Ghrelin Modulation of Mesolimbic Reward Signaling in Stress-induced Hyperphagia

描述(申请人提供)：肥胖症的慢性病程反映了病因特征和维持因素之间的相互作用，其中应激诱导的吞噬功能亢进提供了独特的预后价值。虽然偶尔摄入高卡路里食物以应对压力并不会直接导致肥胖，但对一些人来说，反复暴露在压力之下会触发过度吞噬行为，导致体内平衡通路被推翻，有利于中脑边缘奖赏信号，最终导致体重增加和肥胖。在其最严重的状态下，应激诱导的过度吞噬可能表现为过度吞噬抑制(或慢性应激诱导的过度吞噬；在一次发作中增加食欲/体重)。应激诱导的吞噬行为部分源于控制奖赏的中脑边缘区域的破坏。尽管有关于肥胖和情绪障碍中异常的多巴胺(DA)信号的数据，但慢性应激诱导的过度吞噬的病理生理学仍然知之甚少。临床前工作支持Ghrelin参与调节DA传递和奖赏信号-这一作用最近在人类肥胖中得到证实。Ghrelin是一种主要被认为具有促食欲的肠肽。我们发现，在慢性应激诱导的吞噬过度的女性中，Ghrelin与自我报告的奖赏能力和应激相关的进食显著相关，与腹侧被盖区和伏核对食物奖赏的反应有关。我们假设慢性应激诱导的吞噬反应是由ghreline能信号促进的，这些ghrelin特异性效应与中脑边缘区域的不同奖赏活动和连通性显著相关。这项建议将针对以下具体目标：1.评估在慢性应激诱导的吞噬过多、慢性应激诱导的吞噬减少、吞噬抑制和健康对照组中，Ghrelin与与食物奖励相关的大胆活动/连接之间的关系；2.在慢性应激诱导的吞噬过多、慢性应激诱导的吞噬减少、吞噬抑制和健康对照组中，在心理社会应激后的中脑边缘回路中，检测Ghrelin与与金钱奖励相关的大胆活动/连接之间的关系。我们将使用功能磁共振成像来研究中脑边缘回路，以测量在慢性应激诱导的吞噬过多、慢性应激诱导的吞噬减少、愉悦抑郁的个体和健康对照组中，在心理社会应激后的食物和非食物奖励任务中的大胆活动和连接性。我们的研究将确定压力对ghrelin和大脑奖赏回路之间关系的急性和慢性影响，确定ghrelin相关奖赏增强对食物的特异性或超越食物相关奖赏的泛化，并探索这些变量与随意获取美味食物期间摄入量之间的关系。了解这些影响将在心理社会压力等触发因素的背景下为肥胖的维持提供机械解释，潜在地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.