Visualizing obesity-induced changes in dopamine reinforcement

项目总结/摘要 肥胖是美国和全球的重大公共卫生问题。饮食和锻炼仍然是 肥胖的主要治疗，但行为改变往往是困难的，长期的成功受到复发的限制 过度消费和体重反弹。非常可口和能量丰富的食物， 现代文化被假设通过多巴胺介导的强化来驱动暴饮暴食， 会产生享乐性饥饿和成瘾性强迫性消费。了解多巴胺介导的 强迫性暴饮暴食对于理解和解决行为不稳定性是很重要的， 肥胖症很难长期治疗。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动增强了 大量的证据表明，肥胖实际上会导致 多巴胺功能因此，尽管关于多巴胺在肥胖中的理论至关重要， 多巴胺在肥胖症中发生了改变，而这些变化如何调节不灵活的饮食行为还没有出现。 直接观察清醒的行为动物在行为任务中的多巴胺信号， 深入了解多巴胺功能在肥胖中的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 参加实验，例如做一个压下的任务，食物限制通常需要， 激发参与动机。然而，在饮食诱导的肥胖症中，食物限制干扰了基本的 通过对动物进行热量限制饮食来有效地测试条件。在本提案中，我们将 使用纤维光度法直接测量清醒、行为正常的小鼠多巴胺的释放， 瘦老鼠。我们将使用一种不需要食物限制的光学自我刺激范式来避免 肥胖研究中的食物限制问题以及检查“纯”多巴胺强化，即， 在缺乏实际奖励或需要/剥夺状态的情况下，通过多巴胺激活进行强化。我们会研究 肥胖引起的多巴胺改变的时间过程和相关的强化功效。最后我们将 为肥胖小鼠提供减肥饮食干预，以评估体重减轻的程度。 与多巴胺的潜在正常化有关。通过提供一个直接观察多巴胺信号的窗口， 强化肥胖，拟议的工作将作为一个参考或试金石解释多样化， 有时是关于多巴胺和肥胖的完全不同的数据，并评估相关的理论。

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.