Additive antidepressant‐like effects of fasting with β‐estradiol in mice

Our recent study has shown that acute fasting produces antidepressant‐like effects in male mice. However, there is little evidence regarding the antidepressant‐like effects of acute fasting in female mice. Moreover, it is not yet clear whether estrogen produces additive effects with acute fasting. Therefore, this study aims to investigate the antidepressant‐like effects of acute fasting plus estrogen treatment. In this study, the acute fasting produced antidepressant‐like effects in female mice and the antidepressant‐like effects of 9 hours fasting with those of β‐estradiol (E2) were additive. Activity of the cyclic adenosine monophosphate (cAMP) response element‐binding protein (CREB)‐brain‐derived neurotrophic factor (BDNF) pathway in the prefrontal cortex (PFC) and hippocampus (HP) was increased, as well as neurogenesis in the subgranular zone of the hippocampus. Serum ghrelin and estrogen were also increased by fasting plus E2. Furthermore, RNA‐seq analysis indicated that fasting and E2 co‐regulate similar gene expression pathways, underlying similar neurological functions. Taken together, these data suggest that E2 produces additive antidepressant‐like effects with fasting by activating the CREB‐BDNF pathway in the PFC and HP. Genome‐wide transcriptome mapping suggests that fasting may be used as an adjunct to estrogen replacement therapy for the treatment of depression associated with reduced estrogen function.