Extensive drug histories result in compulsive appetite: functional identification of punishment-reactive neural network re-organization in the rostromedial tegmental nucleus

广泛的用药史导致强迫性食欲：嘴内侧被盖核中惩罚反应神经网络重组的功能识别

• 批准号: 10693347
• 负责人: Nobuyoshi Suto
• 金额: $ 53.44万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693347
• 关键词: 3-Dimensional; Affect; Alcohols; Animal Model; Appetite Regulation; Appetitive Behavior; Behavioral; Binge eating disorder; Brain; Brain region; Bulimia; Calories; Cell Nucleus; Cocaine; Compulsive Behavior; Desire for food; Diet; Dietary History; Drug Addiction; Drug usage; Eating; Eating Disorders; Etiology; Fatty acid glycerol esters; Food; General Population; Genetic Risk; Homeostasis; Impairment; In Situ Hybridization; Incentives; Intake; Knowledge; Life; Link; Liquid substance; Metabolic; Methods; Motivation; Neurons; Patients; Pharmaceutical Preparations; Pilot Projects; Publishing; Punishment; Rattus; Recording of previous events; Regulation; Research; Resistance; Rewards; Saccharin; Site; Study models; System; Testing; Ventral Tegmental Area; Weight Gain; addiction; adverse outcome; brain cell; brain circuitry; comorbidity; design; detection platform; drug craving; food craving; genetic risk factor; hedonic; neural; neural network; neurobiological mechanism; obesogenic; optogenetics; recruit; sugar; therapeutic target; vapor

PROJECT SUMMARY Binge-eating disorder (BED) and bulimia nervosa (BN) are potentially life-threatening eating disorders that share behavioral and brain similarities, genetic risk factors and higher-than-expected comorbidities with drug addiction – suggesting a common etiology. However, no mechanistic study has examined this possibility due in part to the lack of an animal model linking eating disorders and drug addiction. Like drug craving and use in drug addiction, food craving and eating in BED/BN persist despite adverse consequences (punishment). Our finding from rats indicates that extensive cocaine and alcohol histories, known to trigger addiction-like brain changes and punishment-resistant “compulsive” drug intake in rats, trigger punishment-resistant food intake or “compulsive appetite”. These results provide an animal model for studying the neurobiological mechanisms manifesting as compulsive behavior across eating disorders and drug addiction. Food motivation is thought to be regulated by both homeostatic (caloric) and non-homeostatic (hedonic/incentive) systems. The homeostatic system detects energy shortages and elicits food intake. However, like compulsive drug motivation, our finding suggests that compulsive appetite is driven by non-homeostatic ‘motivational/habitual’ dysregulation. Like cocaine and alcohol histories, obesogenic diet histories also led to compulsive appetite via non-homeostatic dysregulation. Thus, similarly common – rather than history-specific – changes in brain sites that control non- homeostatic regulation, such as reward circuits, likely cause compulsive appetite. Our collaborator Dr. Jhou’s group has found that punishments suppress appetitive behavior by recruiting neurons in the rostromedial tegmental nucleus (RMTg), which in turn inhibits reward circuits. Available evidence indicates that extensive drug histories [1] degrade excitatory afferents to RMTg, [2] decrease punishment-reactivity of RMTg neurons and [3] impair inhibitory control of RMTg efferents on reward circuits. Such brain changes would entail “less brakes” on non-homeostatic regulation, potentially manifesting as compulsive appetite. Accordingly, like extensive cocaine/alcohol/obesogenic diet histories, [4] RMTg inactivation results in punishment-resistant compulsive appetite. Based on the rigor of previous research and premise above, this project will test the central hypothesis that extensive cocaine/alcohol/obesogenic diet histories result in punishment-resistant compulsive appetite via decreased neural punishment-reactivity in the RMTg circuitry. RMTg contains neurons selectively reactive to punishments or rewards – likely exerting distinct behavioral functions. Each Aim is thus designed to selectively profile and interrogate punishment-reactive RMTg neurons/afferents/efferents (as Aims 1/2/3) using neural activity-specific methods based on the activation marker Fos. The results will reveal neural activity network reorganizations that are functionally linked to compulsive appetite – an overlapping ramification of extensive drug and obesogenic diet histories. Our hope is that such knowledge will help identify common therapeutic targets for compulsive behavior across drug addiction and eating disorders.

项目摘要 暴饮暴食（BED）和贪食症神经（BN）可能是威胁生命的饮食失调 共享行为和大脑的相似性，遗传危险因素以及药物的合并症高于预期 成瘾 - 提出一种常见的病因。但是，没有机械研究检查 缺乏联系饮食失调和吸毒成瘾的动物模型的一部分。喜欢毒品渴望和使用 吸毒成瘾，渴望食物和在床上/bn持续的目的地广告后果（惩罚）。我们的 从大鼠发现的发现，广泛的可卡因和酒精历史，已知会引发成瘾的大脑 改变大鼠的变化和耐惩罚的“强迫性”药物摄入，触发对惩罚的食物摄入量或 “强迫性食欲”。这些结果为研究神经生物学机制提供了动物模型 表现为跨饮食失调和吸毒成瘾的强迫行为。人们认为食物动机 受体内平衡（热量）和非室内（享乐/激励）系统的调节。稳态 系统检测到能量短缺并引起食物摄入。但是，就像强迫毒品动机一样，我们的发现 表明强迫性食欲是由非防境的“动机/习惯性”失调驱动的。喜欢 可卡因和酒精历史，肥胖饮食史也导致了不间境内的食欲 失调。同样，这同样常见（而不是特定于历史的）大脑部位的变化 稳态调节（例如奖励电路）可能会导致强迫性食欲。我们的合作者Jhou博士 小组发现，惩罚通过招募神经元抑制食欲的行为 换扇形核（RMTG），进而抑制奖励电路。可用证据表明广泛 毒品史[1]将兴奋性传入降低为rmtg，[2]降低RMTG神经元的惩罚性反应性 [3]损害对RMTG对奖励电路有效性的抑制控制。这样的大脑变化将需要“更少 在非固定调节中制动”，可能表现为强迫性食欲。 广泛的可卡因/酒精/肥胖饮食史，[4] RMTG失活导致抗惩罚 强迫性食欲。基于上面的先前研究和前提的严格，该项目将测试 中心假设是，广泛的可卡因/酒精/肥胖饮食史导致抗药性 通过降低RMTG电路中的神经惩罚反应性，强迫性食欲。 RMTG包含神经元 选择性地反应惩罚或奖励 - 可能发挥不同的行为功能。因此，每个目标都是 旨在选择性地介绍和询问惩罚反应性RMTG神经元/传统/传出（作为目标 1/2/3）基于激活标记FOS使用神经活动特异性方法。结果将显示神经 活动网络重组在功能上链接到强迫性食欲 - 重叠的分支机构 广泛的药物和肥胖饮食史。我们的希望是，这种知识将有助于确定共同 跨药物成瘾和饮食失调的强迫行为的治疗靶标。