The varying effects of short-term and long-term corticosterone injections on depression-like behavior in mice

Corticosterone, a principal glucocorticoid synthesized in the rodent adrenal cortex and secreted in response to stress, is reported to produce a biphasic effect on animal behavior. In this study, we determine that corticosterone administration produced different effects on depression-like behavior in mice depending on the length of time it was administered. In addition, we explored the indirect evidence at the cellular and molecular levels in order to support above assertion. Male mice received repeated injections of the vehicle and 20 mg/kg of corticosterone for 6, 18, and 36 days before being subjected to the forced swimming and tail suspension tests. After behavioral tests, we analyzed the number of neuron-specific nuclear protein (NeuN)-positive cells in the hippocampus, and the levels of two important cytoskeleton proteins, microtubule-associated protein 2 (MAP2) and neurofilament light chain protein (NF-L). Our results showed that 18-day and 36-day corticosterone injections caused increased depression-like behavior in male mice and significantly reduced the NF-L protein levels in the hippocampal tissues. However, 6-day corticosterone injection exhibited an anti-depressant effect accompanied by increased levels of MAP2 and NF-L in the hippocampus. Interestingly, no decrement was observed in NeuN-positive cells in the entire hippocampus throughout the experiments. The results support the view that short-term and long-term corticosterone administration produce opposite effects on depression-like behavior. Furthermore, the biphasic regulation of cytoskeleton proteins in the hippocampus might be a mechanism by which corticosterone treatments influence animal behavior.