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

基本信息

  • 批准号:
    10693347
  • 负责人:
  • 金额:
    $ 53.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 暴食症(BED)和神经性贪食症(BN)是潜在的危及生命的饮食失调, 共享行为和大脑相似性,遗传风险因素和高于预期的药物合并症 成瘾-提示一个共同的病因。然而,没有机制研究已经检查了这种可能性, 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。比如对毒品的渴望和使用 尽管有不良后果(惩罚),但在床/BN中吸毒、贪食和进食的情况仍然存在。我们 对老鼠的研究表明,广泛的可卡因和酒精历史,已知触发成瘾样大脑 变化和惩罚抵抗“强迫”药物摄入大鼠,触发惩罚抵抗食物摄入或 “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 表现为饮食失调和吸毒成瘾的强迫行为。食物动机被认为是 受稳态(热量)和非稳态(享乐/激励)系统的调节。内稳态 系统检测能量短缺和营养不良的食物摄入。然而,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的“动机/习惯”失调驱动的。像 可卡因和酒精的历史,肥胖的饮食史也导致强迫性食欲通过非稳态 失调因此,类似的共同-而不是特定的历史-大脑部位的变化,控制非- 自我平衡调节,如奖赏回路,可能导致强迫性食欲。我们的合作者周博士 一个研究小组发现,惩罚通过募集吻内侧核中的神经元来抑制食欲行为 被盖核(RMTg),这反过来又抑制奖励回路。现有证据表明, 药物史[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。这样的大脑变化将需要“更少” 在非稳态调节上“刹车”,可能表现为强迫性食欲。因此,像 广泛的可卡因/酒精/致肥胖饮食史,[4] RMTg失活导致惩罚抵抗 强迫性食欲基于上述研究的严谨性和前提,本项目将测试 广泛的可卡因/酒精/致肥胖饮食史导致惩罚抵抗的中心假设 强迫性食欲通过减少RMTg回路中的神经惩罚反应。RMTg含有神经元 选择性地对惩罚或奖励做出反应-可能发挥不同的行为功能。每个目标都是这样的。 设计用于选择性分析和询问惩罚反应性RMTg神经元/传入/传出(作为目的 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 活动网络重组,在功能上与强迫性食欲相关--一个重叠的分支 大量的药物和致肥饮食史我们希望,这些知识将有助于确定共同的 药物成瘾和饮食失调的强迫行为的治疗目标。

项目成果

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Nobuyoshi Suto其他文献

Nobuyoshi Suto的其他文献

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{{ truncateString('Nobuyoshi Suto', 18)}}的其他基金

Neural activity-based candidate gene identification to link eating disorders and drug addiction
基于神经活动的候选基因识别将饮食失调和药物成瘾联系起来
  • 批准号:
    10528062
  • 财政年份:
    2023
  • 资助金额:
    $ 53.44万
  • 项目类别:
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:
    10522520
  • 财政年份:
    2022
  • 资助金额:
    $ 53.44万
  • 项目类别:
Functional Epigenetic Profiling of Anti-Relapse Cannabidiol
抗复发大麻二酚的功能表观遗传学分析
  • 批准号:
    9317927
  • 财政年份:
    2017
  • 资助金额:
    $ 53.44万
  • 项目类别:
Relapse-suppressing brain mechanisms in alcoholism: role of the mPFC
酗酒中抑制复发的大脑机制:mPFC 的作用
  • 批准号:
    9031014
  • 财政年份:
    2015
  • 资助金额:
    $ 53.44万
  • 项目类别:
Relapse-suppressing brain mechanisms in alcoholism: role of the mPFC
酗酒中抑制复发的大脑机制:mPFC 的作用
  • 批准号:
    9235211
  • 财政年份:
    2015
  • 资助金额:
    $ 53.44万
  • 项目类别:
Cocaine omission cues suppress relapse: role of the medial prefrontal cortex
可卡因遗漏线索抑制复发:内侧前额叶皮层的作用
  • 批准号:
    8817127
  • 财政年份:
    2015
  • 资助金额:
    $ 53.44万
  • 项目类别:
Cocaine omission cues suppress relapse: role of the medial prefrontal cortex
可卡因遗漏线索抑制复发:内侧前额叶皮层的作用
  • 批准号:
    9503832
  • 财政年份:
    2015
  • 资助金额:
    $ 53.44万
  • 项目类别:
Relapse-suppressing neuronal ensembles in cocaine addiction
可卡因成瘾中抑制复发的神经元群
  • 批准号:
    8445181
  • 财政年份:
    2013
  • 资助金额:
    $ 53.44万
  • 项目类别:
Relapse-suppressing neuronal ensembles in cocaine addiction
可卡因成瘾中抑制复发的神经元群
  • 批准号:
    8601922
  • 财政年份:
    2013
  • 资助金额:
    $ 53.44万
  • 项目类别:

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