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

 描述（由申请人提供）：1978年首次报道了哺乳动物的神经解剖学性别差异，并命名为性二形核（SDN），因为雄性比雌性更大。SDN位于视前区（POA），这是一个对交配和母性行为至关重要的区域。SDN体积的这些差异的研究已经确定，男性和女性在发育早期在这个大脑区域产生相同数量的神经元。然而，雌性缺乏雌二醇会导致SDN中的神经元在生命早期选择性死亡，而雄性前体雄激素产生的雌二醇则发挥神经保护作用。雌二醇在该系统中的神经保护作用的机制解释目前尚不清楚。最近发现的非神经元细胞，如小胶质细胞，在塑造发育中的大脑的关键作用，使我们探索这些细胞在神经元结构的性别差异的发展中的作用。我们的实验室已经证明，小胶质细胞对POA神经元树突上棘密度的雄性化以及雄性交配行为至关重要。我最近发现，女性的POA含有较高比例的“测量”吞噬小胶质细胞比男性的POA。我推测，强大的体积性别差异的SDN实现了这一较高的百分比吞噬小胶质细胞在女性SDN。目前的证据表明，小胶质细胞在发育过程中的吞噬作用（吞噬应激但存活的细胞）以及吞噬作用（吞噬死细胞）中起着至关重要的作用。这个概念，再加上已知的雌二醇在这个系统中的作用，使我预测，雌二醇抑制小胶质细胞吞噬在男性SDN，而不是防止传统的神经元启动的细胞凋亡。我们预计，小胶质细胞的启动子的凋亡事件的女性，其中有一个没有雌二醇。我们提出了以下目的来检验这一假设：1.1）确定小胶质细胞吞噬在发展中的SDN的关键时期。1.2)确定雌二醇对发育中的SDN中的小胶质细胞吞噬作用的影响2.1）确定发育中的SDN中的小胶质细胞吞噬作用的细胞靶标和2.2）确定小胶质细胞（吞噬作用相对于常规吞噬作用）在建立SDN大小的性别差异中的作用。提出的实验的完成将挑战的教条，雌二醇防止神经元凋亡的男性SDN，并揭示新的激素和神经免疫机制，调节正常大脑发育过程中的细胞凋亡和神经保护级联反应。了解这些机制不仅有助于研究其他大脑区域的性别差异，还可能导致对发育过程中脆弱性窗口的新见解。更具体地说，与女性相比，围产期缺氧事件更频繁地与男性脑损伤风险增加相关。拟议研究的结果将提供有关免疫细胞和激素的神经保护作用的新信息，以及雌二醇和/或小胶质细胞抑制剂作为神经保护剂的疗效的潜在性别差异。

 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.