Ghrelin Modulation of Mesolimbic Reward Signaling in Stress-induced Hyperphagia

胃饥饿素对应激诱发的食欲过盛中脑边缘奖赏信号的调节

基本信息

批准号：
9198542
负责人：
LAURA McGrath HOLSEN
金额：
$ 54.61万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-23 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198542
关键词：
Acute Address Adult Affect Amygdaloid structure Appetite Stimulants Behavior Behavior Therapy Binding Biological Factors Body Weight decreased Brain Calories Cessation of life Chemosensitization Chronic Chronic Disease Chronic stress Comorbidity Control Groups Cues Data Desire for food Dimerization Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Eating Etiology Exhibits Exposure to Food Functional Magnetic Resonance Imaging Functional disorder GHS-R1a Health Care Costs High Fat Diet Hormones Human Hyperphagia Hypersensitivity Hypothalamic structure Individual Intake Lead Link Maintenance Measures Medical Mental Depression Modeling Mood Disorders Nucleus Accumbens Obesity Palate Pathway interactions Patient Self-Report Peptides Pharmacological Treatment Phenotype Physiological Play Population Property Psychosocial Stress Rest Rewards Risk Rodent Role Signal Transduction Specificity Stress Sucrose Suicide System Time Treatment/Psychosocial Effects Ventral Tegmental Area Weight Weight Gain Woman Work base burden of illness design dimer dopaminergic neuron effective intervention ghrelin hedonic improved increased appetite insight pre-clinical preference prognostic value public health relevance putamen receptor expression relating to nervous system response reward anticipation reward circuitry social stem trait transmission process

项目摘要

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.

描述（由申请人提供）：肥胖的慢性病程反映了病因学特征和维持相关因素之间的相互作用，其中压力引起的食欲亢进提供了独特的预后价值。虽然偶尔摄入高热量食物来应对压力并不会直接导致肥胖，但对某些人来说，反复暴露在压力下会引发暴饮暴食行为，从而导致体内平衡途径被中脑边缘奖赏信号所取代，最终导致体重增加和肥胖。在最严重的状态下，压力引起的食欲过盛可能表现为食欲过盛抑郁症（或慢性压力引起的食欲过盛；发作时食欲增加/体重增加）。压力引起的贪食行为部分源于中脑边缘控制奖赏的区域的破坏。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，但慢性压力引起的食欲亢进的病理生理学仍然知之甚少。临床前工作支持生长素释放肽（一种主要因其促进食欲的特性而被认可的肠道肽）参与调节多巴胺传递和奖励信号传导，这一作用最近在人类肥胖中得到证实。我们发现，在患有慢性压力诱发的食欲亢进的女性中，生长素释放肽与自我报告的奖励能力和压力相关的饮食，以及响应食物奖励的腹侧被盖区和伏核活动显着相关。我们假设慢性压力引起的食欲亢进是由响应心理社会压力的生长素释放肽信号传导促进的，并且这些生长素释放肽特异性作用与中脑边缘区域的差异奖励活动和连接之间显着相关。该提案将解决以下具体目标： 1. 评估在慢性压力诱发的吞咽过多、慢性压力诱发的吞咽不足、吞咽抑制和健康对照中，在心理社会压力后，ghrelin 与与食物奖励相关的 BOLD 活动/连接之间的关系； 2. 在慢性压力诱发的吞咽过多、慢性压力诱发的吞咽不足、吞咽抑郁和健康对照中，检查在心理社会压力后的奖励预期/接收期间，ghrelin 和与中脑边缘回路中的金钱奖励相关的 BOLD 活动/连接之间的关联。我们将使用功能性 MRI 研究中脑边缘回路，以测量患有慢性压力诱发的吞咽过多、慢性压力诱发的吞咽不足、吞咽抑郁和健康对照的个体在心理社会压力后的食物和非食物奖励任务期间的 BOLD 活动和连接。我们的研究将确定压力对生长素释放肽和大脑奖励回路之间关系的急性和慢性影响，确定与生长素释放肽相关的食物奖励增强的特异性或食物相关奖励之外的泛化，并探索这些变量与随意获取期间摄入量之间的关联。美味的食物。了解这些影响将为在社会心理压力等触发因素的背景下维持肥胖提供机制解释，并可能为行为和药物治疗的设计提供信息。