The Impact of Early Life Stress on Reward and Body Weight

早期生活压力对奖励和体重的影响

基本信息

批准号：
10612003
负责人：
Rebecca Foright
金额：
$ 7.18万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10612003
关键词：
Affect Applications Grants Attenuated Behavior Bladder Body Weight Body Weight decreased Brain Caloric Restriction Chronic Clinical Complex Consumption Corticosterone Data Desire for food Development Dopamine Energy Intake Energy Metabolism Environment Etiology Exercise Exposure to Failure Fatty acid glycerol esters Fellowship Food Food Intake Regulation Foundations Functional disorder Genitourinary system Glucocorticoid Receptor Glucocorticoids Goals Health Homeostasis Human Hunger Hydrocortisone Hypersensitivity Impairment Individual Inflammation Intake Knowledge Maintenance Maintenance Therapy Measures Metabolic Metabolic dysfunction Metabolism Methods Motivation Mus Neonatal Neurobiology Nucleus Accumbens Obesity Outcome Pain Physical activity Physiological Processes Pre-Clinical Model Prevalence Production Publishing Rattus Regulation Research Rewards Risk Rodent Running Scientist Serum Signal Transduction Societies Stress Sucrose System Testing Training United States Ventral Tegmental Area Weight Weight Gain Work adverse childhood events behavior test brain reward regions career diet-induced obesity early experience early life stress feeding hypothalamic-pituitary-adrenal axis improved maternal separation mouse model neglect neural circuit neuronal circuitry obesity risk obesity treatment obesogenic pre-clinical programs response reward circuitry reward processing skills success sugar translational model transmission process treadmill weight loss program weight maintenance

项目摘要

PROJECT SUMMARY My long-term professional goal is to become a successful, independent scientist with a research program focused on obesity and the neurobiological regulation of feeding and activity in response to exercise. Obesity continues to be a major health concern and obesity risk is increased with exposure to early life stress. Exposure to early life stress is very common in the United States and yet we do not fully understand how early stress alters reward neurocircuitry to affect the motivation to consume palatable foods and be physically active. The reward system control of body weight relies on the inherently rewarding value of foods, particularly those high in fat and sugar, and of physical activity. Within the brain, the motivation to obtain these natural rewards is driven by dopaminergic activity in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Glucocorticoid receptors are found throughout reward regions of the brain and chronic hypercorticosteronemia, such as that associated with early life stress exposure, has been shown to inhibit dopamine release and turnover in the NAc. Additionally, one of the greatest issues facing individuals with obesity is the failure of weight loss programs to produce meaningful and sustained weight loss. It is unknown whether early life stress worsens the maintenance of lost weight or whether exercise, which is the greatest predictor of weight loss maintenance success, is effective in individuals that have experienced early life stress. Our overall hypothesis is that early life stress impairs reward processing and homeostasis of body weight, which can be partially mitigated by voluntary wheel running. We will test this overall hypothesis using neonatal maternal separation (NMS) in mice, a preclinical model of early life stress. In Aim 1, we will determine if early life stress alters reward sensitivity in response to high fat/high sucrose diet-induced obesity and calorie-restricted weight loss. We expect that NMS mice will display hypercorticosteronemia, which will be negatively associated with dopamine turnover and release in the NAc and VTA. We also anticipate that NMS mice will display altered reward motivation when challenged with behavioral tests during diet-induced obesity and weight loss. In Aim 2, we will test if early life stress potentiates weight regain and metabolic dysfunction and identify whether exercise can counter these early life stress-induced impairments. We anticipate that NMS will cause an increased rate of weight regain, inflammation, and metabolic dysfunction after being allowed to refeed ad libitum following calorie-restricted weight loss. We expect that voluntary wheel running will attenuate weight regain and metabolic dysfunction in naïve mice to a greater extent than in NMS mice. Given the increasing prevalence of both obesity and early life stress, it is highly likely that this is an interaction impacting clinical weight loss maintenance. It is vitally important to understand how early life stress alters reward motivation and weight loss maintenance success to allow for the development of improved weight loss maintenance therapies and better outcomes in obesity treatments.

项目摘要我的长期专业目标是通过研究计划成为一名成功的独立科学家专注于肥胖和对运动的喂养和活动的神经生物学调节。继续是一个主要的健康问题，随着早期生活压力的暴露，肥胖风险会增加。在命令状态下，暴露于早期生活压力非常普遍，但我们并不完全了解早期压力改变了奖励神经循环的动机，以消耗可口的食物并保持身体活跃。奖励系统的体重控制依赖于食物的固有奖励价值，部分脂肪和糖分高以及大脑内的体育锻炼，获得这些奖励的动机受多巴胺能活性的驱动（NAC）和腹侧对盖区域（VTA）的驱动。发现糖皮质激素受体被发现大脑的奖励区域和慢性高皮层血症，例如与地球生命压力外的相关的，toen toen toen toen释放和 NAC的营业额。减肥计划以产生有意义的持续体重减轻。恶化减肥或运动是减肥的最大预测指标我们的整体假设，维持成功，在讨厌早期生活压力的个体中有效。是早期的生活压力会损害奖励加工和体重的体内平衡，这可能部分是通过自愿的轮子进行缓解。（NMS）在AIM 1中的临床前小鼠中，我们将确定早期压力是否改变响应高脂肪/高蔗糖饮食引起的肥胖和卡路里压力减轻的奖励灵敏度。我们预计NMS小鼠将表现出高皮层血症，与之相关。多巴胺的周转和NAC和VTA释放。奖励动机在行为测试中挑战饮食和肥胖症和体重减轻。我们将测试早期压力增强体重是否会恢复和代谢功能障碍，并确定是否运动可以抵抗早期压力引起的障碍。重量恢复，炎症和代谢功能障碍后被允许重新审查卡路里的体重减轻。与NMS小鼠相比，天真小鼠的代谢功能障碍的范围更大。肥胖和早期生活压力都很有可能影响临床体重减轻维护。了解早期压力如何改变动力和体重维护成功，改善损失维持疗法的发展和更好肥胖治疗的结果。