Stress-induced glucocorticoid desensitizes adrenoreceptors to gate the neuroendocrine response to somatic stress in male mice

Noradrenergic afferents to hypothalamic corticotropin releasing hormone (CRH) neurons provide a major excitatory drive to the hypothalamic-pituitary-adrenal (HPA) axis via a1 adrenoreceptor activation. Noradren-ergic afferents are recruited preferentially by somatic, rather than psychological, stress stimuli. Stress -induced glucocorticoids feed back onto the hypothalamus to negatively regulate the HPA axis, providing a critical autoregulatory constraint that prevents glucocorticoid overexposure and neuropathology. Whether negative feedback mechanisms target stress modality-specific HPA activation is not known. Here, we describe a desensitization of the a1 adrenoreceptor activation of the HPA axis following acute stress in male mice that is mediated by rapid glucocorticoid regulation of adrenoreceptor trafficking in CRH neurons. Glucocorticoid-induced a1 receptor trafficking desensitizes the HPA axis to a somatic but not a psycholog-ical stressor. Our findings demonstrate a rapid glucocorticoid suppression of adrenergic signaling in CRH neurons that is specific to somatic stress activation, and they reveal a rapid, stress modality-selective gluco-corticoid negative feedback mechanism.

Automated summary

Noradrenergic signaling via a1 adrenoreceptor activation drives the hypothalamic-pituitary-adrenal axis in response to stress, with somatic stimuli preferentially activating these pathways over psychological stress. Glucocorticoids provide negative feedback onto the hypothalamus to regulate the HPA axis and prevent overexposure and neuropathology. This study demonstrates that acute stress leads to rapid glucocorticoid regulation of adrenoreceptor trafficking in CRH neurons, specifically desensitizing the HPA axis to somatic stress. These findings reveal a stress modality-selective glucocorticoid negative feedback mechanism.