Microglia mediate cell death in a model system for sex differences in the brain
小胶质细胞在大脑性别差异模型系统中介导细胞死亡
基本信息
- 批准号:9051177
- 负责人:
- 金额:$ 3.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-25 至 2018-09-24
- 项目状态:已结题
- 来源:
- 关键词:AndrogensApoptosisApoptoticArchitectureBehaviorBiological ModelsBrainBrain InjuriesBrain regionCase StudyCell CountCell DeathCell NucleusCell physiologyCell surfaceCellsCollectionCoupledDendritesDendritic SpinesDevelopmentDinoprostoneEatingEstradiolEventFemaleGoalsHormonesHypoxiaImmuneInflammationInvestigationLeadLifeLightMammalsMaternal BehaviorMediatingMicrogliaModelingNamesNeonatalNeurogliaNeuroimmunomodulationNeuronsNeuroprotective AgentsPerinatalPhagocytosisPhysiologicalPlayPopulationPregnancyPreoptic AreasPreventionPrevention therapyProductionRattusReportingRiskRoleSerineSex CharacteristicsSignal TransductionSourceStressSurveysSystemTestingThickUp-RegulationVertebral columncalbindincellular targetingcritical periodcytotoxicitydensityimmune activationinhibitor/antagonistinsightinterestmalemedial preoptic nucleusneuron apoptosisneuroprotectionnovelnovel therapeuticspreferencepreventprogenitorprogramspublic health relevanceresearch study
项目摘要
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. èMore 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.
描述(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,并将其命名为性二形核(SDN),因为它在雄性比雌性更大。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。对SDN体积的这些差异的研究已经证实,在发育早期,男性和女性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SDN中前体雄激素产生的雌二醇则起到神经保护作用。雌激素在这一系统中的神经保护作用的机制解释目前尚不清楚。最近关于小胶质细胞等非神经细胞在塑造发育中的大脑中的关键作用的发现,使我们探索了这些细胞在神经元结构中性别差异发育中的作用。我们的实验室已经证明,小胶质细胞对于POA神经元树突上棘突密度的男性化以及雄性交配行为是必不可少的。我最近发现,女性POA比男性POA含有更高比例的吞噬细胞小胶质细胞。我推测,女性SDN中较高比例的吞噬小胶质细胞实现了SDN中显著的体积性别差异。目前的证据表明,在发育过程中,小胶质细胞在吞噬(吞噬应激的但活的细胞)和吞噬(吞噬死亡的细胞)过程中发挥着关键作用。这个概念,再加上雌二醇在这个系统中的已知作用,使我预测雌二醇会抑制男性SDN中的小胶质细胞吞噬,而不是阻止传统的神经元启动的凋亡。我们预计,小胶质细胞是女性细胞凋亡事件的发起者,那里缺乏雌二醇。我们提出了以下目的来验证这一假说:1.1)确定SDN发育过程中小胶质细胞吞噬的关键期。2)确定发育中SDN中小胶质细胞吞噬的细胞靶点;2.2)确定小胶质细胞(吞噬作用与常规吞噬作用)在确定SDN大小性别差异中的作用。拟议中的实验的完成将挑战雌激素阻止男性SDN神经细胞凋亡的教条;并揭示在正常大脑发育过程中调节细胞凋亡和神经保护级联反应的新的激素和神经免疫机制。了解这些机制不仅有助于研究大脑其他区域的性别差异,还可能导致对发育过程中脆弱性窗口的新见解。è更具体地说,与女性相比,围产期缺氧事件更常与男性脑损伤风险增加相关。建议的研究结果将提供关于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潜在性别差异。
项目成果
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Lindsay Ann Pickett其他文献
Lindsay Ann Pickett的其他文献
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{{ truncateString('Lindsay Ann Pickett', 18)}}的其他基金
Microglia mediate cell death in a model system for sex differences in the brain
小胶质细胞在大脑性别差异模型系统中介导细胞死亡
- 批准号:
9349608 - 财政年份:2015
- 资助金额:
$ 3.44万 - 项目类别:
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