Electronic Thesis and Dissertation Repository


Master of Science




Inoue, Wataru


One way that the body actively responds to an impending stressor is by increasing systemic glucocorticoids through the activation of the hypothalamic-pituitary-adrenal (HPA) axis. While it is essential for short-term adaptation to stress, the sustained activation of the HPA axis during chronic stress can be detrimental and is linked to stress-related psychiatric conditions such as anxiety and depression. Therefore, it is important that the HPA axis adapts, or habituates, during chronic stress to minimize the negative consequences. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) function to assimilate incoming information from the stress circuitry and initiate the HPA axis by releasing CRH to the circulation. Here, we report a neurophysiological correlate for the habituation of the HPA axis to daily repeated restraint stress in mice. By using immunohistochemistry, we first show that 21 days of repeated restraint stress decreases restraint-induced c-fos expression in PVN-CRH neurons (i.e. habituation of PVN-CRH neurons to restraint). We then show that this neuronal habituation to repeated restraint stress is accompanied by a robust decrease in the intrinsic excitability of PVN-CRH neurons. Mechanistically, the stress-induced decrease in the intrinsic excitability correlates with a decrease in whole-cell membrane resistance. Surprisingly, the decrease in the membrane resistance is not due to the changes in specific properties of the cell membrane but is best explained by the changes in cell surface area (i.e. cell size), suggesting that stress-induced changes in cell size promote attenuation of incoming stress signals. Together these findings support stress-induced changes during habituation that promote stress resilience.