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.

项目概要 压力性生活事件会导致成瘾和其他精神疾病的风险增加，而日常锻炼可能会增加 有助于降低成瘾的可能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（例如成瘾药物或美味食物）的重要性 驱动线索引起的渴望和复发，这是成瘾性疾病的核心症状之一。然而，压力和 锻炼有差别地调节奖励学习过程，从而驱动激励价值的分配 人们对环境刺激仍然知之甚少。因此，当前项目的目标是确定 压力和日常锻炼对提示奖励学习的机制和规则的影响。 腹侧被盖区（VTA）的多巴胺神经元在基于奖励的学习中发挥着关键作用。这些 在重复的提示-奖励配对过程中，神经元获得对奖励预测线索的短暂爆发反应， 从而为这些线索分配激励价值。我们之前描述过 NMDA 的赫布可塑性 受体介导的谷氨酸能传递到多巴胺神经元上，这可能部分有助于 获得条件爆发反应。该提案将使用老鼠来检验压力和压力的假设 日常锻炼会对 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 提示奖励学习的幅度、速率和时间依赖性。在目标 2 中，我们将确定差异 促肾上腺皮质激素释放因子（CRF）和去甲肾上腺素（NE）这两种主要的压力介质的作用 反应，调节提示奖励学习和 NMDA 可塑性。为了这两个目标，我们还将研究 精神兴奋剂安非他明的影响，它会导致大脑中强烈的去甲肾上腺素释放，并且是一种很好的 并发非药物成瘾的已知危险因素。在目标 3 中，我们将询问每天如何 跑步经验会影响学习和可塑性，从而抵消压力和压力的影响。 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学操作 投射到 VTA 的神经元，以及通过微透析测量 VTA 中的 NE 水平，将被 进行进一步探讨去甲肾上腺素信号传导的作用。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产生相反的影响 脆弱性，并可能导致高风险人群成瘾的新预防策略。