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An ensemble recruited by α2a-adrenergic receptors is engaged in a stressor-specific manner in mice

Neuropsychopharmacology volume 48, pages 1133–1143 (2023)Cite this article

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Abstract

α2a-adrenergic receptor (α2a-AR) agonists are candidate substance use disorder therapeutics due to their ability to recruit noradrenergic autoreceptors to dampen stress system engagement. However, we recently found that postsynaptic α2a-ARs are required for stress-induced reinstatement of cocaine-conditioned behavior. Understanding the ensembles recruited by these postsynaptic receptors (heteroceptors) is necessary to understand noradrenergic circuit control. We utilized a variety of approaches in FosTRAP (Targeted Recombination in Active Populations) mice to define an ensemble of cells activated by the α2a-AR partial agonist guanfacine (“Guansembles”) in the bed nucleus of the stria terminalis (BST/BNST), a region key to stress-induced reinstatement of drug seeking. We define BNST “Guansembles” and show they differ from restraint stress-activated cells. Guanfacine produced inhibition of cAMP-dependent signaling in Guansembles, while chronic restraint stress increased cAMP-dependent signaling. Guanfacine both excited and inhibited aspects of Guansemble neuronal activity. Further, while some stressors produced overall reductions in Guansemble activity, active coping events during restraint stress and exposure to unexpected shocks were both associated with Guansemble recruitment. Using viral tracing, we define a BNST Guansemble afferent network that includes regions involved in the interplay of stress and homeostatic functions. Finally, we show that activation of Guansembles produces alterations in behavior on the elevated plus maze consistent with task-specific anxiety-like behavior. Overall, we define a population of BNST neurons recruited by α2a-AR signaling that opposes the behavioral action of canonical autoreceptor α2a-AR populations and which are differentially recruited by distinct stressors. Moreover, we demonstrate stressor-specific physiological responses in a specific neuronal population.

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Fig. 1: Guanfacine activates a heterogeneous cell population in the BNST.
Fig. 2: Guanfacine decreases PKA and increases calcium activity in BNST Guansembles.
Fig. 3: Guansemble neuronal activity filtered by stress exposure.
Fig. 4: Guanfacine leads to an overall increase in ex vivo calcium activity in Guansembles.
Fig. 5: Anatomical and functional characterization of BNST Guansembles.

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Acknowledgements

We would like to thank Dr. Bernardo L. Sabatini, Harvard University, for the FLEX-FLIM-AKAR virus. Microscopy was performed in part through the use of the Vanderbilt Cell Imaging Shared Resource and the assistance of Dr. Robert Matthews. We also would like to thank Elana Milano, Bridget Morris, Laith Kayat, and Megan Altemus for assistance with mouse colony maintenance and genotyping.

Funding

This work was supported by the following funding sources: Howard Hughes Medical Institute Gilliam Fellowship (Grant No. GT10823 [JAB]), National Institute on Drug Abuse (Grant No. R01-DA042475-06A1[DGW]).

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Authors and Affiliations

  1. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    Jordan A. Brown, Sachin Patel, Erin S. Calipari & Danny G. Winder

  2. Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA

    Jordan A. Brown, Nicholas Petersen, Samuel W. Centanni, Allie Y. Jin, Hye Jean Yoon, Stephanie A. Cajigas, Michelle N. Bedenbaugh, Joseph R. Luchsinger, Sachin Patel, Erin S. Calipari, Richard B. Simerly & Danny G. Winder

  3. Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA

    Nicholas Petersen, Samuel W. Centanni, Hye Jean Yoon, Stephanie A. Cajigas, Joseph R. Luchsinger, Sachin Patel, Erin S. Calipari, Richard B. Simerly & Danny G. Winder

  4. Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    Michelle N. Bedenbaugh, Sachin Patel, Erin S. Calipari, Richard B. Simerly & Danny G. Winder

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Contributions

JAB and DGW designed the project and experiments, and DGW supervised the project. JAB ran all in vivo experiments, including GCaMP fiber photometry, PKA sensor fluorescence lifetime imaging microscopy, and optogenetics. JAB analyzed and graphed all data. JAB ran all in vivo optogenetic experiments using equipment from SP. SWC ran preliminary PKA sensor experiments on D1-Cre and FosTRAP animals. NP ran, analyzed, and graphed all ex vivo calcium imaging. JAB and AYJ ran and analyzed all immunohistochemistry experiments. HJY and SAC ran all shock experiments, supervised by ESC. JRL imaged initial FosTRAP light sheet microscopy with equipment from RBS. MNB assisted with light sheet imaging and analysis, supervised by RBS. JAB and DGW wrote first draft of manuscript with editing and reviewing by NP, SWC, JRL, MNB, RBS, and ESC. Funding was acquired by JAB and DGW.

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Correspondence to Danny G. Winder.

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Brown, J.A., Petersen, N., Centanni, S.W. et al. An ensemble recruited by α2a-adrenergic receptors is engaged in a stressor-specific manner in mice. Neuropsychopharmacol. 48, 1133–1143 (2023). https://doi.org/10.1038/s41386-022-01442-x

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