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BNST PKCδ neurons are activated by specific aversive conditions to promote anxiety-like behavior

Neuropsychopharmacology volume 48, pages 1031–1041 (2023)Cite this article

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Abstract

The bed nucleus of the stria terminalis (BNST) is a critical mediator of stress responses and anxiety-like behaviors. Neurons expressing protein kinase C delta (BNSTPKCδ) are an abundant but understudied subpopulation implicated in inhibiting feeding, but which have conflicting reports about their role in anxiety-like behaviors. We have previously shown that expression of PKCδ is dynamically regulated by stress and that BNSTPKCδ cells are recruited during bouts of active stress coping. Here, we first show that in vivo activation of this population is mildly aversive. This aversion was insensitive to prior restraint stress exposure. Further investigation revealed that unlike other BNST subpopulations, BNSTPKCδ cells do not exhibit increased cfos expression following restraint stress. Ex vivo current clamp recordings also indicate they are resistant to firing. To elucidate their afferent control, we next used rabies tracing with whole-brain imaging and channelrhodopsin-assisted circuit mapping, finding that BNSTPKCδ cells receive abundant input from affective, arousal, and sensory regions including the basolateral amygdala (BLA) paraventricular thalamus (PVT) and central amygdala PKCδ-expressing cells (CeAPKCδ). Given these findings, we used in vivo optogenetics and fiber photometry to further examine BNSTPKCδ cells in the context of stress and anxiety-like behavior. We found that BNSTPKCδ cell activity is associated with increased anxiety-like behavior in the elevated plus maze, increases following footshock, and unlike other BNST subpopulations, does not desensitize to repeated stress exposure. Taken together, we propose a model in which BNSTPKCδ cells may serve as threat detectors, integrating exteroceptive and interoceptive information to inform stress coping behaviors.

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Fig. 1: In vivo activation of BNSTPKCδ cells is aversive and reduces movement.
Fig. 2: BNSTPKCδ cells are resistant to activation.
Fig. 3: BNSTPKCδ cell afferent connectivity.
Fig. 4: BNSTPKCδ cells participate in threat assessment in the elevated plus maze.
Fig. 5: BNSTPKCδ cells do not desensitize to homotypic stress exposure.

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Acknowledgements

We would like to thank Bruce Williams and Roger Williams in the Vanderbilt Scientific Instrumentation core for their assistance in the development and production of the RESTRAINT devices used. Microscopy was performed in part through the use of the Vanderbilt Cell Imaging Shared Resource and the assistance of Dr. Robert Matthews and Dr. Jenny Schafer. We also would like to thank Elana Milano, Bridget Morris, Laith Kayat, and Megan Altemus for assistance with mouse colony maintenance and genotyping, Elana Milano and Megan Altemus for keeping the lab running, and Megan Altemus for her assistance with daily acclimation of mice and other aspects of fiber photometry experiments when an extra set of hands was much needed.

Funding

This work was supported by the following funding sources: Howard Hughes Medical Institute Gilliam Fellowship (Grant No. GT11385 [KMW]), National Institute of Neurological Disorders and Stroke DSPAN Fellowship (Grant No 1F99NS120599-01 [KMW]), National Institute on Drug Abuse (Grant No. R01-DA042475-06A1 [DGW]).

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Authors and Affiliations

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

    Kellie M. Williford, Anne Taylor, Danielle N. Adank, Joseph R. Luchsinger, Samuel W. Centanni, Sachin Patel, Erin S. Calipari, Richard B. Simerly & Danny G. Winder

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

    Kellie M. Williford, Anne Taylor, James R. Melchior, Hye Jean Yoon, Eryn Sale, Milen D. Negasi, Danielle N. Adank, Jordan A. Brown, Michelle N. Bedenbaugh, Joseph R. Luchsinger, Samuel W. Centanni, Sachin Patel, Erin S. Calipari, Richard B. Simerly & Danny G. Winder

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

    James R. Melchior, Hye Jean Yoon, Jordan A. Brown, Sachin Patel, Erin S. Calipari & Danny G. Winder

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

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

  5. Department of Psychiatry and Behavioral Sciences, Vanderbilt University, Nashville, TN, USA

    Sachin Patel, Erin S. Calipari & Danny G. Winder

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  1. Kellie M. Williford
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Contributions

KMW and DGW designed the project and experiments, and DGW supervised the project. KMW ran all in vivo experiments, including optogenetics, GCaMP fiber photometry, and performed all surgical procedures. KMW analyzed and graphed all data. KMW ran all in vivo optogenetic experiments using equipment from SP. JRM ran all basal whole cell patch clamp electrophysiology. AT and DNA ran all PKCd+/− electrophysiological comparison experiments. AT ran all PVT and CeA channelrhodopsin-assisted circuit mapping recordings (CRACM). AT and DNA ran all BLA CRACM. JAB and SWC assisted in analysis of GCaMP fiber photometry. KMW, ES, and MDN ran and analyzed all immunohistochemistry experiments. HJY ran all footshock experiments, supervised by ESC. JRL assisted with preparation and imaging of some light sheet microscopy with equipment from RBS. JAB and MNB assisted with light sheet imaging and analysis, supervised by RBS. KMW wrote the first draft of manuscript with primary editing by DGW, and additional editing and reviewing by AT, JRM, HJY, ES, MDN, DNA, JAB, MNB, JRL, SWC, SP, ESC, and RBS. Funding was acquired by KMW and DGW.

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Correspondence to Danny G. Winder.

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Williford, K.M., Taylor, A., Melchior, J.R. et al. BNST PKCδ neurons are activated by specific aversive conditions to promote anxiety-like behavior. Neuropsychopharmacol. 48, 1031–1041 (2023). https://doi.org/10.1038/s41386-023-01569-5

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