Sex Differences in Developing Microglia: Implications for Synaptic Pruning

描述（由申请人提供）：许多神经精神疾病在患病率和发病年龄方面表现出明显的性别差异。男性更有可能患有幼儿期出现的疾病，包括自闭症、精神分裂症和学习障碍。女性更经常在青春期出现障碍，包括焦虑和抑郁。这种流行病学表明，有基于性别的神经生物学差异，这是可能出现在发展过程中，要么直接促进特定的神经精神疾病或增加易感性的环境因素，导致这种疾病。目前，没有基于性别的差异已经被描述，可以充分解释神经精神疾病的性别二型性。在这个建议中，我们描述了一种性别差异的小胶质细胞定植的模式，在发展中的啮齿动物的大脑中，男性有更多的小胶质细胞在发展的早期，而女性有更多的青春期开始。此外，我们证明，男性的这种模式与特定脑区的炎症反应增加和对相同脑区相关的行为缺陷的易感性增加有关。在我们的模型中，我们看到的基于性别的解剖和功能差异模式与人类神经精神疾病的性别二型性非常相似。对我们 这是第一次描述大脑发育中基于性别的差异，可以解释所观察到的人类神经精神疾病的流行病学。我们的研究结果表明，在神经发育的不同窗口，对情绪和认知重要的特定脑区的小胶质细胞定植的性别差异导致对外源性刺激的炎症反应增加，这反过来又导致这些脑区突触重塑的变化，最终导致长期的神经精神功能障碍。在这个提议中，我们将通过确定感染诱导的小胶质细胞激活对突触重塑和行为异常发展的贡献来测试这个模型的关键方面。这些研究的结果有可能显着推进我们对人类神经精神疾病的理解。我们的模型的确认将为预防，诊断和治疗广泛和衰弱的心理健康障碍开辟新的机会。

DESCRIPTION (provided by applicant): Many neuropsychiatric disorders exhibit marked sex differences in prevalence and age of onset. Males are more likely to have disorders that arise in early childhood, including autism, schizophrenia, and learning disabilities. Females more often have disorders that arise during puberty, including anxiety and depression. This epidemiology suggests that there are sex-based neurobiological differences, which are likely to arise during development, that either directly promote specific neuropsychiatric disorders or increase the susceptibility to environmental factors that lead to such disorders. At present, no sex-based differences have been described that can fully explain the sexual dimorphism of neuropsychiatric disorders. In this proposal, we describe a sex difference in the pattern of microglial colonization of the developing rodent brain in which males have more microglia early in development, while females have more at the onset of puberty. Moreover, we demonstrate that this pattern in males is associated with both an increased inflammatory response in specific brain regions and an increased susceptibility to behavioral deficits related to the same brain regions. The pattern of sex-based anatomic and functional differences we see in our model is striking in its similarity to the sexual dimorphism of neuropsychiatric disorders in humans. To our knowledge, this is the first description of a sex-based difference in brain development that would account for the observed epidemiology of human neuropsychiatric disease. Our findings suggest a model in which sex differences in the microglial colonization of specific brain regions important for emotion and cognition at distinct windows of neural development lead to increased inflammatory responses to exogenous stimuli, which in turn cause changes in synapse remodeling in these brain regions and, ultimately, to long-term neuropsychiatric dysfunction. In this proposal, we will test key aspects of this model by determining the contribution of infection-induced microglial activation to synapse remodeling and the development of behavioral abnormalities. The results of these studies have the potential to significantly advance our understanding of human neuropsychiatric disorders. The confirmation of our model would open new opportunities for the prevention, diagnosis, and treatment of widespread and debilitating mental health disorders.