Experience-Dependent Regulation of Reward Learning and Addiction Vulnerability

奖励学习和成瘾脆弱性的经验依赖性调节

• 批准号: 10579290
• 负责人: HITOSHI MORIKAWA
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579290
• 关键词: Acute; Adrenergic Receptor; Affect; Agonist; Amphetamines; Automobile Driving; Brain; Buffers; Cocaine; Corticotropin-Releasing Hormone; Cues; Dependence; Development; Exercise; Exposure to; Female; Food; Genetic; Glutamates; Goals; Incentives; Inositol; Lead; Learning; Life Style; Location; Long-Term Potentiation; Measurement; Measures; Mediating; Mediator; Memory; Mental disorders; Metabotropic Glutamate Receptors; Microdialysis; Motivation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Norepinephrine; Pharmaceutical Preparations; Phase; Play; Predictive Value; Predisposition; Prevention strategy; Process; Rattus; Regulation; Relapse; Rewards; Risk; Risk Factors; Risk Reduction; Role; Running; Sensory; Shapes; Signal Transduction; Slice; Stimulus; Stress; Stressful Event; Symptoms; Synaptic plasticity; System; Testing; Ventral Tegmental Area; acute stress; addiction; antagonist; biological adaptation to stress; conditioned place preference; conditioning; craving; disorder risk; dopaminergic neuron; experience; genetic manipulation; high risk population; in vivo; incentive salience; insight; locus ceruleus structure; male; non-drug; noradrenergic; psychostimulant; receptor; response; restraint stress; social defeat; synergism; transmission process; tripolyphosphate

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.

项目摘要 压力大的生活事件导致成瘾和其他精神疾病的风险增加，而日常运动可能 有助于降低成瘾的敏感性并减轻压力的影响。激励的适应不良归因 人们认为，与奖励相关的环境线索的显着性，例如上瘾的药物或可口的食物 驱动提示引起的渴望和复发，这是成瘾性疾病的核心症状之一。然而，压力和 行使差异调节奖励学习过程，以使激励价值分配给 环境刺激仍然知之甚少。因此，当前项目的目标是确定 压力和日常锻炼对涉及提示奖励学习的机制和规则的影响。 腹侧盖区域（VTA）中的多巴胺神经元在基于奖励的学习中起着至关重要的作用。这些 神经元在重复提示奖励配对期间获得对预测提示提示的短暂反应， 从而为这些提示分配激励价值。我们以前已经描述了NMDA的Hebbian可塑性 受体介导的谷氨酸能传播到多巴胺神经元上，可能部分有助于 收集条件爆发的响应。使用大鼠，该建议将检验压力和 日常运动将对NMDA可塑性产生相反的影响，并学习与药物/食物相关的线索的学习， 从而使日常运动缓解压力的影响。在AIM 1中，我们将询问压力暴露如何调节 提示奖励学习的规模，速率和时间依赖性。在AIM 2中，我们将确定差异 皮质激素释放因子（CRF）和去甲肾上腺素（NE）的作用，这是两个主要的应激介体 反应，调节提示奖励学习和NMDA可塑性。在这两个目标中，我们还将调查 心理刺激剂苯丙胺的影响，会导致大脑中强大的NE释放，并且是一个很好的 出现并发非药物成瘾的已知风险因素。在AIM 3中，我们将询问每天如何 跑步经验会以抵制压力和压力影响的方式影响学习和可塑性 在前两个目标中检查了苯丙胺。去肾上腺素能活性的化学发生操作 投射到VTA的神经元，以及通过微透析的VTA中NE水平的测量，将是 进行进一步探测去甲肾上腺素能信号传导的作用。该项目将允许确定 可塑性机制可能导致压力和运动对成瘾的影响 脆弱性，可能导致高风险个体成瘾的新预防策略。