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A sex-specific role for the bed nucleus of the stria terminalis in proactive defensive behavior

Neuropsychopharmacology volume 48, pages 1234–1244 (2023)Cite this article

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Abstract

The bed nucleus of the stria terminalis (BNST) is a forebrain region implicated in aversive responses to uncertain threat. Much of the work on the role of BNST in defensive behavior has used Pavlovian paradigms in which the subject reacts to aversive stimuli delivered in a pattern determined entirely by the experimenter. Here, we explore the contribution of BNST to a task in which subjects learn a proactive response that prevents the delivery of an aversive outcome. To this end, male and female rats were trained to shuttle during a tone to avoid shock in a standard two-way signaled active avoidance paradigm. Chemogenetic inhibition (hM4Di) of BNST attenuated the expression of the avoidance response in male but not female rats. Inactivation of the neighboring medial septum in males produced no effect on avoidance, demonstrating that our effect was specific to BNST. A follow up study comparing hM4Di inhibition to hM3Dq activation of BNST in males replicated the effect of inhibition and demonstrated that activation of BNST extended the period of tone-evoked shuttling. These data support the novel conclusion that BNST mediates two-way avoidance behavior in male rats and suggest the intriguing possibility that the systems underlying proactive defensive behavior are sex-specific.

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Fig. 1: Viral expression in all subjects.
Fig. 2: BNST is necessary for the expression of two-way avoidance in MALE rats.
Fig. 3: MS is not required for the expression of two-way avoidance in MALE rats.
Fig. 4: BNST is not required for the expression of two-way avoidance in FEMALE rats.
Fig. 5: BNST is necessary for, and sufficient to enhance, the expression of two-way avoidance in MALE rats.

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Acknowledgements

We thank Dr. Jun Wang for providing the CNO for our slice physiology experiment.

Funding

This work was supported by NIH grant R21MH126327 (JMM) and BBRF NARSAD48 Young Investigator Award 25196 (JMM). The authors have no competing financial interests to disclose.

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Authors and Affiliations

  1. Department of Psychological & Brain Sciences, Texas A&M University, College Station, TX, USA

    Diana P. Guerra & Justin M. Moscarello

  2. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

    Wei Wang

  3. Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX, USA

    Karienn A. Souza

  4. Texas A&M Institute for Neuroscience (TAMIN), Texas A&M University, College Station, TX, USA

    Karienn A. Souza & Justin M. Moscarello

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  1. Diana P. Guerra
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Contributions

DPG assisted in the design of the behavioral experiments, executed those experiments, assisted in the analysis of behavioral data, performed the relevant histology, and contributed to the writing manuscript. WW and KS designed and executed the physiological experiment and edited the manuscript. JM designed the behavioral experiments and supervised their execution, analyzed behavioral data, and wrote the manuscript.

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Correspondence to Justin M. Moscarello.

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Guerra, D.P., Wang, W., Souza, K.A. et al. A sex-specific role for the bed nucleus of the stria terminalis in proactive defensive behavior. Neuropsychopharmacol. 48, 1234–1244 (2023). https://doi.org/10.1038/s41386-023-01581-9

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