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 (Berl). 2023 Feb 27. doi: 10.1007/s00213-022-06285-4.
Yan-Chen Chen  #  1 ,  Yan-Hua Huang  #  2  3 ,  Li Song  #  2  3 ,  Xiao-Han Tong  2  3 ,  Jun-Feng Li  2  3 ,  Song Lin  2  3 ,  Xi Chen  4 ,  Ji-Chun Zhang  5  6 ,  Zi-Li Zhang  7 ,  Qi-Yi Zeng  8
Affiliations
  • 1. Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 2. Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 3. Department of Physiology, School of Medicine, Jinan University, Guangzhou, China.
  • 4. Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou, China.
  • 5. Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. [email protected].
  • 6. Department of Physiology, School of Medicine, Jinan University, Guangzhou, China. [email protected].
  • 7. Department of Reproductive Medicine Center, The First People's Hospital of Foshan (Affiliated FoShan Hospital of Sun Yat-Sen University), Foshan, China. [email protected].
  • 8. Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 36847832 DOI: 10.1007/s00213-022-06285-4
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.

Keywords
Adolescent; Adulthood; BDNF; Depressive- and anxiety-like behaviours; Endotoxaemia; Inflammation; Nrf2; Sepsis.
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