Hippocampal Inflammation and Gene Expression Changes in Peripheral Lipopolysaccharide Challenged Mice Showing Sickness and Anxiety-Like Behaviors

Neuroinflammation is often associated with the development of depressive and anxiety disorders. The hippocampus is one of the brain regions affected by inflammation that is associated with these symptoms. However, the mechanism of hippocampal inflammation-induced emotional behavior remains unknown. The aim of this study was to clarify temporal changes in the neuroinflammatory responses in the hippocampus and the response of dentate gyrus (DG) neurons using peripheral lipopolysaccharide (LPS)-challenged mice. LPS administration induced anxiety-like activity in the elevated plus maze test and social interaction test after 24 h, at which time the mice had recovered from sickness behavior. We examined the hippocampal inflammation-related gene expression changes over time. The expression of interleukin-1 beta (Il1b) and tumor necrosis factor alpha (Tnfa) was rapidly enhanced and sustained until 24 h after LPS administration, whereas the expression of Il6 was transiently induced at approx. 6 h. IL-6-dependent downstream signaling of transducer and activator of transcription 3 (STAT3) was also activated approx. 3-6 h after LPS treatment. The expression of innate immune genes including interferon-induced transmembrane proteins such as interferon induced transmembrane protein 1 (Ifitm1) and Ifitm3 and complement factors such as C1qa and C1qb started to increase approx. 6 h and showed sustained or further increase at 24 h. We also examined changes in the expression of several maturation markers in the DG and found that LPS enhanced the expression of calbindin 1 (Calb1), tryptophan-2,3-dioxigenase 2 (Tdo2), Il1rl, and neurotrophin-3 (Ntf3) at 24 h after LPS treatment. Collectively, these results demonstrate temporal changes of inflammation and gene expression in the hippo campus in LPS-induced sickness and anxiety-like behaviors.