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.

项目概要 暴食症 (BED) 和神经性贪食症 (BN) 是潜在危及生命的饮食失调症， 具有行为和大脑相似性、遗传风险因素以及高于预期的药物合并症 成瘾——表明有一个常见的病因。然而，没有机制研究检验过这种可能性。 部分原因是缺乏将饮食失调和药物成瘾联系起来的动物模型。 尽管产生了不良后果（惩罚），但 BED/BN 中的吸毒、对食物的渴望和饮食仍然存在。 从老鼠身上发现的结果表明，大量的可卡因和酒精史，已知会引发类似成瘾的大脑 老鼠的变化和抵抗惩罚的“强迫性”药物摄入，引发抵抗惩罚的食物摄入或 “强迫性食欲”为研究神经生物学机制提供了动物模型。 食物动机被认为表现为饮食失调和药物成瘾的强迫行为。 受到稳态（热量）和非稳态（享乐/激励）系统的调节。 系统检测到能量短缺并引起食物摄入，但是，就像强迫性药物动机一样，我们的发现。 表明强迫性食欲是由非稳态“动机/习惯”失调驱动的。 可卡因和酒精史、肥胖饮食史也通过非稳态导致强迫性食欲 因此，控制非功能的大脑部位发生同样常见的变化，而不是历史特有的变化。 奖励回路等稳态调节可能会导致强迫性食欲。 研究小组发现，惩罚通过招募嘴内侧神经元来抑制食欲行为 被盖核（RMTg），反过来又抑制奖赏回路。 用药史 [1] 降低 RMTg 的兴奋性传入，[2] 降低 RMTg 神经元的惩罚反应性 [3] 损害 RMTg 传出神经对奖赏回路的抑制控制。这种大脑变化将导致“更少”。 对非稳态调节的“刹车”，可能表现为强迫性食欲，例如。 广泛的可卡因/酒精/致肥胖饮食史，[4] RMTg 失活导致惩罚抵抗 基于先前研究的严谨性和上述前提，本项目将测试强迫性食欲。 中心假设：广泛的可卡因/酒精/致肥胖饮食史导致对惩罚的抵抗 RMTg 回路中的神经惩罚反应性降低导致强迫性食欲。 选择性地对惩罚或奖励做出反应——因此，每个目标可能发挥不同的行为功能。 旨在选择性地分析和询问惩罚反应性 RMTg 神经元/传入/传出神经元（如 Aims 1/2/3) 使用基于激活标记 Fos 的神经活动特定方法，结果将揭示神经活动。 在功能上与强迫性食欲相关的活动网络重组——一个重叠的分支 我们希望这些知识将有助于识别常见的药物和肥胖饮食史。 药物成瘾和饮食失调等强迫行为的治疗目标。