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α-Adrenergic Receptor Activation Decreases Parabrachial Nucleus Excitatory Drive onto BNST CRF Neurons and Reduces Their Activity .

Fetterly TL, Basu A, Nabit BP, Awad E, Williford KM, Centanni SW, Matthews RT, Silberman Y, Winder DG
J Neurosci. 2019 39 (3): 472-484

PMID: 30478032 · PMCID: PMC6335747 · DOI:10.1523/JNEUROSCI.1035-18.2018

Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α-AR is a G-linked GPCR, we assessed the impact of activating the G-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced in BNST neurons. Further, using as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α-AR activation suppresses the activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons. Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α-AR agonist guanfacine reduces activity of these cells , and reduces excitatory PBN inputs onto these cells Additionally, we uncover a novel sex-dependent coexpression of with in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.

Copyright © 2019 the authors 0270-6474/19/390472-13$15.00/0.

MeSH Terms (21)

Adrenergic alpha-2 Receptor Agonists Animals Corticotropin-Releasing Hormone Female Gene Expression Genes, fos Guanfacine Male Mice Mice, Inbred C57BL Neurons Norepinephrine Ovariectomy Parabrachial Nucleus Patch-Clamp Techniques Protein Kinase C-delta Receptors, Adrenergic, alpha-2 Receptors, G-Protein-Coupled Restraint, Physical Septal Nuclei Stress, Psychological

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