Though once considered completely isolated from the immune system, we now know the brain is under constant immune surveillance and that there is two-way communication between the CNS and immune organs like the bone marrow. Similarly, we have come to understand that sex is one of the strongest biological factors influencing development, and that sex differences extend far beyond the reproductive tract. Males are at higher risk for developmental disorders including autism and early onset schizophrenia, diseases associated with maternal immune activation (MIA). Additionally, there are surprisingly consistent reports of the developing male brain exhibiting higher levels of inflammatory signaling molecules, immune cells and gene expression profiles indicative of immune activation compared to female brains even under normal healthy conditions. The McCarthy laboratory has recently observed an increased number of mast cells in the sexually dimorphic preoptic area (POA) of male rats, and that female rats had a greater number of mast cells in the surrounding meninges than in the neuropil of the POA, suggesting differential regulation of immune cell migration to this area. The central hypothesis of this proposal is that inherent sex differences in neonatal neuro-immune cell trafficking increases male vulnerability to neurodevelopmental disorders in response to immune activation. The rationale and long- term objective for this work is to elucidate sex differences in the neonatal neuro-immune profile, in order to better understand the etiology of neurodevelopmental disease. This will be addressed by three aims. 1) Quantify the immune cell composition of the meninges and periventricular neuropil. The hypothesis is that differential immune cell trafficking to the CNS in males and females is important to healthy neural development. This predicts that the sexes will differ in the immune cell content of their meninges and neuropil compartments. Immune cell composition of the meninges and the periventricular neuropil of male and female neonatal rats will be quantified by flow cytometry and immunohistochemistry of meninges, POA, hippocampus and anterior cerebellum. 2) Compare blood-brain-barrier integrity in male and female neonatal rats. The working hypothesis is that under basal conditions during the early postnatal period, the male brain is more accessible to immune cell trafficking by way of increased barrier permeability. This will be tested by measuring sex differences in BBB integrity and expression of endothelial, immune cell adhesion, and extravasation markers, and assessing the relationship between BBB permeability and immune cell migration. 3) Determine the effect of maternal immune activation on immune cell trafficking in the neonate, maintaining sex as a factor. The working hypothesis is that males have more negative outcomes in response to perinatal immune activation because their BBB is more fragile in response to inflammation. This hypothesis predicts that males exposed to MIA will have reduced BBB integrity, increased adhesion and extravasation markers, and increased immune cell migration to periventricular brain regions.
Males are at greater risk for neuropsychiatric disorders that originate in early development and are associated with maternal immune activation, but the reasons for this are unclear. Peripheral immune system activity can affect mental health in adults, and seems likely to be important for normal brain development in neonates. This project examines sex differences in immune system access to the developing brain, and how differences in access may increase vulnerability to maternal immune activation.
