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

Glucocorticoids desensitize hypothalamic CRH neurons to norepinephrine and somatic stress activation via rapid nitrosylation-dependent regulation of α1 adrenoreceptor trafficking

“…1B) and by prior restraint stress-induced endogenous glucocorticoid exposure in vivo (Fig. 1C) 21 . The rapid glucocorticoid-induced desensitization of CRH neurons to NE was blocked by a dynamin inhibitor, indicating that it is dependent on endocytosis (Fig.…”

“…1D). This indicated that the stress-induced desensitization of PVN CRH neurons to activation by NE takes longer than 18 h to fully reverse and suggests a surprisingly long-lasting diminished CRH neuron sensitivity to NE and to adrenoreceptor activation of the HPA axis following exposure to acute stress 21 . Thus, acute glucocorticoid exposure causes a long-lasting desensitization of CRH neurons to NE via a mechanism with rapid onset, which is dependent on dynamindependent endocytosis of the ARα1 (Fig.…”

“…Stimulation of an immune response by systemic lipopolysaccharide (LPS), for example, activates the HPA axis by way of the NTS noradrenergic system 19,20 . Our recent findings suggest that prior priming by acute stress exposure attenuates subsequent LPS activation of the HPA axis via a rapid glucocorticoid-induced desensitization of the CRH neurons to NE activation of ARα1 21 , but the cellular and molecular mechanisms of this desensitization are not known.…”

“…The stress desensitization of PVN CRH neurons to NE is dependent on the ligand-induced internalization of ARα1 21 . ARα1 is internalized by clathrin-mediated endocytosis and is trafficked back to the membrane via recycling endosomes, a process that involves multiple trafficking proteins and that establishes a steady state of surface receptors and NE sensitivity 22 .…”

“…Noradrenergic afferents to the CRH neurons provide a primary excitatory drive for the somatic stress activation of the HPA axis 11 via activation of α1 adrenergic receptors (ARα1) [12][13][14][15] . We recently reported that glucocorticoid rapidly desensitizes PVN CRH neurons to ARα1 activation by norepinephrine (NE), which suppresses the HPA response to somatic stress, but not psychological stress, due to the NE dependence of somatic stress activation of the HPA axis 11,16 . A main source of noradrenergic input to PVN CRH neurons is the brainstem nucleus of the solitary tract (NTS) 17 .…”