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

基本信息

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
项目类别：
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

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 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。来自老鼠的试验数据表明，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”。这些结果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，我们的数据。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，药物/饮食引起的控制非稳态调节的大脑部位发生变化，例如奖励回路，可能会导致强迫性食欲。我们之前发现，食欲行为在一定程度上是，由边缘下皮层 (IL) 中的“食物反应”神经元（如激活标记 Fos 所示）控制 – 奖励回路的一部分被认为可以独立于能量稳态调节药物和食物动机；因此，这些神经元似乎充当非稳态食欲调节的“加速器”。发现广泛的用药史会增加 IL 和奖励内其他大脑部位的神经食物反应电路，同时优先诱导与异常神经可塑性和成瘾相关的基因表达变化这种大脑变化会导致对食物有反应的神经元（而不是无反应的神经元）产生更多的“加速”。通过非稳态失调的食物动机，因此可能表现为强迫性食欲。在先前研究的严谨性和上述前提的基础上，该项目将检验中心假设，即广泛的可卡因/酒精/致肥胖饮食史通过独特的基因表达变化诱导强迫性食欲奖励回路中的食物反应神经元包含对每个食物有选择性反应的神经元。特定的行为相关刺激——可能会发挥不同的行为功能，因此我们将利用神经系统。活动特异性基因表达谱（目标 1）和拯救（目标 2）以针对食物反应神经元。预期结果将确定与强迫性食欲功能相关的基因表达变化。知识可能有助于确定新的治疗目标，以对抗饮食失调的强迫行为和毒瘾。