Experience-Dependent Regulation of Reward Learning and Addiction Vulnerability

项目摘要 压力大的生活事件会导致成瘾和其他精神疾病的风险增加，而日常锻炼可能 有助于减少成瘾的易感性和减轻压力的影响。激励的不适应性归因 与奖励相关的环境线索，如成瘾药物或可口的食物，被认为是显着的， 驱动线索引起的渴望和复发，成瘾性疾病的核心症状之一。然而，压力和 运动差异调节奖励学习过程，驱动激励价值分配， 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励学习机制和规则的影响。 腹侧被盖区（VTA）的多巴胺神经元在奖赏学习中起着重要作用。这些 神经元在重复的线索-奖励配对过程中获得对奖励-预测线索的瞬时爆发响应， 从而为这些线索分配激励值。我们以前曾描述过NMDA的赫布可塑性 受体介导的多巴胺能传递到多巴胺神经元，这可能部分有助于 条件爆发反应的获得。利用老鼠，这项提议将检验压力和 日常锻炼将对NMDA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如何调节 线索奖励学习的幅度、速率和时间依赖性。在目标2中，我们将确定 促肾上腺皮质激素释放因子（CRF）和去甲肾上腺素（NE）的作用，两种主要的应激介质 反应，调节线索奖励学习和NMDA可塑性。在这两个目标中，我们还将研究 精神兴奋剂安非他明的影响，它导致大脑中NE的大量释放，是一种良好的- 并发非药物成瘾的已知风险因素。在目标3中，我们将问如何每天 跑步经验会影响学习和可塑性，从而抵消压力的影响， 在前两个目标中检查的安非他明。去甲肾上腺素能神经递质活性的化学发生学调控 投射到VTA的神经元，以及用微透析测量VTA中的NE水平， 进一步探索去甲肾上腺素能信号传导的作用。该项目将允许确定 可塑性机制，可能有助于压力和运动对成瘾的相反影响 脆弱性，并可能导致新的预防战略，成瘾的高风险个人。

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.