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

项目总结 暴食障碍(Bed)和神经性暴食症(BN)是潜在威胁生命的饮食障碍， 行为和大脑相似，遗传风险因素和与药物的共病高于预期 上瘾--表明这是一种常见的病因。然而，到目前为止，还没有机械论研究来检验这种可能性。 部分原因是缺乏将进食障碍和药物成瘾联系起来的动物模型。比如对毒品的渴求和吸毒 吸毒、渴望食物和在床上吃东西/国阵，尽管有不良后果(惩罚)，但仍然存在。我们的 对老鼠的研究表明，大量的可卡因和酒精史会触发类似成瘾的大脑 改变和抵抗惩罚的大鼠“强制”药物摄入，引发抵抗惩罚的食物摄入或 “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。 表现为进食障碍和吸毒成瘾的强迫行为。食物动机被认为是 受稳态(卡路里)和非稳态(享乐/激励)系统的调节。动态平衡 系统检测到能源短缺，并引发食物摄入量。然而，就像强迫性吸毒动机一样，我们的发现 这表明强迫性食欲是由非动态平衡的“动机/习惯性”失调所驱动的。喜欢 可卡因和酒精史，肥胖饮食史也通过非体内平衡导致强迫性食欲 监管失调。因此，同样常见的--而不是特定于历史的--大脑部位控制非 动态平衡调节，如奖励回路，可能会导致强迫性食欲。我们的合作者侯博士的 研究小组发现，惩罚通过在吻侧内侧脑区招募神经元来抑制食欲行为 被盖核(RMTg)，这反过来又抑制奖赏回路。现有证据表明，广泛的 药物史[1]降低了RMTg的兴奋性传入，[2]降低了RMTg神经元的惩罚反应性 和[3]削弱奖赏回路上RMTg传出的抑制控制。这样的大脑变化会带来更少的影响 在非体内平衡调节上“刹车”，潜在地表现为强迫性食欲。相应地，喜欢 广泛的可卡因/酒精/肥胖饮食病史，[4]RMTg灭活导致惩罚抵抗 强迫性食欲。基于前人研究的严谨性和上述前提，本项目将对 中心假设，大量的可卡因/酒精/肥胖饮食史会导致惩罚抵抗 通过减少RMTG回路中的神经惩罚反应而导致的强迫性食欲。RMTg含有神经元 对惩罚或奖励有选择性的反应--可能发挥不同的行为功能。每个目标是这样的 旨在选择性地描述和询问惩罚反应性RMTg神经元/传入/传出(目的 1/2/3)使用基于激活标记Fos的神经活动特异性方法。结果将揭示神经性 在功能上与强迫症相关的活动网络重组--一个重叠的分支 有大量的药物和肥胖饮食史。我们希望这样的知识将有助于识别共同的 针对药物成瘾和饮食失调的强迫行为的治疗目标。

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.