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）：肥胖的慢性疾病过程反映了病因学性状和所涉及的维护因素之间的相互作用，其中压力诱导的超晶状体提供了独特的预后价值。尽管偶尔摄入高热量食物会响应压力并不会直接引起肥胖症，但对于某些重复暴露于压力的情况下，触发了超晶状体的行为，因此稳态途径被覆盖而有利于中溶液奖励信号传导，从而导致体重增加和肥胖。在最严重的状态下，压力诱导的心形可能表现为倍感抑郁症（或慢性应激诱发的应激性止痛；发作中的食欲/体重增加增加）。压力引起的倍感行为部分源于中断奖励中的中脑边缘区域的中断。尽管肥胖和情绪障碍中多巴胺异常（DA）信号传导的数据，但慢性应激诱导的心phagia的病理生理学仍然知之甚少。临床前的工作支持Ghrelin的参与，Ghrelin是一种主要以其侵蚀性特性认可的肠肽，在调节DA传播和奖励信号传导方面 - 最近在人类肥胖中证实了这一作用。我们在患有慢性应激诱发的女性的女性中表明，生长素素与自我报告的奖励能力和与压力相关的饮食以及腹侧偏段区域和伏隔核的活性相关。我们假设慢性应激诱导的心脏通过响应社会心理应激而促进了慢性应激蛋白能信号传导，并且这些生长素素特异性的作用与中边缘区域之间的差异奖励活动和连通性显着相关。该提案将解决以下特定目的：1。评估慢性应激诱发的心脏压力，慢性应激诱发的下型，急救抑郁症和健康控制的心理压力后，与食物奖励相关的大胆活动/连通性之间的关系； 2。检查在慢性应激诱发的多晶状体，慢性应激诱发的下型，euphagic抑郁症和健康对照组中，在奖励预期/收到的奖励预期/收据期间，在奖励预期/收到的奖励预期/接收期间，与货币奖励相关的大胆活性/连通性之间的关联。我们将使用功能性MRI研究中唇电路，以测量食物和非食品期间的大胆活性和连通性奖励在心理压力的慢性压力诱导的人，慢性应激诱导的下型肌张力，急切性抑郁症和健康对照组中。我们的研究将确定压力对生长素蛋白和脑奖励回路之间关系的急性和慢性影响，确定与食物相关的奖励增强对食物的特异性或与食物相关的奖励之外的概括，并探索这些变量和摄入量之间的关联。理解这些影响将为在诸如社会心理压力等触发因素的背景下维持肥胖症提供一个机械解释，从而有可能为行为和药理治疗的设计提供信息。