Ghrelin Modulation of Mesolimbic Reward Signaling in Stress-induced Hyperphagia

描述（由申请人提供）：肥胖的慢性疾病过程反映了病因学特征和维持相关因素之间的相互作用，其中应激诱导的摄食过多提供了独特的预后价值。虽然偶尔摄入高热量食物不会直接导致肥胖，但对一些人来说，反复暴露于压力会触发过度进食行为，从而使稳态通路被中脑边缘奖励信号所取代，最终导致体重增加和肥胖。在其最严重的状态下，应激诱导的摄食过多可能表现为摄食过多性抑郁症（或慢性应激诱导的摄食过多;发作时食欲增加/体重增加）。压力引起的过度进食行为部分源于控制奖励的中脑边缘区的中断。尽管有关于肥胖和情绪障碍中异常多巴胺（DA）信号传导的数据，但慢性应激诱导的暴食症的病理生理学仍然知之甚少。临床前工作支持ghrelin（一种主要因其食欲特性而被认可的肠道肽）参与调节DA传输和奖励信号传导-最近在人类肥胖中证实了这一作用。我们发现，在慢性应激诱发的暴食症的女性中，ghrelin与自我报告的奖励能力和与应激相关的进食显著相关，并且与腹侧被盖区和背核对食物奖励的反应活性显著相关。我们推测，慢性应激诱导的暴食症是促进ghrelin能信号响应心理社会压力，这些ghrelin特异性的影响显着相关的差异奖励活动和中脑边缘区之间的连接。本提案将针对以下具体目标：1.评估慢性应激诱导的食欲过盛、慢性应激诱导的食欲减退、欣快性抑郁和健康对照中与心理社会应激后食物奖励相关的胃饥饿素和BOLD活性/连接之间的关系; 2.在慢性应激诱导的食欲过盛、慢性应激诱导的食欲减退、欣快感抑郁和健康对照组中，研究在心理社会应激后的奖励预期/接受过程中，与中脑边缘回路中的金钱奖励相关的ghrelin和BOLD活动/连接之间的相关性。我们将使用功能性磁共振成像研究中脑边缘回路，以测量BOLD活动和连接在食物和非食物奖励任务后的心理社会压力与慢性应激诱导的暴食，慢性应激诱导的食欲减退，欣快抑郁症，和健康对照组的个人。我们的研究将确定急性和慢性应激对ghrelin和大脑奖励回路之间关系的影响，确定ghrelin相关的奖励增强食物或食物相关奖励之外的泛化的特异性，并探索这些变量之间的关联和随意获取可口食物的摄入量。了解这些影响将提供一个机制解释的背景下，如社会心理压力的触发维持肥胖，潜在的通知行为和药物治疗的设计。

DESCRIPTION (provided by applicant): The chronic disease course of obesity reflects interactions between etiological traits and factors involved in maintenance, of which stress-induced hyperphagia offers unique prognostic value. Although occasional intake of high-calorie foods in response to stress does not directly cause obesity, for some, repeated exposure to stress triggers hyperphagic behaviors such that homeostatic pathways are overridden in favor of mesolimbic reward signaling, culminating in weight gain and obesity. In its most severe state, stress-induced hyperphagia may manifest as hyperphagic depression (or chronic stress-induced hyperphagia; increased appetite/weight gain in an episode). Stress-induced hyperphagic behaviors stem, in part, from disruption in mesolimbic regions governing reward. Despite data on abnormal dopamine (DA) signaling in obesity and mood disorders, the pathophysiology of chronic stress-induced hyperphagia remains poorly understood. Preclinical work supports involvement of ghrelin, a gut peptide primarily recognized for its orexigenic properties, in modulating DA transmission and reward signaling - a role recently corroborated in human obesity. We showed, in women with chronic stress-induced hyperphagia, that ghrelin was significantly related to self-reported reward capacity and stress-related eating, and to ventral tegmental area and nucleus accumbens activity in response to food reward. We hypothesize that chronic stress-induced hyperphagia is promoted by ghrelinergic signaling in response to psychosocial stress, and that these ghrelin-specific effects are significantly associated with differential reward activity in and connectivity between mesolimbic regions. This proposal will address the following Specific Aims: 1. To assess relationships between ghrelin and BOLD activity/connectivity related to food reward after psychosocial stress in chronic stress-induced hyperphagia, chronic stress-induced hypophagia, euphagic depression, and healthy controls; 2. To examine associations between ghrelin and BOLD activity/connectivity related to monetary reward in mesolimbic circuitry during reward anticipation/receipt after psychosocial stress in chronic stress-induced hyperphagia, chronic stress-induced hypophagia, euphagic depression, and healthy controls. We will study mesolimbic circuitry using functional MRI to measure BOLD activity and connectivity during food and non-food reward tasks following psychosocial stress in individuals with chronic stress-induced hyperphagia, chronic stress-induced hypophagia, euphagic depression, and healthy controls. Our study will identify acute and chronic effects of stress on relationships between ghrelin and brain reward circuitry, determine specificity of ghrelin-related reward potentiation to food or generalization beyond food-related reward, and explore associations between these variables and intake during ad libitum access to palatable foods. Understanding these effects will provide a mechanistic explanation for the maintenance of obesity in the context of triggers such as psychosocial stress, potentially informing the design of behavioral and pharmacologic treatments.