Acute But Not Chronic Calorie Restriction Defends against Stress-Related Anxiety and Despair in a GHS-R1a-Dependent Manner

Ghrelin is an important orexigenic brain-gut hormone that regulates feeding, metabolism and glucose homeostasis in human and rodents at multiple levels. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), which is widely expressed both inside and outside of the brain. Both acute and chronic calorie restrictions (CRs) were reported to increase endogenous ghrelin levels and lead to beneficial effects on brain functions, including anti-anxiety effects, anti-depressive effects, and memory improvement. However, the causal relationship and underlying mechanisms are not fully understood. Here, we introduced acute or chronic CR to both GHS-R1a KO (Ghsr−/−) mice and WT (Ghsr+/+) littermates, and investigated anxiety- and despair-related behaviors in the elevated plus maze (EPM), open field (OF) and forced swimming (FS) tests. We found that acute and chronic CR produced similar anxiolytic and anti-despair responses in Ghsr+/+ mice but opposite responses in Ghsr−/− mice. In particular, acute CR enhanced while chronic CR reduced anxiety- and despair-like behaviors in Ghsr−/− mice. Acute CR triggered anxiolytic and anti-despair responses in Ghsr+/+ mice. This effect was abolished by a GHS-R1a antagonist, suggesting a GHS-R1a dependent mechanism. Ad-libitum refeeding masked behavioral responses induced by acute CR in both Ghsr−/− and Ghsr+/+ mice. Altogether, our findings indicate that acute and chronic CRs mitigate anxiety- and despair-like behaviors with different physiological mechanisms, with the former being dependent on endogenous ghrelin release and GHS-R1a signaling, while the latter may not be. •Both acute and chronic calorie restrictions (CRs) mitigate anxiety-related behaviors, and refeeding abolishes such effect.•GHS-R deletion or GHS-R1a antagonist suppresses acute CR-induced anxiolytic effect, but has no effect after refeeding.•GHS-R deletion or GHS-R1a antagonist has no impact on chronic CR-induced anxiolytic effect.