Neural activity-based candidate gene identification to link eating disorders and drug addiction

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 来自老鼠的试验数据表明，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，我们的数据 认为强迫性食欲是由非动态平衡的“动机/习惯性”失调驱动的。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，药物/饮食导致控制非体内平衡调节的大脑部位发生变化，例如 奖赏回路，可能会引起强迫性食欲。我们之前发现，食欲行为在一定程度上是 由下缘皮质(IL)的“食物反应性”神经元(如激活标记Fos所示)控制。 奖赏回路的一部分，被认为独立于能量平衡来调节药物和食物的动机； 因此，这些神经元似乎起到了非稳态食欲调节的“加速器”的作用。我们还有 发现广泛的吸毒史增加了IL和其他大脑部位的神经食物反应性 电路诱导基因表达变化优先与异常神经可塑性和成瘾相关 在食物中-反应性-而不是非反应性-神经元。这样的大脑变化会导致更多的脑部 食物动力通过非体内平衡失调，从而很可能表现为强迫性食欲。基座 在前人研究的严谨性和上述前提的基础上，本项目将检验广泛性的中心假设 可卡因/酒精/肥胖饮食史通过独特的基因表达变化诱导强迫性食欲 奖赏回路中的食物反应神经元。奖赏回路包含选择性地对每个神经元产生反应的神经元。 特定的行为相关刺激--可能发挥不同的行为功能。因此，我们将利用神经 针对食物反应神经元的特定活性基因表达谱(目标1)和拯救(目标2)。这个 预期的结果将决定与强迫症食欲有关的基因表达变化。是这样的 知识可能有助于确定新的治疗靶点，以对抗进食障碍中的强迫行为 和吸毒成瘾。

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 pilot data from rats indicate 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 data suggest 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, drug/diet-induced changes in brain sites that control non-homeostatic regulation, such as reward circuits, likely cause compulsive appetite. We previously found that appetitive behavior is, in part, controlled by ‘food-reactive’ neurons (as indicated by the activation marker Fos) in the infralimbic cortex (IL) – a part of reward circuits thought to regulate drug and food motivation independently of energy homeostasis; these neurons thus appear to function as “accelerators” for non-homeostatic appetite regulation. We have also found that extensive drug histories increase neural food-reactivities in IL and other brain sites within reward circuits while inducing gene expression changes linked to aberrant neural plasticity and addiction preferentially in food-reactive – rather than non-reactive – neurons. Such brain changes would entail more “acceleration” on food motivation via non-homeostatic dysregulation, thereby likely manifesting as 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 induce compulsive appetite via gene expression changes unique to food-reactive neurons in the reward circuits. The reward circuits contain neurons selectively reactive to each specific behaviorally relevant stimuli – likely exerting different behavioral functions. We will thus utilize neural activity-specific gene expression profiling (Aim 1) and rescuing (Aim 2) to target food-reactive neurons. The expected results will determine genes expression changes functionally linked to compulsive appetite. Such knowledge may help identify novel therapeutic targets to counter compulsive behavior across eating disorders and drug addiction.