Sex-Biased Mitochondrial Alterations Underlying Male Susceptibility to Neurodevelopmental Disorders

项目总结 自闭症谱系障碍(ASD)是一组复杂的神经发育障碍 以重复的行为和社交互动和交流中的变化为特征的，目前 在美国，每68名儿童中就有一名受到影响。尽管自闭症的患病率明显偏向于男性 (男女比例约为4：1)，这种男性易感性背后的机制仍然难以捉摸。而ASD是 完全异质性的证据表明，神经炎症在这些神经性疾病的发展中发挥了作用。 异常现象。小胶质细胞是大脑的常驻免疫细胞，是神经反应的关键调节器。 免疫激活和神经回路的发育组织，独特地定位它们以翻译 早期生命对神经结果的挑战。此外，新出现的证据表明线粒体 功能障碍在ASD等神经精神/神经发育障碍中起着重要作用 线粒体功能的抑制可能在小胶质细胞激活过程中起关键作用。新兴市场 对线粒体和小胶质细胞生理学上的性别差异的理解表明，对它们的进一步研究 在诸如ASD等神经发育障碍的发展中可能起到的作用是有根据的。为此，我 将首先描述早期免疫挑战的影响(在小鼠中建立的ASD模型 在线粒体基因/蛋白质水平和功能上表现出强烈的性别偏见)。在此基础上，我将 然后评估早期免疫刺激如何影响男性线粒体DNA的表观遗传调节 女性。最后，我会问，在早期发育过程中，可能会发生什么，可能会调解这些早期- 出现性别差异。性腺激素水平激增，只有在男性处于危急状态时才会出现 出生前后负责使男性大脑男性化的一段时间。注射这些 研究表明，在这一“关键时期”，女性体内的荷尔蒙会使她们的大脑“男性化”成类似男性的大脑。 州政府。使用这个模型，我将确定男性荷尔蒙是否存在于分娩前后的关键时期 (雄性化的雌性小鼠)将使随后的免疫挑战变得敏感。我希望这个项目能 通过将三个刚刚开始合作的研究机构联系起来，产生了几个新的影响： (I)线粒体生物学在神经发育和疾病中的作用；(Ii)神经免疫功能障碍的作用 和小胶质细胞功能在神经发育和疾病中的作用，以及(Iii)男性和女性的显著差异 对病理生理侮辱的反应。

PROJECT SUMMARY Autism Spectrum Disorders (ASD) are a collection of complex neurodevelopmental disorders characterized by repetitive behaviors and alterations in social interaction and communication that currently affect 1 in 68 children in the United States. Although it is clear that ASD prevalence is biased towards males (~4:1 male to female ratio), the mechanisms behind this male susceptibility remain elusive. While ASDs are quite heterogenous, evidence suggests a role for neuroinflammation in the development of these neurological abnormalities. Microglia, the resident immune cells of the brain, are key regulators of the neural response to immune activation and developmental organization of neural circuits, uniquely positioning them to translate early-life challenges into neural outcomes. Additionally, emerging evidence suggests that mitochondrial dysfunction plays an important role in neuropsychiatric/neurodevelopmental disorders such as ASD, and that inhibition of mitochondrial function may be critical in the processes of microglial activation. The emerging understanding of sex differences in mitochondrial and microglial physiology suggest that further study into their potential roles in the development of neurodevelopmental disorders such as ASD are warranted. To that end, I will first characterize the effect of early-life immune challenge (an established model for ASD in mice that presents with a strong sex bias) on mitochondrial gene/protein levels and functions. Building upon this, I will then assess how an early-life immune stimulus affects epigenetic regulation of mitochondrial DNA in males and females. Finally, I will ask what could be occurring during early development that may mediate these early- onset sex differences. There is a surge in gonadal hormone levels that occurs only in males during a ‘critical period’ of days surrounding birth that is responsible for masculinizing male brains. Injections of these hormones into females during this ‘critical period’ has been shown to ‘masculinize’ their brains to a male-like state. Using this model, I will determine if male sex hormones present during a critical period surrounding birth (‘masculinizing’ female mice) will impart susceptibility to subsequent immune challenge. I expect this project to result in several novel implications by bridging three bodies of research that are only beginning to collaborate: (i) the role of mitochondrial biology in neurodevelopment and disease, (ii) the role of neuroimmune dysfunction and microglial function in neurodevelopment and disease, and (iii) the striking differences in male and female responses to pathophysiological insults.