Abstract
The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of not only drug addiction but also diet-induced obesity. In the present study, we examined whether signaling through glucocorticoid receptors (GRs) in the reward system affects the rewarding value of a high-fat diet (HFD). To do so, we generated mice that lack functional GRs specifically in dopaminergic neurons (D-KO mice) or corticostriatal neurons (CS-KO mice), subjected the mice to caloric restriction stress conditions, and evaluated the rewarding value of a HFD by conditioned place preference (CPP) test. Caloric restriction induced increases in serum corticosterone to similar levels in all genotypes. While CS-KO as well as WT mice exhibited a significant preference for HFD in the CPP test, D-KO mice exhibited no such preference. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test. These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress.
Highlights
The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of drug addiction and diet-induced obesity
Immunostaining for both dopamine transporter (DAT) and glucocorticoid receptors (GRs) revealed that GRs were expressed in dopaminergic neurons of the VTA in WT mice, whereas GR-expressing cells in the VTA were rarely detected in D-KO mice (Fig. 1C)
GRloxP/loxP GPR88-Cre R26GRRmice expressed tdsRed-positive cells in the nucleus accumbens (NAc) and CPu, and GR immunostaining revealed that GR was expressed in the tdsRed-positive cells in the NAc and CPu in WT but not in CS-KO mice (Fig. 1D,E), while GR was expressed in the tdsRed-positive cells in mPfc and Ofc in WT as well as CS-KO mice (Supplementary Figure 1)
Summary
The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of drug addiction and diet-induced obesity. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress. Stress promotes consumption of palatable food[11], and previous studies have shown that increases in serum cortisol concentrations in response to stress are closely correlated with the amount of snack intake in human s ubjects[12], and that mice which were moderately food-restricted in advance showed a significant increase in binge eating of a palatable high-fat food during stress e xposure[13] These results suggest that glucocorticoid signaling activated by stress can stimulate the reward system and thereby increase intake of palatable food, the detailed mechanisms have not yet been clarified. We generated mice that lack functional GRs in dopaminergic and corticostriatal neurons, and examined whether signaling through GRs in the reward system affects the rewarding value of a HFD by using a conditioned place preference (CPP) test, in order to investigate the role of glucocorticoid signaling in the reward system
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