Genetic data implicate microglia as central players in brain health and disease, urging the need to better understand what microglia do in the brain. Microglia are critical partners in neuronal wiring and function during development and disease. Emerging literature suggests that microglia have diverse functional roles, raising the intriguing question of which functions of microglia become impaired in disease to undermine proper neuronal function. It is also becoming increasingly clear that microglia exist in heterogeneous cell states. Microglial cell states appear context-dependent, that is, age, sex, location, and health of their microenvironment; these are further influenced by external signaling factors including gut microbiota and lipid metabolites. These data altogether suggest that microglia exist in functional clusters that impact, and are impacted by, surrounding neuronal microenvironment. However, we still lack understanding of how we can translate microglia cell states into function. Here, we summarize the state-of-the-art on the diverse functions of microglia in relation to neuronal health. Then, we discuss heterogeneity during developing, healthy adult and diseased brains, and whether this may be predetermined by origin and/or regulated by local milieu. Finally, we propose that it is critical to gain high-resolution functional discernment into microglia-neuron interactions while preserving the spatial architecture of the tissue. Such insight will reveal specific targets for biomarker and therapeutic development toward microglia-neuron crosstalk in disease.

中文翻译：

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了解小胶质细胞多样性及其对健康和疾病中神经元功能的影响

遗传数据表明小胶质细胞是大脑健康和疾病的核心参与者，这促使我们需要更好地了解小胶质细胞在大脑中的作用。小胶质细胞是发育和疾病过程中神经元布线和功能的重要伙伴。新出现的文献表明，小胶质细胞具有多种功能作用，这提出了一个有趣的问题：小胶质细胞的哪些功能在疾病中受损，从而破坏了正常的神经元功能。人们也越来越清楚，小胶质细胞以异质细胞状态存在。小胶质细胞状态似乎与环境相关，即年龄、性别、位置和微环境的健康状况；这些进一步受到外部信号因素的影响，包括肠道微生物群和脂质代谢物。这些数据共同表明，小胶质细胞存在于影响周围神经元微环境并受其影响的功能簇中。然而，我们仍然缺乏对如何将小胶质细胞状态转化为功能的了解。在这里，我们总结了小胶质细胞与神经元健康相关的多种功能的最新技术。然后，我们讨论发育中的健康成人和患病大脑期间的异质性，以及这是否可能由起源预先确定和/或受当地环境调节。最后，我们提出，在保留组织的空间结构的同时，获得小胶质细胞-神经元相互作用的高分辨率功能辨别至关重要。这种见解将揭示疾病中小胶质细胞-神经元串扰的生物标志物和治疗开发的具体目标。