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Visualizing obesity-induced changes in dopamine reinforcement

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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.
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