32. Polarization to M1 microglia in high-anxiety inbred mice in response to LPS challenge

Objectives: Microglia play important roles in neurodevelopmental and pathological progression of mental disorders. But how genetic predisposition and environment risk factors may act in combination to affect microglial activation and the underlying molecular mechanisms remains unclear. Methods: Flow cytometry, RT-qPCR, and analysis of genome-wide brain transcriptomes, genotype–phenotype correlation, and gene functional clustering were employed to study the microglial profile both before and after LPS treatment across four inbred mice strains (C57BL/6J, FVB/N, DBA/2J, and 129S2/Sv) with different anxiety traits, and its relationship with anxiety traits and brain gene expression. Results: We found that naive DBA/2J mice had significantly more M1 microglia. After a systemic LPS challenge, polarization to M1 microglia in DBA/2J and 129S2/Sv mice was more prominent than the other strains, and was correlated with their anxiety-like behaviors. Macrophage M1/M2 polarization in the spleen showed a similar pattern in DBA/2J and 129S2/Sv mice in response to LPS challenge. Furthermore, DBA/2J mice expressed higher mRNA levels of Il1b , Il6 , and Tnf , and higher Nos2/Arg1 ratio but lower Chi3l3 level in the hypothalamus before and after LPS stimulation, respectively. We further discovered a group of myeloid transcription factors that may underpin strain-specific differences in microglial activation. Conclusions: Proinflammatory microglial activation reflects anxiety traits in mice, especially after LPS challenge. Our work sheds new light in understanding the potential molecular mechanisms of stress-induced microglial activation and polarization.