Microglia and Sex Differences in the Developing Brain

描述(申请人提供)：许多大脑疾病在患病率上显示出强烈的性别偏见，这表明大脑中正常的性别差异可能是其病因之一。这项提议的广泛目标是了解大脑中性别差异背后的神经机制，以阐明性别特有的发育如何产生一个易受特定大脑疾病影响的大脑。我们的实验室已经证实，视前区(POA)的性别分化是由脂类分子前列腺素E2调节的，视前区是大脑中参与生殖行为的关键区域。前列腺素与损伤或感染时大脑中的致炎信号有关，但它们也在POA的正常突触发育中发挥关键作用。我们建议研究小胶质细胞在POA性别分化中的作用，因为在脑部炎症和损伤的背景下，小胶质细胞既是前列腺素的来源，也是前列腺素的反应。小胶质细胞是大脑中主要的免疫活性细胞，在发育中的大脑中也处于主要激活状态，这表明它们有助于正常的大脑发育和可塑性。两个特定的目标将通过确定1)发育中的视前区小胶质细胞数量、活性或细胞因子信号是否存在性别差异以及2)新生儿小胶质细胞抑制是否扰乱视前区的形态性别分化和由此产生的性别特异性行为来检验几个假说。这些实验将深入了解神经、内分泌和免疫系统之间的相互作用，以产生特定性别的大脑发育。 公共卫生相关性：一个人对任何特定神经疾病的易感性的一个主要预测因素是他们的性别：男性表现出更高的自闭症谱系障碍、ADHD和癫痫的发生率，而女性表现出更高的偏头痛、慢性疼痛、抑郁症和多发性硬化症的发生率。生命早期的脑部炎症是发展成神经疾病的风险因素。研究大脑中性别差异建立的基本机制以及炎症信号如何促进大脑发育，将有助于深入了解特定性别的大脑发育如何导致易受大脑异常和紊乱的影响。

DESCRIPTION (provided by applicant): Many brain disorders show a strong gender bias in prevalence, suggesting that normal sex differences in the brain may contribute to their etiology. The broad goal of this proposal is to understand the neural mechanisms underlying sex differences in the brain, in order to elucidate how sex-specific development can produce a brain that is susceptible to specific brain disorders. Our laboratory has established that sexual differentiation of the preoptic area (POA), a key brain region involved in reproductive behavior, is regulated by the lipid molecule, prostaglandin E2. Prostaglandins are associated with proinflammatory signaling in the brain in response to injury or infection, however they also play a key role in normal synaptic development in the POA. We propose to investigate the role that microglial cells play in sexually differentiating the POA, as microglial cells are both a source of and responsive to prostaglandins in the context of brain inflammation and injury. Microglia, the primary immunocompetent cells in the brain, are also in a predominantly activated state in the developing brain, suggesting they contribute to normal brain development and plasticity. Two specific aims will test several hypotheses by determining 1) whether there are sex differences in microglial cell number, activity, or cytokine signaling in the developing preoptic area and 2) whether neonatal microglial inhibition disrupts the morphological sexual differentiation of the preoptic area and resulting sex-specific behaviors. These experiments will give insight into the interaction between the nervous, endocrine, and immune systems to produce sex-specific brain development. PUBLIC HEALTH RELEVANCE: A major predictor of an individual's susceptibility to any given neurological disorder is their sex: Males show much higher rates of autism spectrum disorders, ADHD, and epilepsy, whereas females show higher rates of migraine headaches, chronic pain, depression, and multiple sclerosis. Brain inflammation early in life is a risk factor for developing a neurological disorder. Studying the basic mechanisms through which sex differences in the brain are established and how inflammatory signaling contributes to brain development will provide insight into how sex-specific brain development can lead to vulnerability to brain abnormality and disorders.