The Impact of Early Life Stress on Reward and Body Weight

项目总结 我的长期职业目标是成为一名有研究计划的成功的独立科学家 重点关注肥胖和运动对摄食和活动的神经生物学调节。肥胖 肥胖仍然是一个主要的健康问题，肥胖的风险随着早期生活压力的暴露而增加。 在美国，暴露在早期生活压力下非常普遍，但我们并不完全了解 压力会改变神经回路，从而影响人们食用美味食物和进行体育锻炼的动机。 控制体重的奖励系统依赖于食物本身的奖励价值，特别是那些 脂肪和糖含量高，体力活动多。在大脑内部，获得这些自然奖励的动机是 由伏核(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赏区域和慢性高皮质酮血症， 如与早期生活压力暴露相关的，已被证明抑制多巴胺的释放和 NAC的营业额。此外，肥胖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。尚不清楚早年的生活压力是否 更糟糕的是保持减肥或是否锻炼，这是减肥的最大预测因素 维持成功，对于经历过早期生活压力的个人来说是有效的。我们的总体假设 早期生活压力损害了体重的奖赏处理和动态平衡，这可能部分地 通过自愿转动轮子减轻了压力。我们将使用新生儿母体分离来检验这一总体假设 (NMS)，这是一种早期生活应激的临床前模型。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卡路里限制的减肥做出反应的奖励敏感性。 我们预计NMS小鼠将表现出高皮质酮血症，这将与 多巴胺在NAc和VTA的周转和释放。我们还预计NMS小鼠将显示出改变 在饮食诱导的肥胖和减肥期间接受行为测试挑战时的奖励动机。在目标2中， 我们将测试早期生活压力是否会加剧体重恢复和代谢功能障碍，并确定锻炼是否 可以对抗这些早年应激导致的损伤。我们预计NMS将导致费率增加 在被允许自由进食后体重恢复、炎症和代谢功能障碍 限制卡路里的减肥。我们预计，自愿的车轮运行将减弱体重恢复和 幼稚小鼠的代谢功能障碍比NMS小鼠更严重。鉴于日益盛行的 肥胖和早期生活压力，很可能是影响临床减肥的交互作用。 维修。了解早年生活压力如何改变奖赏动机和减肥是至关重要的。 维护的成功，使改进的减肥维护疗法的开发和更好 肥胖症治疗的结果。

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.