Predictable chronic mild stress promotes recovery from LPS-induced depression

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Clinical depression often co-occurs with chronic inflammatory diseases, with neuroinflammation implicated in major depressive disorders.
• Predictable chronic mild stress (PCMS), unlike unpredictable stress, may improve mood and memory, offering a potential resilience factor.
• Lipopolysaccharide (LPS) is used to induce peripheral immune challenges, leading to depressive-like behaviors and neuroinflammation.

Purpose of the Study:

• To investigate the effects of PCMS on depressive-like behavior, neuroinflammation, oxidative stress, and NLRP3 inflammasome activation in LPS-treated mice.
• To explore the role of Nrf2 signaling in mediating the protective effects of PCMS against LPS-induced impairments.

Main Methods:

• Mice were subjected to daily PCMS (5 min restraint stress for 4 weeks) followed by LPS injection.
• Assessment of depressive- and anxiety-like behaviors, hippocampal neuroinflammation (cytokine expression, microglia activation), oxidative stress, and NLRP3 inflammasome components (NLRP3, ASC, Caspase-1, IL-1β).
• Evaluation of Nrf2 signaling pathway activation and thioredoxin-interacting protein (TXNIP) expression.

Main Results:

• PCMS significantly facilitated recovery from LPS-induced depressive- and anxiety-like behaviors.
• PCMS suppressed LPS-induced neuroinflammation, microglia activation, and oxidative stress in the hippocampus.
• PCMS inhibited the overactivation of the NLRP3 inflammasome pathway and IL-1β maturation, while activating Nrf2 signaling and reducing TXNIP expression.

Conclusions:

• PCMS demonstrates a resilience effect against LPS-induced behavioral deficits and neuroinflammation.
• PCMS alleviates impairments in the Nrf2-TXNIP-Trx system, counteracting inflammatory brain damage and redox imbalance.
• This study provides a mechanistic link between PCMS, Nrf2 activation, and resilience to stress-induced depressive-like behaviors.