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上表现出明显的性别差异。男性更有可能在儿童早期出现疾病，包括自闭症、精神分裂症和学习障碍。女性更常在青春期出现疾病，包括焦虑和抑郁。这种流行病学表明，在发育过程中可能出现的基于性别的神经生物学差异，要么直接促进特定的神经精神疾病，要么增加对导致此类疾病的环境因素的易感性。目前，还没有基于性别的差异被描述，可以充分解释神经精神疾病的性别二态性。在这个提议中，我们描述了发育中的啮齿动物大脑中小胶质细胞定植模式的性别差异，其中雄性在发育早期有更多的小胶质细胞，而雌性在青春期开始时有更多。此外，我们证明，男性的这种模式与特定大脑区域的炎症反应增加和对同一大脑区域相关的行为缺陷的易感性增加有关。我们在我们的模型中看到的基于性别的解剖学和功能差异的模式与人类神经精神疾病的性别二态性非常相似。对我们的

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.