“Diet-induced Obesity Enhances Prelimbic Inputs Onto Accumbal D1-SPNs and Increases Effort of Food Seeking”

Hosted by the Center for the Investigation of Membrane Excitability Diseases (CIMED)

Abstract: Obesity is a leading cause of preventable death and is linked to multiple comorbidities. While many people lose weight with diet and exercise, maintenance of weight loss is difficult – most people who lose weight regain it. Studies in rodents and humans demonstrate that obesity alters neural circuits associated with reward, leading us to hypothesize that these circuits may underlie the challenges associated with maintaining weight loss. To test this hypothesis, we asked how reward circuits are dysregulated in obese animals, and how manipulating these circuits alters food seeking. We used a force-sensing lever to characterize how much effort mice would expend to obtain food, and found that obese mice exerted more effort during food seeking than lean controls. We next performed in vivo recordings in awake mice which revealed that the strength of prelimbic cortical (PL) inputs to the nucleus accumbens core (NAc) was enhanced in obese mice. With ex vivo slice experiments, we found that this enhanced PL-NAc input in obese mice preferentially target D1-spiny projection neurons (D1-SPNs). We performed ex vivo recordings after weight loss and found that enhancements in PL-D1-SPN input persisted after weight loss, as did enhancements in effort during food seeking. This may suggest that these changes are responsible for increases in food-seeking that persist in obese mice even after weight loss. Finally, to test the necessity of D1-SPNs in controlling food seeking effort, we reduced D1-SPN output via expression of a tetanus toxin subunit, and found that this both decreased lever-pressing effort during food seeking, and surprisingly attenuated diet-induced obesity. These experiments suggest that PL inputs to NAc-D1-SPNs are enhanced in obese mice, and these changes persist after weight loss. This may explain persistent behavioral effects in people with obesity, and why weight loss maintenance is so difficult. Controlling the PL-D1-SPN projection may be effective for modulating food seeking and body weight in obesity. 

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