Sex Differences in Developing Microglia: Implications for Synaptic Pruning

描述(由申请人提供)：许多神经精神障碍在患病率和发病年龄方面表现出显著的性别差异。男性更有可能患有儿童早期出现的疾病，包括自闭症、精神分裂症和学习障碍。女性更多的是在青春期出现疾病，包括焦虑和抑郁。这一流行病学表明，存在基于性别的神经生物学差异，这种差异可能在发育过程中出现，要么直接促进特定的神经精神障碍，要么增加导致此类障碍的环境因素的易感性。目前，还没有基于性别的差异能够完全解释神经精神障碍的性别二型性。在这项建议中，我们描述了发育中的啮齿动物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的小胶质细胞。此外，我们还证明，在男性中，这种模式与特定脑区炎症反应的增加以及与相同脑区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和功能差异的模式与人类神经精神障碍的性别二形性相似，这一点令人震惊。致我们的 知识，这是第一次描述基于性别的大脑发育差异，这将解释观察到的人类神经精神疾病的流行病学。我们的发现提出了一个模型，在这个模型中，在神经发育的不同窗口，对情绪和认知至关重要的特定大脑区域的小胶质细胞定植的性别差异导致对外部刺激的炎症反应增加，这反过来又导致这些大脑区域突触重塑的变化，最终导致长期的神经精神功能障碍。在这个提案中，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的发展的贡献来测试这一模型的关键方面。这些研究的结果有可能极大地促进我们对人类神经精神障碍的理解。我们模型的确认将为预防、诊断和治疗广泛的、令人衰弱的精神健康疾病打开新的机会。

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.