Tolerance-inducing effect and properties of innate immune stimulation on chronic stress-induced behavioral abnormalities in mice

Over-activation of the innate immune system constitutes a risk factor for the development of nervous system disorders but may reduce the severity of these disorders by inducing tolerance effect. Here, we studied the tolerance-inducing effect and properties of innate immune stimulation on chronic social defeat stress (CSDS)induced behavioral abnormalities in mice. A single injection of the innate immune enhancer lipopolysaccharide (LPS) one day before stress exposure prevented CSDS-induced impairment in social interaction and increased immobility time in the tail suspension test and forced swimming test. This effect was observed at varying doses (100, 500, and 1000 mu g/kg) and peaked at 100 mu g/kg. A single LPS injection (100 mu g/kg) either one or five but not ten days before stress exposure prevented CSDS-induced behavioral abnormalities. A second LPS injection ten days after the first LPS injection, or a 2 x or 4 x LPS injections ten days before stress exposure also induced tolerance against stress-induced behavioral abnormalities. Our results furthermore showed that a single LPS injection one day before stress exposure skewed the neuroinflammatory response in the hippocampus and pre frontal cortex of CSDS-exposed mice toward an anti-inflammatory phenotype. Inhibiting the central innate immune response by pretreatment with minocycline or PLX3397 abrogated the tolerance-inducing effect of LPS preconditioning on CSDS-induced behavioral abnormalities and neuroinflammatory responses in the brain. These results provide evidence for a prophylactic effect of innate immune stimulation on stress-induced behavioral abnormalities via changes in microglial activation, which may help develop novel strategies for the prevention of stress-induced psychological disorders.

Automated summary

The study found that injecting the innate immune enhancer LPS can prevent behavioral abnormalities induced by chronic social defeat stress in mice, with the optimal effect observed at specific doses and time points. Additionally, innate immune stimulation can alter neuroinflammatory responses in the brain, and inhibiting central innate immune response can eliminate the tolerance-inducing effect of LPS preconditioning.