Microglia mediate cell death in a model system for sex differences in the brain

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 DESCRIPTION (provided by applicant): The first neuroanatomical sex difference in mammals was reported in 1978, and named the sexually dimorphic nucleus (SDN) due to its larger size in males compared to females. The SDN is located within the preoptic area (POA), a region critical to copulatory and maternal behaviors. Studies of these differences in SDN volume have established that males and females generate the same number of neurons in this brain region early in development. However, the lack of estradiol in females causes neurons in the SDN to selectively die off early in life, whereas the production of estradiol from precursor androgens in males exerts a neuroprotective effect. A mechanistic explanation for the neuroprotective effects of estradiol in this system is currently unknown. Recent discoveries on the critical role of non-neuronal cells, such as microglia, in sculpting the developing brain have led us to explore the role of these cells in development of sex differences in neuronal architecture. Our lab has demonstrated that microglia are essential for the masculinization of spine density on dendrites of POA neurons, as well as male copulatory behavior. I recently discovered that the female POA contains a higher percentage of "surveying" phagocytic microglia than the male POA. I speculate that robust volumetric sex differences in the SDN are achieved by this higher percentage of phagocytic microglia in the female SDN. Current evidence suggests that microglia play a crucial role in phagoptosis (engulfment of stressed, but viable cells) as well as phagocytosis (engulfment of dead cells) during development. This notion, coupled with the known role of estradiol in this system, has led me to predict that estradiol suppresses microglial phagoptosis in the male SDN, rather than preventing conventional neuron-initiated apoptosis. We anticipate that microglia are the initiators of the apoptotic events in females, where there is an absence of estradiol. We have proposed the following aims to test this hypothesis: 1.1) Identify the critical period for microglial phagocytosis in the developing SDN. 1.2) Determine the impact of estradiol on microglial phagocytosis in the developing SDN 2.1) Determine the cellular targets of microglial phagocytosis in the developing SDN and 2.2) Determine the role of microglia (phagoptosis versus conventional phagocytosis) in establishing the sex difference in size of the SDN. Completion of the experiments proposed will challenge the dogma that estradiol prevents neuronal apoptosis in the male SDN; and reveal novel hormone and neuroimmune mechanisms that regulate apoptotic and neuroprotective cascades during normal brain development. Understanding these mechanisms will not only facilitate studies of sex differences in other brain regions, but may also lead to novel insights into windows of vulnerability during development. èMore specifically, perinatal hypoxic events are more frequently associated with an increased risk of brain damage in males compared to females. The results of the proposed studies will provide new information on the neuroprotective roles of immune cells and hormones, and potential sex differences in efficacy of estradiol and/or microglial inhibitors as neuroprotective agents.