Microglia are the resident immune cells of the brain. They are involved in many processes of brain development, the maintenance of the neural homeostasis, as well as the response to infection or injury, and repair. We have recently found a striking sex difference in the number of microglia in the developing rat brain. On postnatal day (P) 4 neonatal male rats have significantly more microglia than females in the hippocampus, cortex, and amygdala -- brain regions critical for emotion and cognition. At birth, P0, males have significantly elevated levels of two chemokines (chemotactic cytokines), CCL20 and CCL4, within the hippocampus and cortex than females. Given these data, the purpose of the present proposal is to test two interrelated hypotheses: (1) Neonatal testosterone increases the colonization of microglia in the developing male brain via the elevated expression of CCL20 and CCL4, and (2) Increased numbers of microglia within the developing male brain increases the vulnerability of males to the effects of a neonatal infection when compared to females. These data are consistent with epidemiological data that indicate males are more likely to be diagnosed with certain neurodevelopmental disorders that also have known or suspected immune etiologies, including autism, ADHD, schizophrenia, and cerebral palsy. Thus the proposed experiments will explore an important mental health issue from a novel perspective by identifying the interaction between microglial colonization of the developing brain in males and females, and the sex-dependent vulnerability of males to developmental/cognitive brain disorders.
Epidemiological data indicate that perinatal infection increases the risk of developing certain neurodevelopmental disorders. Newborns are particularly susceptible to bacterial infections due to qualitative and quantitative deficiencies i the neonatal innate immune system. Activation of microglia, the immune cells of the brain, is associated with multiple neurodevelopmental disorders that also have known or suspected immune etiologies, including autism, ADHD, schizophrenia, and cerebral palsy. Notably, all of these disorders exhibit a strong sex bias in males. Despite these data, the effect of sex on neonatal infection and subsequent cognitive outcomes has not been explored. We have recently determined that neonatal male rats have significantly more microglia than females in brain regions critical for emotion and cognition. We propose that understanding the development of the neuroimmune system, in particular the colonization of microglia in the developing male and female brain, may be a key link to understanding the sex-dependent vulnerability of males to these neurodevelopmental disorders.
