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A projection from the medial prefrontal cortex to the lateral septum modulates coping behavior on the shock-probe test

Neuropsychopharmacology volume 50, pages 1245–1255 (2025)Cite this article

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Abstract

Effective coping plays an important role in preventing stress-induced neuropsychiatric conditions. The ventromedial prefrontal cortex (vmPFC) has been associated with active, adaptive coping in humans and rodents. Chronic or severe stress has been shown to induce a maladaptive shift from active to passive coping behavior; however, the neural circuits for effective coping strategies remain unclear. In the current study, we demonstrated that neurons in the infralimbic (IL) subregion of rat vmPFC that project to the lateral septum (LS) were recruited by exposure to the shock probe in the shock-probe defensive burying (SPDB) test. Both chemogenetic inhibition of LS-projecting neurons in the IL and optogenetic inhibition of glutamatergic IL terminals in the LS selectively suppressed active burying responses in the SPDB test in non-stressed rats. In contrast, chemogenetic activation of the IL-LS pathway effectively reversed the shift from active coping to passive immobility in the SPDB test induced by chronic unpredictable stress (CUS). These results indicate that top-down regulation of the LS by a projection from the IL cortex is necessary for an active, adaptive behavioral coping response, and is sufficient to restore active coping that has been compromised by chronic stress. More broadly, these results point to the IL-to-LS circuit as a potential substrate underlying maladaptive shifts from active to passive coping behavior that are often associated with stress-related neuropsychiatric disorders.

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Fig. 1: Neurons projecting from infralimbic cortex to lateral septum were activated during the shock-probe defensive burying test.
Fig. 2: Fos expression IL neurons projecting to LS was correlated with both the active burying response and immobility.
Fig. 3: Chemogenetic inhibition of the IL-LS pathway reduced active burying behavior in the SPDB test.
Fig. 4: Optogenetic inhibition of the IL-LS pathway reduced active burying behavior in the SPDB test.
Fig. 5: Effects of chemogenetic activation of the IL-LS pathway on coping behavior of non-stressed and chronically stressed rats.

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Primary data generated, analyzed and included in the results reported in the current study are available from the corresponding author upon reasonable written request.

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Acknowledgements

We thank Anna R. Knippenberg and Livia Ferreira for technical assistance. Confocal images were generated in the Core Optical Imaging Facility which is supported by UT Health San Antonio and NIH-NCI grant P30 CA54174.

Funding

This work was supported by research grant R01MH053851 from the National Institute of Mental Health, National Institutes of Health; by Merit Award I01BX003512 from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Program; and by a grant from the William and Ella Owens Medical Research Foundation, none of which had any role in study design, data collection, analysis or interpretation, nor in the preparation or decision to submit this paper for publication. The contents of this paper do not represent the views of the Department of Veterans Affairs or the U.S. Government.

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Authors and Affiliations

  1. Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

    Jing Liu, Kayla M. Tabisola & David A. Morilak

  2. South Texas Veterans Health Care System, San Antonio, TX, 78229, USA

    David A. Morilak

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JL contributed to experimental design and conception, data collection, analysis and interpretation of the results, and wrote and edited the manuscript. KT contributed to data collection and edited the manuscript. DAM was responsible for funding and resources necessary to conduct the research, contributed to experimental design and conception, data interpretation, editing and final approval of the manuscript.

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Correspondence to David A. Morilak.

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Liu, J., Tabisola, K.M. & Morilak, D.A. A projection from the medial prefrontal cortex to the lateral septum modulates coping behavior on the shock-probe test. Neuropsychopharmacol. 50, 1245–1255 (2025). https://doi.org/10.1038/s41386-025-02074-7

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