Gene Expression Regulation in Brain Underlying Innate Immune Memory

As the brain's resident immune cells, microglia upregulate inflammatory gene expression to promote immune functions. Following the response to early life infection, microglia can remain in a “primed” state in which a subsequent immune trigger produces a hyper-activation. Paradoxically, multiple repeated immune activating events can lead to tolerance, the suppression of immune gene expression and function. Both priming and tolerance represent a form of cellular memory that may be disrupted in neurodevelopmental disorders and is largely unexplored in microglia. We hypothesize that acute versus repeated immune activation engages expression of distinct sets of genes, leading to either microglial priming or tolerance. Using in vivo peripheral injections of low dose liposaccharide (LPS 500ug/kg intraperitoneal) to mimic bacterial infection in mice, we compared animals recievig 1, 2, 3, or 4 daily doses of LPS compared to Vehicle (PBS) controls. We examined tissue from three brain regions, the hippocampus, striatum and frotal cortex by RNAseq. Overall design: 10 week old male mice were injected intraperitoneally with low-dose lipopolysaccharide (LPS, Sigma) at a daily dose of 500 ug/kg bodyweight or an equal volume of vehicle PBS. Each mouse was given a total of four injections spaced 24 hours apart. Animals received either four LPS injections on four consecutive days (4xLPS), a single vehicle injection followed by three LPS injections on the following three days (3xLPS), two vehicle injections on two consecutive days followed by two LPS injections on the following two days (2xLPS), three vehicle injections on three consecutive days followed by a single LPS injection on the fourth day (1xLPS), or four vehicle injections (PBS control).