Visualizing obesity-induced changes in dopamine reinforcement

可视化肥胖引起的多巴胺强化变化

基本信息

批准号：
10291445
负责人：
JEFF A. BEELER
金额：
$ 46.2万
依托单位：
QUEENS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291445
关键词：
Address Animal Testing Animals Automobile Driving Behavior Behavioral Binge Eating Body Weight Changes Body Weight decreased Caloric Restriction Cells Chronic Consensus Consumption Cues Data Desire for food Development Diet Dietary Intervention Dopamine Eating Behavior Effectiveness Extinction (Psychology)Fiber Food High Fat Diet Human Hunger Hyperphagia Impairment Intervention Laboratories Measurement Measures Mediating Modernization Modification Motivation Mus Obese Mice Obesity Optics Palate Phase Photometry Physiological Play Psychological reinforcement Public Health Relapse Resistance Rewards Role Satiation Self Stimulation Signal Transduction Specificity Testing Thinness Time Weight Work addiction awake base behavior change behavioral study blood glucose regulation cell behavior cell type deprivation design diet and exercise dietary dietary restriction dieting dopamine system drug of abuse experimental study feeding food environment food restriction healthy weight hedonic insight mouse genetics obesity development obesity treatment obesogenic optogenetics reinforced behavior reinforcer relating to nervous system response success theories tool

项目摘要

PROJECT SUMMARY/ABSTRACT Obesity is significant public health problem in the US and globally. Diet and exercise continue to be the primary treatment for obesity, but behavioral change is often difficult and long-term success limited by relapse to overconsumption and weight regain. The highly palatable and energy rich food that are readily available in modern culture has been hypothesized to drive overeating through dopamine-mediated reinforcement that generates hedonic hunger and addiction-like, compulsive consumption. Understanding dopamine mediated compulsive overeating is important for understanding and addressing the behavioral inflexibility that makes obesity so difficult to treat in the long-term. However, how dopamine may mediate compulsive consumption remains unclear. While the basic premise of dopamine theories of obesity is that dopamine activity reinforces consumption of tasty food, considerable evidence suggest that obesity actually induces impairments in dopamine function. Thus, although theories on dopamine in obesity are crucial, a clear picture of how dopamine is altered in obesity and how these changes mediate inflexible eating behavior has not emerged. Direct observation of dopamine signaling during behavioral tasks in awake, behaving animals would provide insight into how dopamine function changes in obesity and how those changes correspond to behavior. However, one challenge in studying behavior in obesity in animals is that in order to get the animal to participate in the experiment, for example to do a lever-pressing task, food restriction is typically required to induce participatory motivation. In dietary induced obesity, however, food restriction interferes with the basic condition being tested by, effectively, putting the animals on a calorie restricted diet. In this proposal, we will use fiber photometry to directly measure dopamine release in awake, behaving mice comparing obese and lean mice. We will use an optical self-stimulation paradigm that does not require food restriction to avoid the problems of food restriction in obesity studies as well as to examine ‘pure’ dopamine reinforcement, i.e., reinforcement via dopamine activation absent actual reward or need/deprivation state. We will examine the timecourse of obesity-induced alterations in dopamine and associated reinforcement efficacy. Finally, we will provide a weight-loss dietary intervention with the obese mice to assess the extent to which weight-loss correlates with potential normalization of dopamine. By providing a direct window onto dopamine signaling and reinforcement in obesity, the proposed work will serve as a reference or touchstone for interpreting diverse, sometimes disparate data on dopamine and obesity and for evaluating associated theories.

项目摘要/摘要肥胖是美国和全球的重大公共卫生问题。饮食和运动继续是肥胖的主要治疗方法，但行为改变通常很困难，长期成功受到退休的限制过度消费和体重仍然存在。非常容易获得的高度可口和能量丰富的食物假设现代文化可以通过多巴胺介导的增强来推动暴饮暴食产生享乐饥饿和类似成瘾的强迫性消费。了解多巴胺介导的强迫性暴饮暴食对于理解和解决使行为僵化的重要性很重要从长远来看，肥胖很难治疗。但是，多巴胺如何介导强迫性消费仍然不清楚。多巴胺理论的基本前提是多巴胺活性增强食用美味的食物，大量证据表明肥胖实际上会引起损害多巴胺功能。因此，尽管肥胖中多巴胺的理论至关重要，但清楚地了解了如何多巴胺在肥胖症中发生了改变，这些变化如何变化媒体不灵活的饮食行为尚未出现。直接观察在清醒行为任务期间多巴胺信号传导，行为动物将提供有关多巴胺功能在肥胖症中的变化以及这些变化方式与行为相对应的洞察力。但是，研究动物肥胖行为的一个挑战是，为了使动物成为参加实验，例如，要执行杠杆压榨任务，通常需要食物限制引起参与动机。但是，在饮食诱发的肥胖症中，食物限制干扰了基本通过有效地将动物限制在限制卡路里的饮食中的病情测试。在此提案中，我们将使用纤维光度法直接测量醒着中的多巴胺释放，表现出比较肥胖和的小鼠瘦老鼠。我们将使用不需要食物限制的光学自刺激范式来避免肥胖研究中的食物限制问题以及检查“纯”多巴胺增强的问题，即没有实际的奖励或需求/剥夺状态通过多巴胺激活加强。我们将检查肥胖诱导的时间诱导的多巴胺和相关增强效率的改变。最后，我们会的与肥胖小鼠提供减轻体重的饮食干预措施，以评估减肥的程度与多巴胺的潜在归一化相关。通过向多巴胺信号传导提供一个直接的窗口和在肥胖症中加强拟议的工作将作为解释潜水员的参考或试金石，有时关于多巴胺和肥胖症以及评估相关理论的数据不同。