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: 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
• 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

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 我的长期职业目标是成为一个成功的，独立的科学家与研究计划 集中在肥胖和进食的神经生物学调节和对运动的反应。肥胖 仍然是一个主要的健康问题，肥胖的风险随着早年生活压力的增加而增加。 在美国，早期生活压力是很常见的，但我们并不完全了解早期生活压力是如何产生的。 压力会改变奖赏神经回路，从而影响人们食用可口食物和进行体力活动的动机。 奖赏系统控制体重依赖于食物固有的奖赏价值，特别是那些 富含脂肪和糖分，以及体力活动。在大脑中，获得这些自然奖励的动机是 由中脑核（NAc）和腹侧被盖区（VTA）中的多巴胺能活性驱动。 糖皮质激素受体遍布大脑的奖赏区域， 例如与早期生活压力暴露相关的，已经显示出抑制多巴胺释放， 在NAC的营业额。此外，肥胖症患者面临的最大问题之一是， 减肥计划，以产生有意义的和持续的减肥。尚不清楚早期生活压力是否 是维持减肥还是运动，这是减肥的最大预测因素 维持成功，对经历过早期生活压力的人有效。我们的总体假设 早期的生活压力会损害奖赏过程和体重的自我平衡，这可能是部分原因。 通过自愿的车轮运行来缓解。我们将使用新生儿母亲分离来检验这一总体假设 (NMS)在小鼠中，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/高蔗糖饮食诱导的肥胖和热量限制的体重减轻的反应中的奖赏敏感性。 我们预期NMS小鼠将表现出高皮质酮血症，这将与 NAc和VTA中的多巴胺周转和释放。我们还预计，NMS小鼠将显示出改变的 在饮食诱导的肥胖和减肥过程中进行行为测试时，奖励动机。在目标2中， 我们将测试早期生活压力是否会加重体重反弹和代谢功能障碍， 可以对抗这些早期生活压力导致的损伤。我们预计NMS将导致 体重恢复，炎症和代谢功能障碍后，被允许随意再喂养后， 热量限制减肥。我们预计，自愿轮运行将减弱体重反弹， 代谢功能障碍在幼稚小鼠中比在NMS小鼠中更大程度。鉴于日益普遍的 肥胖和早期生活压力，这很可能是一种相互作用，影响临床减肥 上维护了解早期生活压力如何改变奖励动机和减肥是至关重要的 维持成功，以允许开发改进的减肥维持疗法， 肥胖治疗的结果。