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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

基本信息

批准号：
10442868
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
项目类别：
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/10442868
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 Glutamates Goals Incentives Individual Inositol Lead Learning Life Style Location Long-Term Potentiation Measurement Measures Mediating Mediator of activation protein Memory Mental disorders Metabotropic Glutamate Receptors Microdialysis Motivation N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Norepinephrine Palate Pharmaceutical Preparations Phase Play Predictive Value Predisposition Prevention strategy Process Rattus Regulation Relapse Rewards Risk Risk Factors Role Running Sensory Shapes Signal Transduction Slice Stimulus Stress Stressful Event Symptoms Synaptic plasticity System Testing Ventral Tegmental Area acute stress addiction antagonist base biological adaptation to stress conditioned place preference conditioning craving disorder risk dopaminergic neuron experience high risk in vivo incentive salience insight locus ceruleus structure male non-drug noradrenergic psychostimulant receptor response restraint stress social defeat synergism transmission process tripolyphosphate ward

项目摘要

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.

项目总结