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

• 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
• 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

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。肥胖 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。 在美国暴露于早期生活压力非常普遍，但我们并不完全了解早期 压力会改变奖励神经记录，以影响消耗可口食品并保持身体活跃的动机。 奖励系统的体重控制取决于食物的固有奖励价值，尤其是那些食物的价值 高脂肪和糖，体育锻炼。在大脑中，获得这些自然奖励的动力是 由伏隔核（NAC）和腹侧段区域（VTA）的多巴胺能活性驱动。 在整个大脑的奖励区域和慢性高皮质骨血症中都发现了糖皮质激素受体， 例如与早期生活压力暴露相关的，已显示可抑制多巴胺释放和 NAC的营业额。此外，肥胖个人面临的最大问题之一是失败 减肥计划以产生有意义的持续体重减轻。未知早期生活是否压力 恶化减肥或运动是减肥的最大预测指标 维护成功，对经历早期生活压力的个体有效。我们的总体假设 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 通过自愿车轮跑步来缓解。我们将使用新生儿材料分离来检验这一总体假设 （NMS）在小鼠中，这是早期生活压力的临床前模型。在AIM 1中，我们将确定早期生活压力是否在改变 响应高脂肪/高蔗糖饮食引起的肥胖症和限制卡路里的体重减轻的奖励灵敏度。 我们预计NMS小鼠将表现出高皮层血症，这将与 多巴胺转移并在NAC和VTA中释放。我们还预计NMS小鼠将显示已更改 在饮食引起的肥胖症和体重减轻期间对行为测试挑战时，奖励动机。在AIM 2中， 我们将测试早期生活压力潜在的体重是否仍然存在和代谢功能障碍，并确定是否运动 可以应对这些早期生活压力引起的损害。我们预计NMS会导致率提高 重量恢复，炎症和代谢功能障碍后被允许转介出来。 卡路里限制体重减轻。我们预计自愿车轮跑步会减轻体重的剩余，并且 与NMS小鼠相比，幼稚小鼠的代谢功能障碍在更大程度上。考虑到越来越多的患病率 肥胖和早期生活压力，这很可能是影响临床体重减轻的相互作用 维护。了解早期生活压力如何改变奖励动机和减肥至关重要 维护成功，以允许改善减肥疗法的发展和更好 肥胖治疗的结果。