Visualizing obesity-induced changes in dopamine reinforcement

项目概要/摘要 肥胖是美国和全球的重大公共卫生问题。饮食和运动仍然是 肥胖症的主要治疗方法，但行为改变往往很困难，而且长期成功会因复发而受到限制 过度消耗和体重反弹。非常美味且富含能量的食物，在 人们假设现代文化通过多巴胺介导的强化来驱动暴饮暴食 产生享乐性饥饿和类似成瘾的强迫性消费。了解多巴胺介导 强迫性暴饮暴食对于理解和解决导致行为不灵活的行为非常重要 肥胖症从长远来看很难治疗。然而，多巴胺如何介导强迫性消费 仍不清楚。虽然多巴胺肥胖理论的基本前提是多巴胺活性增强了 食用美味食物，大量证据表明肥胖实际上会导致 多巴胺功能。因此，尽管多巴胺与肥胖相关的理论至关重要，但清楚地了解多巴胺如何影响肥胖 多巴胺在肥胖症中发生改变，但这些改变如何介导不灵活的饮食行为尚不清楚。 在清醒、有行为能力的动物的行为任务中直接观察多巴胺信号传导 深入了解肥胖中多巴胺功能如何变化以及这些变化如何与行为相对应。 然而，研究动物肥胖行为的一个挑战是，为了让动物 参与实验，例如执行压杆任务，通常需要限制食物 激发参与动机。然而，在饮食引起的肥胖中，食物限制会干扰基本的 通过对动物进行热量限制饮食来有效地测试病情。在本提案中，我们将 使用光纤光度法直接测量清醒、行为正常的小鼠的多巴胺释放，比较肥胖和肥胖小鼠的多巴胺释放情况。 瘦老鼠。我们将使用不需要食物限制的光学自刺激范例来避免 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，通过多巴胺激活进行强化。我们将检查 肥胖引起的多巴胺变化的时间进程和相关的强化功效。最后，我们将 对肥胖小鼠进行减肥饮食干预，以评估减肥的程度 与多巴胺的潜在正常化相关。通过提供多巴胺信号传导的直接窗口 肥胖症的强化，拟议的工作将作为解释多样化的参考或试金石， 有时关于多巴胺和肥胖以及评估相关理论的数据不同。

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.