Corticosterone Excess-Mediated Mitochondrial Damage Induces Hippocampal Neuronal Autophagy in Mice Following Cold Exposure

SIMPLE SUMMARY: In this study, the phenomenon of ‘autophagy’ was demonstrated in the hippocampus following cold exposure. Persistent neuronal stimulation of the hippocampus after corticosterone (CORT) treatment induced mitochondrial damage and autophagy by activating the AMPK/mTOR signaling pathway, which did not rely on glucocorticoid receptors (GRs). The phenomenon in the hippocampus of the cold stress mice was also a sex-related difference in the response to cold stress; the phenomenon of autophagy was more severe in males. These findings provided a new understanding of the underlying mechanisms of the cold stress response, which may influence the selection of animal models in future stress-related studies. ABSTRACT: Cold stress can induce autophagy mediated by excess corticosterone (CORT) in the hippocampus, but the internal mechanism induced by cold stress is not clear. In vivo, male and female C57BL/6 mice were stimulated in 4 °C, 3 h per day for 1 week to build the model of cold sress. In vitro, hippocampal neuronal cell line (HT22) cells were incubated with or without mifepristone (RU486) for 1 h, then treated with 400 μM cortisol (CORT) for 3 h. In vivo, autophagy was measured by western blotting. In vitro, monodansylcadaverine staining, western blotting, flow cytometry, transmission electron microscopy, and immunofluorescence were used to characterize the mechanism of autophagy induced by excess CORT. Autophagy was shown in mouse hippocampus tissues following cold exposure, including mitochondrial damage, autophagy, and 5’ AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway activation after CORT treatment. Autophagy did not rely on the glucocorticoid receptor. In addition, autophagy in male mice was more severe. The study would provide new insight into the mechanisms and the negative effect of the cold stress response, which can inform the development of new strategies to combat the effects of hypothermia.