Abstract # 1849 The role of immune system maturation in development of normal behavior in mice

Previous studies demonstrated differences in behavior and brain biochemistry between germ-free and conventional mice. We showed that mono-colonization with E. coli induces similar changes in behavior as with complex microbiota. BDNF and cFos expression in the amygdala and hippocampus regions were also changed after mono-colonization. Furthermore, using permanent colonizer E. coli JM83 and transient colonizer E. coli HA107 (mutant form of E. coli JM83) we demonstrated that changes in behavior persist despite mice reverting to germ-free status. Using mono-colonized SCID and MyD88-/- Ticam-/- mice we now show that signaling via the innate, and not adaptive immune pathway is crucial for this change in behavior. Analysis of colonic and brain tissues using NanoString technique has revealed that multiple innate immunity and neural system related genes are significantly altered after colonization, including networks previously linked to neuronal plasticity. To further investigate the role of Toll-like receptors, we gavaged germ-free mice with LPS and poly I:C for two weeks. Only mice given LPS displayed altered behavior suggesting that TLR-4 related pathways are crucial for the development of normal mouse behavior. In conclusion, bacterial colonization induces long lasting changes in behavior and brain chemistry, which are associated with alterations in multiple innate immunity and neural system related gene networks. Signalling via TLR-4 pathway appears to be crucial for gut-microbiota-brain axis communication and for the development of normal behavioral.