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
• 负责人: Nobuyoshi Suto
• 金额: $ 27.15万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10528062
• 关键词: Ablation; Acceleration; Affect; Alcohols; Amygdaloid structure; Animal Model; Appetite Regulation; Appetitive Behavior; Behavioral; Binge eating disorder; Brain; Brain region; Bulimia; Calories; Candidate Disease Gene; Cell Separation; Cells; Cocaine; Compulsive Behavior; Data; Desire for food; Diet; Dietary History; Down-Regulation; Drug Addiction; Drug usage; Eating; Eating Disorders; Etiology; Fatty acid glycerol esters; Food; Gene Expression; Gene Expression Profiling; General Population; Genes; Genetic Risk; Genetic Transcription; Homeostasis; Incentives; Intake; Knowledge; Life; Link; Liquid substance; Metabolic; Methods; Motivation; Neuronal Plasticity; Neurons; Nucleus Accumbens; Patients; Pharmaceutical Preparations; Pilot Projects; Publishing; Punishment; Rattus; Recording of previous events; Regulation; Research; Resistance; Rewards; Saccharin; Shock; Site; Stimulus; Study models; System; Testing; Weight Gain; addiction; adverse outcome; comorbidity; detection platform; drug craving; food craving; gene induction; genetic risk factor; hedonic; inducible Cre; neural; neurobiological mechanism; new therapeutic target; obesogenic; recruit; sugar; transcriptome sequencing; 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 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.

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 来自大鼠的飞行员数据表明​​，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，像强迫性毒品动机一样，我们的数据 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。这，药物/饮食引起的控制非固定调节的大脑部位的变化，例如 奖励电路，可能会引起强迫性食欲。我们以前发现，开胃菜的行为部分是 由“食物反应性”神经元（如激活标志物FO所示）控制，在输液皮层（IL） - 奖励电路的一部分被认为是独立于能量稳态来调节药物和食物动机的一部分； 因此，这些神经元似乎充当非防境食欲调节的“加速器”。我们也有 发现广泛的药物史增加了奖励中IL和其他大脑部位的神经食物反应性 电路虽然诱导的基因表达变化与异常神经可塑性和成瘾相关 在食物反应性（而不是非反应性）神经元中。这种大脑变化将需要更多的“加速” 食物动机通过非室外失调，因此可能表现为强迫性食欲。基于 在上面的先前研究和前提下，该项目将检验一个中心假设，即广泛的假设 可卡因/酒精/肥胖饮食史通过基因表达引起强迫性食欲，而对 奖励电路中的食物反应性神经元。奖励电路包含神经元对每个神经元有选择性反应性 特定行为相关的刺激 - 可能发挥不同的行为函数。因此，我们将使用神经 活动特异性基因表达分析（AIM 1）和拯救（AIM 2）靶向食物反应性神经元。这 预期结果将确定基因表达在功能上与强迫性食欲联系在一起的变化。这样的 知识可能有助于确定新型的热目标，以应对跨饮食失调的强迫行为 和吸毒成瘾。