Ghrelin Modulation of Mesolimbic Reward Signaling in Stress-induced Hyperphagia

描述（由申请人提供）：肥胖的慢性病程反映了病因特征和维持相关因素之间的相互作用，其中应激性贪食具有独特的预后价值。虽然为了应对压力而偶尔摄入高热量食物并不会直接导致肥胖，但对一些人来说，反复暴露在压力下会引发贪食行为，使体内平衡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，应激性贪食可表现为贪食抑郁（或慢性应激性贪食；发作时食欲增加/体重增加）。压力引起的贪食行为部分源于控制奖励的中脑边缘区域的破坏。尽管有数据表明肥胖和情绪障碍中多巴胺（DA）信号异常，但慢性应激性贪食的病理生理机制仍然知之甚少。临床前研究支持胃饥饿素（ghrelin）参与调节DA传递和奖励信号，最近在人类肥胖中证实了这一作用。胃饥饿素是一种肠道肽，主要被认为具有摄氧特性。我们发现，在患有慢性应激性贪食症的女性中，胃饥饿素与自我报告的奖励能力和应激相关的进食，以及腹侧被盖区和伏隔核对食物奖励的反应显著相关。我们假设慢性应激性贪食是由胃饥饿素能信号对社会心理应激的反应所促进的，并且这些胃饥饿素特异性效应与中脑边缘区域的不同奖励活动和连接显著相关。该提案将解决以下具体目标：评估慢性应激性贪食、慢性应激性贪食、贪食抑郁症和健康对照者在心理社会应激后，胃饥饿素与食物奖励相关的BOLD活动/连通性之间的关系；2. 研究慢性应激性贪食、慢性应激性贪食、贪食抑郁症和健康对照者在心理社会应激后的奖励预期/接受过程中，胃饥饿素与中脑边缘回路中与货币奖励相关的BOLD活动/连通性之间的关系。我们将使用功能性MRI来研究中脑边缘回路，以测量慢性应激性贪食、慢性应激性低食、食源性抑郁症和健康对照者在社会心理应激后的食物和非食物奖励任务中BOLD的活动和连通性。我们的研究将确定压力对胃饥饿素和大脑奖励回路之间关系的急性和慢性影响，确定胃饥饿素相关奖励增强对食物的特异性或超越食物相关奖励的泛化，并探索这些变量与随意获取美味食物时摄入之间的关系。了解这些影响将为肥胖在社会心理压力等触发因素下的维持提供一个机制解释，可能为行为和药物治疗的设计提供信息。

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.