Abstract
Rationale
Sepsis is a severe inflammatory response to infection that leads to long-lasting cognitive impairment and depression after resolution. The lipopolysaccharide (LPS)-induced endotoxaemia model is a well-established model of gram-negative bacterial infection and recapitulates the clinical characteristics of sepsis. However, whether LPS-induced endotoxaemia during adolescence can modulate depressive and anxiety-like behaviours in adulthood remains unclear.
Objectives
To determine whether LPS-induced endotoxaemia in adolescence can modulate the stress vulnerability to depressive and anxiety-like behaviours in adulthood and explore the underlying molecular mechanisms.
Methods
Quantitative real-time PCR was used to measure inflammatory cytokine expression in the brain. A stress vulnerability model was established by exposure to subthreshold social defeat stress (SSDS), and depressive- and anxiety-like behaviours were evaluated by the social interaction test (SIT), sucrose preference test (SPT), tail suspension test (TST), force swimming test (FST), elevated plus-maze (EPM) test, and open field test (OFT). Western blotting was used to measure Nrf2 and BDNF expression levels in the brain.
Results
Our results showed that inflammation occurred in the brain 24 h after the induction of LPS-induced endotoxaemia at P21 but resolved in adulthood. Furthermore, LPS-induced endotoxaemia during adolescence promoted the inflammatory response and the stress vulnerability after SSDS during adulthood. Notably, the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and BDNF in the mPFC were decreased after SSDS exposure in mice treated with LPS during adolescence. Activation of the Nrf2-BDNF signalling pathway by sulforaphane (SFN), an Nrf2 activator, ameliorated the effect of LPS-induced endotoxaemia during adolescence on stress vulnerability after SSDS during adulthood.
Conclusions
Our study identified adolescence as a critical period during which LPS-induced endotoxaemia can promote stress vulnerability during adulthood and showed that this effect is mediated by impairment of Nrf2-BDNF signalling in the mPFC.
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Data availability
Data arising from this study will be made freely available upon request.
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Funding
This work is supported by the Science and Technology Program of Guangzhou (2014Y2-00181 to QY.Z), the Foshan Science and Technology Innovation Project (2020001005326 to ZL.Z), Science and Technology Program of Guangzhou (202102010325 to X.C; 202201010195 to S.L), and the Fundamental Research Funds for the Central Universities (11620425 to JC.Z).
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QY.Z. and ZL.Z designed research. YC.C., YH.H., and L.S. performed research with the help of XH.T., X.C. and JF.L.. QY.Z., ZL.Z., JC.Z. S.L. wrote the paper.
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Chen, Yc., Huang, Yh., Song, L. et al. Lipopolysaccharide-induced endotoxaemia during adolescence promotes stress vulnerability in adult mice via deregulation of nuclear factor erythroid 2-related factor 2 in the medial prefrontal cortex. Psychopharmacology 240, 713–724 (2023). https://doi.org/10.1007/s00213-022-06285-4
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DOI: https://doi.org/10.1007/s00213-022-06285-4