Neuron-Microglia Crosstalk in Development: A new role for the neuron-derived cytokine IL34 in microglial function

发育中的神经元-小胶质细胞串扰：神经元源性细胞因子 IL34 在小胶质细胞功能中的新作用

• 批准号: 10601226
• 负责人: Benjamin Devlin
• 金额: $ 4.77万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601226
• 关键词: Adult; Age; Alzheimer' s Disease; Animals; Anterior; Behavior; Blocking Antibodies; Brain; Brain region; CSF1R gene; Communication; Corpus striatum structure; Data; Designer Drugs; Development; Embryo; Ensure; Excitatory Synapse; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Goals; Immunohistochemistry; Inflammatory; Interleukins; Interneurons; LacZ Genes; Ligands; Macrophage; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Measures; Messenger RNA; Microglia; Molecular; Mus; Neonatal; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuroglia; Neurons; Organ; Parkinson Disease; Phagocytosis; Proteins; Proxy; Regulation; Reporter; Reporting; Research; Role; Signal Transduction; Synapses; Synaptic plasticity; Testing; Tissues; Ultrasonics; Work; cell type; cingulate cortex; cohort; critical developmental period; critical period; cytokine; designer receptors exclusively activated by designer drugs; developmental plasticity; excitatory neuron; experimental study; mRNA Expression; neural; neural circuit; neurodevelopment; neuronal circuitry; novel; postnatal; prevent; protein expression; receptor; reconstruction; social cognition; synaptic pruning; synaptogenesis; timeline; vocalization

SUMMARY OF WORK Microglia-neuron crosstalk in development is critical for the formation and refinement of synaptic connections. In this project, I propose to investigate a novel role for the neuron-derived cytokine IL34 in controlling the function of microglia to close critical periods of synaptic plasticity in development. IL34, along with the canonical ligand CSF1, signals through the CSF1 receptor on microglia to promote differentiation. Previous work suggests that embryonic and neonatal microglia depend primarily on CSF1 from other glia, while adult microglia in regions such as the cortex and striatum depend on IL34 from neurons. I have shown that IL34 expression increases between postnatal day 8 (P8) and P15 in the anterior cingulate cortex. Interestingly, this window corresponds with peak synapse engulfment in the ACC, suggesting that IL34 may play a role in dictating microglial function rather than just survival. Furthermore, my preliminary data demonstrate that microglia in mice lacking functional IL34LacZ/LacZ show an elevated inflammatory profile and do not upregulate microglial “maturity” marker TMEM119 between P8 and P15. The overarching goal of this proposal is to test the hypothesis that IL34 is a neuronal activity-dependent signal that influences microglia function to close critical periods of developmental plasticity. In Aim 1 I will investigate how chemogenetic activation or inhibition of neuronal activity in development controls IL34 gene and protein expression in all neuron subtypes. In Aim 2, I will determine whether transiently blocking IL34 or CSF1 impacts microglial pruning of thalamocortical synapses in the ACC, and if this has an effect of communicative behaviors (USVs). These studies will elucidate the mechanistic implications of differential CSF1R signaling in the brain during development, and the functional consequences for microglial.

工作概要 发育中的小胶质细胞-神经元串扰对于突触连接的形成和细化至关重要。在 在本项目中，我建议研究神经源性细胞因子IL 34在控制功能中的新作用。 关闭发育中突触可塑性的关键时期。IL 34，沿着典型配体 CSF 1通过小胶质细胞上的CSF 1受体发出信号以促进分化。以前的工作表明， 胚胎和新生儿小胶质细胞主要依赖于来自其他胶质细胞的CSF 1，而成年小胶质细胞在区域 例如皮质和纹状体依赖于来自神经元的IL 34。我已经证明IL 34表达增加， 出生后第8天（P8）和P15之间的前扣带皮层。有趣的是，这个窗口对应着 在ACC中突触吞噬达到峰值，表明IL 34可能在支配小胶质细胞功能中发挥作用。 而不仅仅是生存。此外，我的初步数据表明，缺乏功能的小鼠中的小胶质细胞， IL 34 LacZ/LacZ显示升高的炎症特征并且不上调小胶质细胞“成熟”标记物TMEM 119 在P8和P15之间。该提议的总体目标是测试IL 34是神经元特异性受体的假设。 影响小胶质细胞功能的活动依赖性信号，以关闭发育可塑性的关键时期。 在目标1中，我将研究在发育过程中化学发生激活或抑制神经元活动如何控制 IL 34基因和蛋白在所有神经元亚型中的表达。在目标2中，我将确定是否瞬时阻塞 IL 34或CSF 1影响ACC中丘脑皮质突触的小胶质细胞修剪，并且如果这具有以下作用： 交际行为（USV）。这些研究将阐明差异CSF 1 R的机制影响 发育过程中大脑中的信号传导，以及小胶质细胞的功能后果。