Prenatal neuroinflammation: maternal microbiome contributions and behavioral consequences - Summary: Prenatal stress is pervasive and negatively impacts both the mother and the developing fetus; offspring bear an increased risk of aberrant neurodevelopment and psychiatric disorders. Indeed, there is a critical window in utero where neurodevelopment is vulnerable to stress-induced alterations in the intrauterine environment, including inflammation; how alterations in the maternal milieu are transmitted to the developing brain, contributing to behavioral alterations, requires scrutinizing. We have established a mouse model of prenatal stress, which in addition to altering maternal and offspring microbiota, induces inflammation in utero, including increases in the chemokine C-C motif chemokine ligand 2 (CCL2), resulting in reduced social behaviors and longstanding neuroinflammation. Furthermore, we have exciting supporting and preliminary data suggesting that normal neurodevelopment is disrupted by prenatal stress in a microbe- and CCL2-dependent manner. As a chemokine, CCL2 has a key role in both attracting myeloid cells and enhancing their inflammatory profile. Within the brain, the myeloid compartment includes microglia, the resident macrophages of the central nervous system; border-associated macrophages (BAMs), which are found in the perivascular space, choroid plexus, and meninges; and circulating monocytes. However, the effects of prenatal stress and CCL2 on the composition of and cytokine production by these subpopulations has yet to be elucidated, and is critical as cytokine signaling is important for homeostatic functions during neurodevelopment, including regulating neuro- and gliogenesis. Therefore, the goal of this R01 is to investigate the relationship between prenatal stress, brain macrophages and monocytes, and social behavior. Our model of prenatal stress will be used to test the highly novel, and integrative hypothesis that, during prenatal stress, there are alterations in the composition of brain macrophages and monocytes in the fetal brain, increasing cytokine production, influencing neurodevelopment. Next, we will determine whether cell-specific elimination of CCL2 production is able to prevent neuroinflammation and subsequent alterations in social behavior. Finally, in an exploratory aim, we will test whether alterations in the maternal microbiome are necessary and sufficient to induce the persistent neuroinflammation and concomitant reduction in social behavior in adult offspring. Our overarching hypothesis is that prenatal stress leads to fetal neuroinflammation that results in long term behavioral abnormalities by altering the composition of macrophages and monocytes in the developing brain and increasing their inflammatory profile, which is driven by disruption of maternal microbes and CCL2. This hypothesis will be tested by pursuing these aims: 1) Determining whether prenatal stress alters the composition of fetal brain macrophages and monocytes 2) Elucidating whether CCL2 drives inflammation in fetal macrophages and monocytes following prenatal stress 3) Determining whether prenatal stress-induced microbiome disruptions drive offspring neuroinflammation and reduced social behaviors.
