This project addresses a deceptively simple question, yet one that has so far been largely overlooked: What are the consequences of birth (parturition) for brain development? Most mammals enter the world in a fairly dramatic fashion. A vaginal birth is accompanied by marked hormonal changes, mechanical stimuli associated with labor and delivery, and a transition from the sterile environment of the womb to one teeming with microorganisms. The fetus makes many physiological adjustments to survive outside the womb, and labor and delivery are the most reliable predictors of the upcoming challenges. This project examines the effect of birth on brain development, using mice as a model species. The investigators will look at effects of the timing of birth (within the normal range) and mode of birth (vaginal versus cesarean birth) on measures such as cell death and brain inflammation. Birth triggers major developmental switches for the lungs, heart, and other peripheral organs, and may play a similar role in brain development. If so, results from this project could fundamentally change the way we think about the role of birth in neural development. Both principal investigators are unusually active in education and outreach at the local, national, and international levels, and the project will involve undergraduates and graduate students. The home institution is ranked first in the nation among not-for-profit institutions in awarding bachelor's degrees to African-American and disadvantaged students, and the investigators' laboratories reflect this diversity.
The team of investigators will test the idea that birth alters brain development by varying the timing or mode of birth and examining effects on the patterning of neuronal cell death, and colonization of the brain by microglia. About 50% of the neurons that are initially produced are eliminated by apoptosis. The investigators recently found that cell death peaks just after birth in most forebrain regions of mice. In Aim 1, the investigators will vary the timing of parturition to test whether the association of birth with cell death is causal. Parturition also abruptly activates the peripheral immune system. The investigators hypothesize that this immune activation extends to the brain and will test that here. Microglia, the resident immune cells of the brain, are in an activated state perinatally, and increase in number soon after birth, but whether birth causes changes in microglia is unknown. The peripheral immune activation after delivery also varies by mode of birth: vaginal birth is associated with a greater increase of many immune markers compared to cesarean delivery. Interestingly, the investigators' preliminary data show that mode of birth affects cell death in several brain regions. Thus, to identify aspects of "birth" that influence brain development, Aim 2 will contrast effects of vaginal and cesarean delivery on cell death and neuroimmune activation. In Aim 3, the investigators will interfere with immune activation to determine whether effects of birth on microglia and cell death occur in parallel or are related (i.e., microglia may promote cell death).
