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Nucleus accumbens D1R expressing spiny projection neurons control food motivation and obesity.

      Abstract:

      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 HFD (HFD) 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 D1SPNs) during food-seeking in obese mice relative to lean mice. This enhanced activity was not observed in D2-receptor expressing neurons (D2SPNs). Consistent with these in vivo findings, both intrinsic excitability and excitatory drive onto D1SPNs were enhanced in obese mice relative to lean, and these measures were selective for D1SPNs. Finally, blocking synaptic transmission from D1SPNs, but not D2SPNs, in the NAc core decreased physical work during food-seeking and, critically, attenuated HFD-induced weight gain.

      Conclusions

      These experiments demonstrate the necessity of NAc core D1SPNs in food motivation and the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity.

      Key words

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