权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A circuit-driven evaluation of the use of physical activity interventions to improve binge-like ethanol drinking

对使用体力活动干预措施改善酗酒的循环驱动评估

基本信息

批准号：
10643436
负责人：
Kolter Grigsby
金额：
$ 18.55万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643436
关键词：
Acute Address Adult Alcohol consumption Alcoholic beverage heavy drinker Alcohols American Amygdaloid structure Automobile Driving Behavioral Brain Brain region C57BL/6 Mouse Cell Nucleus Chronic Complex Comprehension Consumption Darkness Development Ethanol Evaluation FOS gene Female Genetic Risk Goals Guidelines Health Health Benefit Heavy Drinking Human Immunohistochemistry Insula of Reil Interoception Intoxication Literature Maintenance Measures Medial Modeling Mus National Institute on Alcohol Abuse and Alcoholism Nucleus Accumbens Personal Satisfaction Physical activity Physiological Play Population Study Preoptic Areas Psychological reinforcement Rattus Recombinant adeno-associated virus (rAAV)Reporting Rewards Rodent Role Running Sex Differences Slice Stress System Testing Therapeutic Tracer Training Translating Ventral Tegmental Area Work acute stress alcohol effect alcohol use disorder binge drinking cost effective designer receptors exclusively activated by designer drugs drinking estrogenic exercise intervention genetic manipulation immunoreactivity improved male motivated behavior neural neural circuit neural network neuromechanism pre-clinical preference prevent sex sexual dimorphism social

项目摘要

Project Summary Physical activity (PA) is a cornerstone of human health and well-being; however, its implementation as a viable treatment and preventative option for alcohol use disorders (AUDs) remains understudied. This is underscored at the social level by the ~26% of adult U.S. citizens that report binge drinking and the mere 3% of citizens who manage to meet daily U.S. PA guidelines. The NIAAA recognizes the importance of understanding and promoting the use of PA for treating AUDs. The effects of voluntary PA on preclinical measures of excessive alcohol intake are mixed. We seek to better evaluate this relationship by addressing the role of voluntary PA in reducing binge-like ethanol drinking in a unique genetic risk model of drinking to intoxication, the High Drinking in the Dark (HDID-1) mouse line (Aim 1). Understanding and defining key stages of PA development and reinforcement may be important for determining its potential as an AUD treatment option. Chronic PA and alcohol use create neural remodeling across interconnected brain regions belonging to the mesocorticolimbic system. This neural network comprises of interoceptive brain regions – those responsible for the processing and translating the internal body state [such as the insula cortex (IC)] - aversion-related brain regions [such as the basolateral amygdala (BLA)] and brain regions important for reinforcement [i.e., the ventral tegmental area (VTA)]. Here, we plan to retrogradely trace the nucleus accumbens (NAc) - the central point of convergence for this system – and determine which neural inputs are engaged at 2- and 4-weeks of wheel-running. Prior wheel- running work has characterized cFos using slice-based immunohistochemistry, but only in male rodents. Considering stark sex differences in PA in humans and rodents, this application addresses a major gap in the literature. cFos immunoreactivity (IR) will be used in combination with a retrograde tracer (rAAV2-retro-GFP) to reliably characterize and trace the neural inputs to the NAc. We hypothesize that distinct aversion-related NAc projections (e.g. extended amygdala) will be engaged during acute wheel-running and that regions important for interoception and reinforcement (such as the IC and NAc) will be engaged following chronic PA. The IC relays relevant interoceptive information to limbic regions, such as the NAc, and influences motivated behaviors (like PA and alcohol use). Chemogenetically silencing the IC  NAc circuit has been shown to increase interoceptive effects of alcohol in rats. To determine the importance of the IC in the reinforcement of PA, we will test whether chemogenetically silencing or activating the IC  NAc circuit [using designer receptors exclusively activated by designer drugs (DREADDs)] will modulate voluntary PA at acute and chronic timepoints. We hypothesize that chemogenetically silencing the IC  NAc projection will increase acute PA (associated with aversion) and reduce chronic PA (associated with reward). In contrast, we hypothesize that chemogenetically activating the IC  NAc projection will decrease acute PA and increase chronic PA. To compliment prior alcohol work, we will to determine the importance of this circuit in PA.

项目总结