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Dorsal CA3 overactivation mediates witnessing stress-induced recognition memory deficits in adolescent male mice

Neuropsychopharmacology volume 49, pages 1666–1677 (2024)Cite this article

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Abstract

Witnessing violent or traumatic events is common during childhood and adolescence and could cause detrimental effects such as increased risks of psychiatric disorders. This stressor could be modeled in adolescent laboratory animals using the chronic witnessing social defeat (CWSD) paradigm, but the behavioral consequences of CWSD in adolescent animals remain to be validated for cognitive, anxiety-like, and depression-like behaviors and, more importantly, the underlying neural mechanisms remain to be uncovered. In this study, we first established the CWSD model in adolescent male mice and found that CWSD impaired cognitive function and increased anxiety levels and that these behavioral deficits persisted into adulthood. Based on the dorsal-ventral functional division in hippocampus, we employed immediate early gene c-fos immunostaining after behavioral tasks and found that CWSD-induced cognition deficits were associated with dorsal CA3 overactivation and anxiety-like behaviors were associated with ventral CA3 activity reduction. Indeed, chemogenetic activation and inhibition of dorsal CA3 neurons mimicked and reversed CWSD-induced recognition memory deficits (not anxiety-like behaviors), respectively, whereas both inhibition and activation of ventral CA3 neurons increased anxiety-like behaviors in adolescent mice. Finally, chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dorsal CA3 neurons and the cognitive deficits in CWSD mice. Together, our findings suggest that dorsal CA3 overactivation mediates CWSD-induced recognition memory deficits in adolescent male mice, shedding light on the pathophysiology of adolescent CWSD-induced adverse effects and providing preclinical evidence for early treatment of stress-induced cognitive deficits.

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Fig. 1: Effects of chronic witnessing social defeat stress on cognition and anxiety-like behaviors in adolescent mice.
Fig. 2: Neural alterations in dorsal and ventral CA3 in adolescent mice exposed to chronic witnessing social defeat stress (CWSD).
Fig. 3: Dorsal CA3 neuronal activity mediates witnessing stress-induced recognition memory deficits in adolescent mice.
Fig. 4: Inhibition or activation of vCA3 neuronal activity increases anxiety in adolescent male mice.
Fig. 5: Chronic systemic administration of vortioxetine reverses CWSD-induced recognition memory deficits and dCA3 neuronal over-activation.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Acknowledgements

Special thanks to Xiao-Dong Wang, PhD, for technical assistance and feedback.

Funding

This work was supported by the Beijing Natural Science Foundation (grant No., 7222236), the National Natural Science Foundation of China (grant No., 82271569, 82171529, 82071528, and 82001418), the Capital Medical Development Research Fund (2020-2-4113 and 2022-1-4111). The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. These authors contributed equally: Xiao Liu, Rui Liu.

Authors and Affiliations

  1. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China

    Xiao Liu, Rui Liu, Ya-Xin Sun, Hong-Li Wang, Han Wang, Ting Wang, Yu-Nu Ma, Xue-Xin Li, Qi Wang, Yun-Ai Su, Ji-Tao Li & Tian-Mei Si

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Contributions

TS, JL, and Y-AS designed research; XL, RL, Y-XS, H-LW, and HW performed research; RL, XL, TW, YM, X-XL, and QW analyzed data; JT, TS, and XL wrote the manuscript.

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Liu, X., Liu, R., Sun, YX. et al. Dorsal CA3 overactivation mediates witnessing stress-induced recognition memory deficits in adolescent male mice. Neuropsychopharmacol. 49, 1666–1677 (2024). https://doi.org/10.1038/s41386-024-01848-9

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