The hypothalamic-pituitary-adrenal (HPA) axis is sexually dimorphic. However, little is known about sex differences in the HPA axis’ adaptation to chronic stress. Here, we studied sex-dependent neural plasticity mechanisms relevant to the habituation of the HPA axis to repeated stress. This habituation manifests as decreased excitability of HPA axis output neurons, which are neuroendocrine neurons that express corticotropin releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN). Mice were first subjected to 1 hour of daily restraint stress for 3 weeks, and were then challenged with the same stressor after either 1 day, 1 week, or 4 weeks of no-stress recovery periods. As controls, one group of mice received 1 hour of restraint without prior stress, and another control group received no stress. Using immunohistochemistry, we quantified the induction of the immediate early gene (IEG) c-Fos, a marker of neuronal activation, in PVN-CRH neurons. We found that, in both sexes, 3 weeks of repeated stress decreased restraint-induced c-Fos expression in the PVN-CRH neurons. Furthermore, this habituation was fully reversed by 4 weeks without stress. However, females showed greater habituation and a slower recovery; significant attenuation persisted after 1 week without stress whereas males had fully recovered by that time. In summary, we found sex differences in the neural plasticity associated with the HPA axis habituation to and recovery from repeated stress. These findings should be further explored to elucidate the mechanistic causes for these differences in c-Fos expression.
Written By Aoi Ichiyama, Xue Fan Wang, Sara Matovic, Wataru Inoue
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