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：
10407491
负责人：
Rebecca Foright
金额：
$ 6.76万
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/10407491
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 Palate 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 base 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.

项目概要我的长期职业目标是成为一名成功的、拥有研究计划的独立科学家专注于肥胖以及对肥胖的进食和活动的神经生物学调节。仍然是一个主要的健康问题，并且随着早期生活压力的暴露，肥胖风险会增加。在美国，早年承受生活压力是很常见的，但我们并不完全了解早年经历的压力有多大。压力会改变奖励神经回路，从而影响消费美味食物和进行身体活动的动机。体重的奖励系统控制依赖于食物固有的奖励价值，特别是那些高脂肪和高糖，以及大脑内的体力活动，获得这些自然奖励的动机是。由伏隔核（NAc）和腹侧被盖区（VTA）的多巴胺能活动驱动。糖皮质激素受体遍布大脑的奖励区域和慢性高皮质酮血症，例如与早期生活压力暴露相关的药物已被证明可以抑制多巴胺的释放此外，肥胖症患者面临的最大问题之一是失败。减肥计划能否产生有意义且持续的减肥效果，早期是否存在生活压力尚不得而知。减重的维持或运动是否恶化，这是减重的最大预测因素我们的总体假设是，维持成功对于经历过早期生活压力的个体来说是有效的。早期生活压力会损害奖赏处理和体重稳态，这可能会部分影响我们将通过新生儿母亲分离来测试这一总体假设。（NMS）小鼠，早期生活压力的临床前模型在目标 1 中，我们将确定早期生活压力是否会改变。对高脂肪/高蔗糖饮食引起的肥胖和热量限制减肥的奖励敏感性。我们预计 NMS 小鼠将表现出高皮质酮血症，这将与我们还预计 NMS 小鼠的 NAc 和 VTA 中的多巴胺周转和释放会发生改变。在目标 2 中，在饮食引起的肥胖和减肥过程中受到行为测试挑战时奖励动机。我们将测试早期生活压力是否会加剧体重反弹和代谢功能障碍，并确定运动是否有效可以对抗这些早期生活压力引起的损伤，我们预计 NMS 将导致发病率增加。允许随意重新进食后体重反弹、炎症和代谢功能障碍我们预计自愿跑轮会减轻体重反弹并减少体重。鉴于患病率不断增加，首次接触小鼠的代谢功能障碍程度高于 NMS 小鼠。肥胖和早期生活压力，这很可能是影响临床减肥的相互作用了解早期生活压力如何改变奖励动机和减肥至关重要。维持成功，以开发改进的减肥维持疗法和更好的减肥维持疗法肥胖治疗的结果。