Visualizing obesity-induced changes in dopamine reinforcement

项目摘要/摘要 肥胖是美国乃至全球的重大公共健康问题。饮食和锻炼仍然是最重要的 肥胖症的初步治疗，但行为改变往往是困难的和长期的成功受限于复发 过度消费和体重恢复。非常美味和富含能量的食物，在中国随时可以买到 现代文化被假设是通过多巴胺介导的强化来推动过量饮食 产生享乐式的饥饿感和类似上瘾的强迫性消费。了解多巴胺介导的 强迫性暴食对于理解和解决行为不灵活是很重要的，这种行为不灵活会使 肥胖症很难长期治疗。然而，多巴胺可能如何调节强迫性消费 目前仍不清楚。而肥胖的多巴胺理论的基本前提是，多巴胺的活动加强了 食用美味的食物，相当多的证据表明肥胖实际上会导致 多巴胺的功能。因此，尽管关于多巴胺在肥胖中的理论至关重要，但清楚地了解 多巴胺在肥胖中会发生变化，而这些变化是如何调节不灵活的饮食行为的还没有出现。 在清醒、表现良好的动物的行为任务中直接观察多巴胺信号将 洞察肥胖中多巴胺功能的变化，以及这些变化与行为的对应关系。 然而，研究动物肥胖行为的一个挑战是，为了让动物 参加实验，例如做一个杠杆按压的任务，通常要求限食 激发参与性动机。然而，在饮食诱导的肥胖中，食物限制干扰了基本的 通过有效地让动物进行卡路里限制饮食来测试条件。在这项提案中，我们将 用纤维光度法直接测量清醒、行为肥胖和肥胖小鼠的多巴胺释放 瘦小的老鼠。我们将使用一种光学自我刺激模式，它不需要限制食物来避免 肥胖研究中的食物限制问题，以及检查“纯”多巴胺强化，即， 在没有实际奖励或需要/剥夺状态的情况下，通过多巴胺激活来强化。我们将研究 肥胖引起的多巴胺改变和相关强化效果的时程。最后，我们会 为肥胖小鼠提供减肥饮食干预，以评估其减肥程度 与多巴胺的潜在正常化有关。通过提供了解多巴胺信号的直接窗口和 对于肥胖的强化，拟议的工作将作为解释不同的、 有时，关于多巴胺和肥胖以及评估相关理论的数据是不同的。

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.