Nucleus Accumbens D₁ Receptor–Expressing Spiny Projection Neurons Control Food Motivation and Obesity

Background: Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. There is growing recognition that food motivation is altered in people with obesity. However, it remains unclear how brain circuits that control food motivation are altered in obese animals. Methods: Using a novel behavioral assay that quantifies work during food seeking, in vivo and ex vivo cell-specific recordings, and a synaptic blocking technique, we tested the hypothesis that activity of circuits promoting appetitive behavior in the core of the nucleus accumbens (NAc) is enhanced in the obese state, particularly during food seeking. Results: We first confirmed that mice made obese with ad libitum exposure to a high fat diet work harder than lean mice to obtain food, consistent with an increase in food motivation in obese mice. We observed greater activation of D₁ receptor–expressing NAc spiny projection neurons (NAc D1^SPNs) during food seeking in obese mice relative to lean mice. This enhanced activity was not observed in D₂ receptor–expressing neurons (D2^SPNs). Consistent with these in vivo findings, both intrinsic excitability and excitatory drive onto D1^SPNs were enhanced in obese mice relative to lean mice, and these measures were selective for D1^SPNs. Finally, blocking synaptic transmission from D1^SPNs, but not D2^SPNs, in the NAc core decreased physical work during food seeking and, critically, attenuated high fat diet–induced weight gain. Conclusions: These experiments demonstrate the necessity of NAc core D1^SPNs in food motivation and the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity.