Ghrelin/GHS-R1a signaling plays different roles in anxiety-related behaviors after acute and chronic caloric restriction.

The brain-gut hormone ghrelin and its receptor GHS-R1a, the growth hormone secretagogue receptor 1a, regulates diverse functions of central nervous system including stress response and mood. Both acute and chronic caloric restrictions (CR) were reported to increase endogenous ghrelin level meanwhile regulate anxiety-related behaviors; however, the causal relationship between CR-induced ghrelin elevation and anxiety are not fully established. Here, we introduced an acute (24 h) and a chronic (10wks) CR procedure to both GHS-R1a KO (Ghsr-/-) mice and WT (Ghsr+/+) littermates, and compared their anxiety-related behaviors. We found that acute CR induced anxiolytic and anti-despairing behaviors in Ghsr+/+ mice but not in Ghsr-/- mice. Ad-libitum refeeding abolished the effect of acute CR on anxiety-related behaviors. In contrast, chronic CR for 10wks facilitated despair-like behavior meanwhile inhibited anxiety-like behavior in Ghsr+/+ mice. GHS-R1a deficiency rescued despair-like behavior while did not affect anxiolytic response induced by chronic CR. In addition, we found elevated interleukin-6 (IL-6) in serum of Ghsr+/+ mice after chronic CR, but not in Ghsr-/- mice. Altogether, our findings indicated that acute CR and chronic CR have different impacts on anxiety-related behaviors, and the former is dependent on ghrelin/GHS-R1a signaling while the latter may not always be. In addition, our findings suggested that GHS-R1a-dependent elevation in serum IL-6 might contribute to increased despair-like behavior in chronic CR state.