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Dorsal peduncular cortex activity modulates affective behavior and fear extinction in mice

Neuropsychopharmacology volume 49, pages 993–1006 (2024)Cite this article

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Abstract

The medial prefrontal cortex (mPFC) is critical to cognitive and emotional function and underlies many neuropsychiatric disorders, including mood, fear and anxiety disorders. In rodents, disruption of mPFC activity affects anxiety- and depression-like behavior, with specialized contributions from its subdivisions. The rodent mPFC is divided into the dorsomedial prefrontal cortex (dmPFC), spanning the anterior cingulate cortex (ACC) and dorsal prelimbic cortex (PL), and the ventromedial prefrontal cortex (vmPFC), which includes the ventral PL, infralimbic cortex (IL), and in some studies the dorsal peduncular cortex (DP) and dorsal tenia tecta (DTT). The DP/DTT have recently been implicated in the regulation of stress-induced sympathetic responses via projections to the hypothalamus. While many studies implicate the PL and IL in anxiety-, depression-like and fear behavior, the contribution of the DP/DTT to affective and emotional behavior remains unknown. Here, we used chemogenetics and optogenetics to bidirectionally modulate DP/DTT activity and examine its effects on affective behaviors, fear and stress responses in C57BL/6J mice. Acute chemogenetic activation of DP/DTT significantly increased anxiety-like behavior in the open field and elevated plus maze tests, as well as passive coping in the tail suspension test. DP/DTT activation also led to an increase in serum corticosterone levels and facilitated auditory fear extinction learning and retrieval. Activation of DP/DTT projections to the dorsomedial hypothalamus (DMH) acutely decreased freezing at baseline and during extinction learning, but did not alter affective behavior. These findings point to the DP/DTT as a new regulator of affective behavior and fear extinction in mice.

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Fig. 1: Chemogenetic activation of the DP/DTT increases anxiety-like behavior in the open field and elevated plus maze tests.
Fig. 2: Chemogenetic activation of the DP/DTT increases immobility in the tail suspension test, but has no effect on forced swim behaviors.
Fig. 3: Chemogenetic inhibition of the DP/DTT has a modest effect on auditory fear acquisition, but activation of the DP/DTT facilitates within-session extinction, extinction retrieval and increases serum corticosterone levels.
Fig. 4: Mapping of DP/DTT downstream projections and characterization of activity-tagged DP/DTT neurons following the OFT.
Fig. 5: Optogenetic activation of the DP/DTT-DMH pathway acutely suppresses freezing but has no effect on affective behavior.

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Acknowledgements

We thank Hathairat Chanphao, Tejnarine Persaud, Bebhinn Treanor, and Christina Guzzo for their generous and fundamental assistance with the corticosterone ELISA experiment and use of the Guzzo lab plate reader. We would also like to thank Unza Mumtaz and Mehreen Inayat for their help with animal colony management. Some figure diagrams were created with the assistance of BioRender.com.

Funding

This work was supported by grants from CIHR (PJT 399790), Human Frontier Science Program Organization (CDA00009/2018 and RGY0072/2019), the SickKids Foundation and Canadian Institutes of Health Research (CIHR) – Institute of Human Development, Child and Youth Health (NI19-1132R), and Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-06344) to MAC.

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  1. These authors contributed equally: Justin J. Botterill, Abdessattar Khlaifia.

Authors and Affiliations

  1. Department of Psychology, University of Toronto Scarborough, Toronto, ON, M1C1A4, Canada

    Justin J. Botterill, Abdessattar Khlaifia, Ryan Appings, Jennifer Wilkin, Francesca Violi, Hanista Premachandran, Arely Cruz-Sanchez, Anna Elisabete Canella, Ashutosh Patel, S. Danyal Zaidi & Maithe Arruda-Carvalho

  2. Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada

    Justin J. Botterill

  3. Department of Cell and Systems Biology, University of Toronto, Toronto, ON, M5S3G5, Canada

    Arely Cruz-Sanchez & Maithe Arruda-Carvalho

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Contributions

Designed Research: JJB, AK, MAC. Performed Research: JJB, AK, RA, JW, FV, HP, ACS, AEC, AP, SDZ, MAC. Analyzed/Interpreted Data: JJB, AK, JW, FV, AEC, AP, MAC. Wrote the paper: JJB, AK, MAC. All authors reviewed and approved the manuscript.

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Correspondence to Maithe Arruda-Carvalho.

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Botterill, J.J., Khlaifia, A., Appings, R. et al. Dorsal peduncular cortex activity modulates affective behavior and fear extinction in mice. Neuropsychopharmacol. 49, 993–1006 (2024). https://doi.org/10.1038/s41386-024-01795-5

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