LPS preconditioning attenuates inflammation-associated social behavioral changes and hippocampal glial reactivity in male mice

Abstract Neuroinflammation contributes to brain dysfunction and behavioral abnormalities relevant to psychiatric symptoms. Here, we show that lipopolysaccharide (LPS) preconditioning attenuates hippocampal glial reactivity and attenuates the inflammation-associated reduction in social preference in male mice. Mice received low-dose LPS preconditioning (0.2 mg/kg for two consecutive days), followed by high-dose LPS challenge (5 mg/kg) seven days later. LPS preconditioning attenuated the LPS-induced increase in the TSPO/IBA1 signal ratio in the hippocampal CA1 region and attenuated the LPS-induced reduction in social preference. LPS challenge reduced locomotor activity irrespective of preconditioning, and sickness-related behavioral changes may therefore also contribute to the observed behavioral phenotype. In an exploratory experiment using a chronic corticosterone model, LPS preconditioning attenuated the corticosterone-induced increase in marble burying and the upregulation of hippocampal Il1b expression. When preconditioning was delivered during depletion of CSF1R-sensitive myeloid cells using PLX3397, attenuation of both the behavioral change and the increase in the TSPO/IBA1 ratio was no longer detected, although depletion was partial and the myeloid compartment had not returned to control levels at the time of sampling. These findings are consistent with a requirement for CSF1R-sensitive cells during the induction phase of preconditioning, but peripheral and central myeloid populations cannot be distinguished by this approach. Flow cytometric and transcriptomic analyses further revealed that LPS preconditioning altered the composition of TMEM119/CD45-defined brain macrophage subpopulations. TMEM119-positive CD45-intermediate cells increased in proportion after preconditioning, and enrichment of lipopolysaccharide- and NF-κB-related terms was confined to this population. The functional roles of these subpopulations were not tested. These findings indicate that LPS preconditioning attenuates the inflammation-associated reduction in social preference and alters the composition and transcriptional state of brain myeloid cells. This study provides evidence that prior modulation of innate immune cell states can influence inflammation-associated behavioral outcomes, and identifies the cell populations responsible as a question for future work.