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a2A-Adrenergic Receptor Activation Decreases Parabrachial Nucleus Excitatory
Drive onto BNST CRF Neurons and Reduces Their Activity In Vivo.
Fetterly TL, Basu A, Nabit BP, Awad E, Williford KM, Centanni SW, Matthews RT,
Silberman Y, Winder DG
Submitted Externally on 2/22/2019
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume : Pages
39 : 472 - 484
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 a2A-adrenergic receptors (ARs) by the agonist guanfacine
reduced cFos expression in these neurons both in stressed and unstressed
conditions. Further, we find that a- and ß-ARs differentially regulate
excitatory drive onto these neurons. Pharmacological and
channelrhodopsin-assisted mapping experiments suggest that a2A-ARs specifically
reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF
neurons. Given that the a2A-AR is a Gi-linked GPCR, we assessed the impact of
activating the Gi-coupled DREADD hM4Di in the PBN on restraint stress regulation
of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced Fos in
BNST Crh neurons. Further, using Prkcd as an additional marker of BNST neuronal
identity, we uncovered a female-specific upregulation of the coexpression of
Prkcd/Crh in BNST neurons following stress, which was prevented by ovariectomy.
These findings show that stress activates BNST CRF neurons, and that a2A-AR
activation suppresses the in vivo activity of these cells, at least in part by
suppressing excitatory drive from PBN inputs onto CRF neurons.SIGNIFICANCE
STATEMENT 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 a2A-AR agonist
guanfacine reduces activity of these cells in vivo, and reduces excitatory PBN
inputs onto these cells ex vivo Additionally, we uncover a novel sex-dependent
coexpression of Prkcd with Crh 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.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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