Jeffrey Tasker, Ph.D.
Professor
Department of Cell and Molecular Biology
Tulane University
“Stress desensitization of hypothalamic CRH neurons to adrenergic activation”
Noradrenergic innervation of corticotropin releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN) provides an excitatory drive to the HPA axis in response to physiological stress. Glucocorticoids secreted in response to HPA activation feed back to arrest HPA activation in a negative feedback manner. Slice-patch recordings of CRH neurons revealed a novel norepinephrine (NE) regulation of PVN CRH neurons, involving a retrograde neuronal-glial activation of local excitatory and inhibitory circuits. The NE response is triggered by activation of postsynaptic alpha1 adrenoreceptors (AR1a’s) in the CRH neurons. Prior restraint stress caused desensitization of the CRH neurons to the NE excitatory effect, which was prevented by inhibiting glucocorticoid synthesis. Preincubation of brain slices in corticosterone (5-10 min) also caused AR1a desensitization in the CRH neurons, which was prevented by an endocytosis inhibitor, suggesting that glucocorticoid-induced NE desensitization is mediated by AR1a internalization. Live-cell imaging of AR1a’s in a hypothalamic cell line showed that corticosterone, without effect alone, rapidly facilitated NE-induced AR1a internalization. Corticosterone increased AR1a interaction with the late endosomal marker Rab 11, but had no effect on interaction with the early endosomal marker Rab 5, suggesting that corticosterone prevents AR1a recycling to the membrane. These studies demonstrate a stress desensitization of CRH neurons to noradrenergic activation by the rapid glucocorticoid-induced inhibition of AR1a trafficking to the membrane. This stress desensitization of the excitatory adrenergic drive to the CRH neurons may contribute to the rapid negative feedback regulation of the HPA axis by glucocorticoids. Supported by NIH 2R01 MH066958.
Friday, March 9, 2018, 11:00AM-12:00PM, LIB-110
University of North Texas Health Science Center
Fort Worth, Texas