Abstract
Cold stress can induce neuronal apoptosis in the hippocampus, but the internal mechanism involving neuronal loss induced by cold stress is not clear. In vivo, male and female C57BL/6 mice were exposed to 4 °C, 3 h per day for 1 week. In vitro, HT22 cells were treated with different concentrations of cortisol (CORT) for 3 h. In vivo, CORT levels in the hippocampus were measured using ELISA, western blotting, and immunohistochemistry to assess the neuronal population and oxidation of the hippocampus. In vitro, western blotting, immunofluorescence, flow cytometry, transmission electron microscopy, and other methods were used to characterize the mechanism of mitochondrial damage induced by CORT. The phenomena of excessive CORT-mediated oxidation stress and neuronal apoptosis were shown in mouse hippocampus tissue following cold exposure, involving mitochondrial oxidative stress and endogenous apoptotic pathway activation. These processes were mediated by acetylation of lysine 9 of histone 3, resulting in upregulation involving Adenosine 5‘-monophosphate (AMP)-activated protein kinase (APMK) phosphorylation and translocation of Nrf2 to the nucleus. In addition, oxidation in male mice was more severe. These findings provide a new understanding of the underlying mechanisms of the cold stress response and explain the apoptosis process induced by CORT, which may influence the selection of animal models in future stress-related studies.
Highlights
Stress is the endogenous response of the body to internal or external factors, and appropriate stress reactions are positive for survival and adaption to stress [1], but chronic stress agents can induce abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis, which will secrete stress hormones to induce a series of effects in the brain, such as post-traumatic stress disorder, depression, and chronic anxiety [2,3]
The CORT levels were significantly increased in the the CORT levels were significantly increased in the cold exposure male (CEM) group when compared to the hippocampus of the cold exposure (CE) groups of male and female mice when compared with the room temperature (RT) groups
The results showed an increase in Nrf2 (Figure 2D) and Keap1 (Figure 2E) in the CEM and cold exposure female (CEF) groups compared with the room temperature male (RTM) or REF groups, and both proteins were remarkably increased in the CEM group compared to the CEF group
Summary
Stress is the endogenous response of the body to internal or external factors, and appropriate stress reactions are positive for survival and adaption to stress [1], but chronic stress agents can induce abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis, which will secrete stress hormones to induce a series of effects in the brain, such as post-traumatic stress disorder, depression, and chronic anxiety [2,3]. Studies have reported the induction of chronic stress and the exacerbation of neuronal loss [4]. Cold exposure is a common form of stress in some extreme cold environments for humans and other organisms [5,6]. Working or living in cold weather environments may increase the risk of cold stress-induced chronic disease and degenerative diseases. Cold stress syndrome induced by cold exposure disturbs energy metabolism and immunological functions [7], resulting in endogenous or secondary diseases [8,9].
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