Modulation of brain activity by bacterial peptidoglycans – PG-Brain

Metazoans have developed highly conserved pathways to detect the proliferation of bacteria through the recognition of peptidoglycans (PG) shed from the bacterial cell wall. In mammals, the cytosolic receptors Nod1 and Nod2 recognize PG and activate an array of functions in the immune system. PG-mediated activation of Nod1 and Nod2 is also involved in the development of the immune system and acts in organs distant from bacterial niches, such as the bone marrow and the brain. In preliminary experiments, we found that Nod2-deficient mice develop significant affective, cognitive and behavioral defects. Furthermore, we observed expression of Nod2 by neurons and microglia in specific areas of the brain, and that PG given by oral gavage penetrates the brain. Thus, we suggest that a universal recognition system of bacterial activity, used by the innate immune system, serves also in the brain to adjust cognitive functions and behavioral responses. To further investigate this hypothesis based on concerted peripheral and central actions, we propose to perform a series of experiments to understand how PG-mediated activation of Nod2 translates into effects on brain functions and behaviors. This project may lead to novel therapeutic avenues against mental diseases based on the recognition of microbiota by the nervous system.