Summary: A new study reveals a unique population of corticotropin releasing factor neurons in female mice that may mediate differences in stress response.
Source: Vanderbilt University.
Stress contributes to psychiatric diseases including depression, eating disorders and addiction. Neurons that express the stress signal corticotropin releasing factor (CRF) in a brain region called the BNST are thought to promote negative responses to stress.
Danny Winder, PhD, and colleagues reported in The Journal of Neuroscience that acute restraint stress in mice activates CRF neurons in the BNST, supporting a role for these neurons in stress-related behaviors. They showed that the drug guanfacine, which acts on inhibitory alpha2A-adrenergic receptors, reduces CRF neuron activity in both stressed and unstressed conditions.
In mapping experiments, the researchers found that alpha2A-adrenergic receptors reduce excitatory input to the BNST from neurons in the parabrachial nucleus brain region. They also discovered a unique population of CRF neurons in female mice that may mediate sex differences in responses to stress.
The findings demonstrate interactions between norepinephrine, which works through adrenergic receptors, and CRF, and they offer valuable insights for the development of therapeutics that can alter negative responses to stress.
About this neuroscience research article
Funding: This research was supported by grants from the National Institutes of Health (DA042475, AA019455, AA022937).
Source: Leigh MacMillan – Vanderbilt University Publisher: Organized by NeuroscienceNews.com. Image Source: NeuroscienceNews.com image is adapted from the Vanderbilt University news release. Original Research:Abstract for “α2A-Adrenergic Receptor Activation Decreases Parabrachial Nucleus Excitatory Drive onto BNST CRF Neurons and Reduces Their Activity In Vivo” by Tracy L. Fetterly, Aakash Basu, Brett P. Nabit, Elias Awad, Kellie M. Williford, Samuel W. Centanni, Robert T. Matthews, Yuval Silberman and Danny G. Winder in Journal of Neuroscience. Published January 16 2019. doi:10.1523/JNEUROSCI.1035-18.2018
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[cbtabs][cbtab title=”MLA”]Vanderbilt University”Modulating Stress Circuits.” NeuroscienceNews. NeuroscienceNews, 18 February 2019. <https://neurosciencenews.com/stress-modulation-10763/>.[/cbtab][cbtab title=”APA”]Vanderbilt University(2019, February 18). Modulating Stress Circuits. NeuroscienceNews. Retrieved February 18, 2019 from https://neurosciencenews.com/stress-modulation-10763/[/cbtab][cbtab title=”Chicago”]Vanderbilt University”Modulating Stress Circuits.” https://neurosciencenews.com/stress-modulation-10763/ (accessed February 18, 2019).[/cbtab][/cbtabs]
α2A-Adrenergic Receptor Activation Decreases Parabrachial Nucleus Excitatory Drive onto BNST CRF Neurons and Reduces Their Activity In Vivo
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 α2A-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 α2A-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α2A-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 α2A-AR activation suppresses the in vivo 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 α2A-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.