Molecular Endocannabinoid Mediators of Impaired Aversive Learning in Low Weight Eating Disorders

低体重饮食失调中厌恶学习受损的分子内源性大麻素调节剂

• 批准号: 9752085
• 负责人: ANAT BIEGON
• 金额: $ 26.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-16 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752085
• 关键词: Acute; Affect; Affinity; Aftercare; Age; Agonist; Amygdaloid structure; Anorexia Nervosa; Anterior; Anxiety; Anxiety Disorders; Area; Behavior; Body mass index; Brain; Bulimia; CNR1 gene; Consumption; Corpus striatum structure; Cues; Data; Disease; Eating; Eating Behavior; Eating Disorders; Endocannabinoids; Expectancy; Extinction (Psychology); FAAH inhibitor; Food; Food Patterns; Food Poisoning; Gender; HIV Wasting Syndrome; Habits; Hippocampus (Brain); Human; Hunger; Hypothalamic structure; Impairment; Individual; Insula of Reil; Interoception; Intervention; Laboratories; Learning; Ligands; Link; Measures; Mediating; Mediator of activation protein; Mental Health; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Motivation; Nausea; Nutritional; Obesity; Pain; Pain Disorder; Palate; Participant; Pathologic; Patients; Pharmacology; Physiological; Plasma; Play; Pontine structure; Population; Positron-Emission Tomography; Publishing; Reflex action; Relapse; Response to stimulus physiology; Rewards; Role; Signal Transduction; Sleep Disorders; Standardization; Starvation; Stress; System; Testing; Therapeutic; Time; Treatment Efficacy; Underweight; Up-Regulation; Variant; Weight; Woman; addiction; base; behavior measurement; chemotherapy; endocannabinoid signaling; endogenous cannabinoid system; energy balance; feeding; food avoidance; food challenge; food consumption; healthy weight; hedonic; imaging modality; individual variation; interest; mortality; motivated behavior; novel; novel therapeutics; outcome forecast; prevent; putamen; receptor; regional difference; response; restoration; self-directed learning; stress disorder; theories; therapeutic target

Project summary: Low weight eating disorders (LW-EDs), including anorexia nervosa and related atypical variants, are characterized by persistent food avoidance. Disturbances in behavior among individuals with LW-EDs persist beyond the acute starvation stage into the period of weight normalization, with abnormalities observed in food- cue learning, expectancies related to food, and food choice. We hypothesize that the persistence of disordered affect and food-cue learning result from an allostatic disruption of endocannabinoid (eCB) tone, as specifically evidenced by an upregulation of eCB1 receptors and an impaired responsivity and tone of eCBs. This proposal therefore aims to test this theory using the novel PET ligand [(18)F]MK-9470, a robust and reliable measure of brain eCB1 receptor availability in 6 women recently weight restored from a LW-ED and 6 age, gender, and body mass index matched control women. Participants will complete behavioral measures of food-cue learning and food choice, PET measures of CB1 receptor availability, time course changes in plasma eCBs to a palatable food challenge, and objective and subjective measures of eating behavior. We will: (1) model both region specific and whole brain measures of eCB1 receptor availability, and (2) test whether eCB1 receptor discriminates those with LW-EDs from healthy controls. Further, we will evaluate if this upregulation mediates impaired time course response of plasma eCBs to food challenge. Results from this study will provide critical data about the unique role of eCBs in pathological patterns of food choice and avoidance in those with LW- EDs. Successful completion of this study will offers a tangible and robust target for novel treatment intervention with pharmacological, nutritional, or combination therapeutics among those with LW-EDs.

项目概要： 低体重饮食失调 (LW-ED)，包括神经性厌食症和相关的非典型变异，是 其特点是持续回避食物。 LW-ED 患者的行为障碍持续存在 过了急性饥饿阶段，进入体重正常化阶段，观察到食物异常 提示学习、与食物相关的期望以及食物选择。我们假设无序状态的持续存在 情感和食物线索学习是由内源性大麻素 (eCB) 音调的变稳态破坏造成的，具体而言 eCB1 受体上调以及 eCB 反应性和音调受损即可证明。这个提议 因此，旨在使用新型 PET 配体 [(18)F]MK-9470 来测试这一理论，这是一种稳健且可靠的测量方法 近期从 LW-ED 恢复体重的 6 名女性的大脑 eCB1 受体可用性以及 6 名年龄、性别和年龄 体重指数与对照女性相匹配。参与者将完成食物线索学习的行为测量 和食物选择、CB1 受体可用性的 PET 测量、血浆 eCB 的时间过程变化 可口的食物挑战，以及饮食行为的客观和主观测量。我们将：（1）对两者进行建模 eCB1 受体可用性的区域特异性和全脑测量，以及 (2) 测试 eCB1 受体是否 将 LW-ED 患者与健康对照者区分开来。此外，我们将评估这种上调是否介导 血浆 eCB 对食物挑战的时程反应受损。这项研究的结果将提供关键的 关于 ECB 在 LW-患者食物选择和避免的病理模式中的独特作用的数据 ED。这项研究的成功完成将为新型治疗干预提供切实而有力的目标 对 LW-ED 患者进行药物、营养或联合治疗。