

Project Summary Stressful life events lead to increased risk of addiction and other psychiatric disorders, while daily exercise may help reduce susceptibility to addiction and mitigate the influence of stress. Maladaptive attribution of incentive salience to environmental cues associated with rewards, such as addictive drugs or palatable foods, is thought drive cue-induced craving and relapse, one of the core symptoms of addictive disorders. Yet, how stress and exercise differentially regulate the reward learning processes that drive assignment of incentive value to environmental stimuli remains poorly understood. Thus, the goal of the current project is to determine the impact of stress and daily exercise on the mechanisms and rules governing cue-reward learning. Dopamine neurons in the ventral tegmental area (VTA) play a critical role in reward-based learning. These neurons acquire transient bursting responses to reward-predicting cues during repeated cue-reward pairing, thereby assigning incentive value to those cues. We have previously described Hebbian plasticity of NMDA receptor-mediated glutamatergic transmission onto dopamine neurons that may, in part, contribute to the acquisition of conditioned bursting responses. Using rats, this proposal will test the hypothesis that stress and daily exercise will exert opposing influences on NMDA plasticity and learning of drug/food-associated cues, thus enabling daily exercise to buffer the impact of stress. In Aim 1, we will ask how stress exposure regulates the magnitude, rate, and timing dependence of cue-reward learning. In Aim 2, we will determine the differential roles of corticotropin-releasing factor (CRF) and norepinephrine (NE), two major mediators of stress responses, in regulating cue-reward learning and NMDA plasticity. In these two aims, we will also investigate the influence of the psychostimulant amphetamine, which causes robust NE release in the brain and is a well- known risk factor for the development of concurrent non-drug addictions. In Aim 3, we will ask how daily running experience affects learning and plasticity in a manner that counteracts the effects of stress and amphetamine examined in the first two aims. Chemogenetic manipulations of the activity of noradrenergic neurons projecting to the VTA, together with measurement of NE levels in the VTA with microdialysis, will be performed to further probe the role of noradrenergic signaling. This project will allow determination of a plasticity mechanism that may contribute to the opposing effects of stress and exercise on addiction vulnerability and may lead to new preventive strategies for addiction in high-risk individuals.