Perinatal Gonadal Hormones Impart Male-Biased Neuroimmune, Mitochondrial, and Behavioral Vulnerabilities.

项目总结 这一R01建议测试了性腺激素存在于性腺激素的关键窗口的中心假说 围产期脑组织导致明显的性别特异性小胶质细胞和线粒体表型增加 男性对围产期免疫刺激的易感性。在许多早发性疾病的发病率中有很强的男性偏见 神经发育障碍。尽管神经发育障碍是相当不同的，但随着 有证据表明，这些患者中的一部分出现了免疫和线粒体异常。小胶质细胞， 大脑中的先天免疫细胞，已经成为这种神经免疫交流的关键效应者。我们发现 从暴露于早期免疫挑战的小鼠分离的小胶质细胞显示出显著的下调 编码线粒体电子传输基因的基因，特别是在男性。此外，我们发现这一点 早期免疫挑战导致男性偏向社会行为缺陷，特别是导致功能障碍 在男性小胶质细胞线粒体功能的其他方面。以确定可能是什么在调解这些 早发的性别差异，我们首先利用的知识是性腺激素会激增 仅限于处于围产期大脑发育关键期的男性。在这个过程中给雌性小鼠注射 围产期有雌二醇，这是雄激素睾酮的芳香化形式，直接 使男性大脑男性化，形成典型的男性表型。我们发现，雄性化的雌性 接受早期免疫挑战的人在社会行为方面表现出与免疫挑战类似的缺陷 男性，具有与免疫挑战男性相似的小胶质细胞线粒体改变。我们 也证明了已知的影响线粒体功能的雌激素受体是不同的 在男性和女性的小胶质细胞上表达。利用这些知识，我们可以改变雌激素受体 细胞特异性信号转导研究小胶质细胞雌激素受体对男性偏向的重要性 神经发育障碍的脆弱性。 在这项建议中，我们将评估线粒体形态、基因和小胶质细胞特异性改变 表达和生物能量功能依赖于小胶质细胞特异性雌激素或雄激素受体 信号，以及评估早期免疫挑战是否通过异常 突触的小胶质细胞吞噬作用，以及围产期性腺激素激增和 小胶质细胞雌激素/雄激素受体在这些过程中。这项提案将是第一个审查 围产期小胶质细胞雌激素暴露与性激素水平的关系 雄激素受体与导致男性偏见的性别偏见神经发育的建立 神经发育障碍的脆弱性。

PROJECT SUMMARY This R01 proposal tests the central hypothesis that gonadal hormones present during a critical window of perinatal brain organization result in distinct sex-specific microglial and mitochondrial phenotypes that increase male vulnerability to perinatal immune stimuli. There is a strong male bias in the incidence of many early-onset neurodevelopmental disorders. Although neurodevelopmental disorders are quite heterogeneous, growing evidence demonstrates immune and mitochondrial abnormalities in a subset of these patients. Microglia, the innate immune cells of the brain, have emerged as key effectors of this neuroimmune communication. We find that microglia isolated from mice exposed to an early-life immune challenge show significant downregulation of genes encoding mitochondrial electron transport genes, specifically in males. Additionally, we find that this early-life immune challenge results in male-biased social behavior deficits, and specifically induces dysfunction in other aspects of male microglial mitochondrial functionality. To determine what could be mediating these early-onset sex differences, we first used the knowledge that there is a surge of gonadal hormones that occurs only in males during a perinatal critical period of brain development. Injecting female mouse pups during this perinatal critical period with estradiol, the aromatized form of the androgen testosterone that directly masculinizes the male brain, results in a male-typical phenotype. We have found that masculinized females subjected to early-life immune challenge display similar deficits in social behavior as did immune-challenged males, with similar microglial mitochondrial alterations as were observed in immune-challenged males. We have also demonstrated that estrogen receptors known to influence mitochondrial function are differentially expressed on microglia between males and females. Using this knowledge, we can alter estrogen receptor signaling in a cell-specific manner to study the importance of microglial estrogen receptors to male-biased neurodevelopmental disorder vulnerabilities. In this proposal, we will assess whether microglia-specific alterations in mitochondrial morphology, gene expression, and bioenergetic function are dependent upon microglia-specific estrogen or androgen receptor signaling, as well as assess whether early-life immune challenge impacts social behavior through aberrant microglial phagocytosis of synapses, as well as the impact of the perinatal gonadal hormone surge and microglial estrogen/androgen receptors on these processes. This proposal will be the first to examine a mechanistic relationship between perinatal gonadal hormone exposure through microglial estrogen and androgen receptors and the establishment of sex-biased neurodevelopment that induce male-biased vulnerabilities to neurodevelopmental disorders.