Impact and regional aspects of glia to neuron exosome transfer in the CNS

少突胶质细胞使轴突髓鞘化，并且另外通过为神经元提供支持来维持轴突完整性。我们已经证明，少突胶质细胞分泌称为外泌体的纳米大小的囊泡，介导双向神经元-胶质细胞通讯。然而，它们对大脑生理学的影响在很大程度上尚未得到解决。外泌体在神经递质信号传导后由少突胶质细胞释放，并通过内吞作用由神经元内化，将多种生物分子（包括RNA）从少突胶质细胞递送至神经元。接受外泌体的培养神经元对压力更具弹性，表明少突胶质细胞外泌体介导神经保护作用。利用修饰外泌体以携带报告酶如Cre重组酶来说明外泌体及其货物向靶神经元的转移，从而允许鉴定脑中的靶神经元。在这个项目中，我们的目标是确定大脑区域，其中外泌体从少突胶质细胞转移到神经元是普遍的，以及外泌体靶向的特定神经元亚群。我们的策略利用他莫昔芬诱导的CreERT 2介导的靶细胞重组来追踪报告小鼠脑中的外泌体转移。此外，将评估外泌体转移与神经电活动的耦合。外泌体从NG 2-细胞转移到神经元和成熟少突胶质细胞转移到神经元将比较它们的靶向特征，揭示潜在的不同功能意义。此外，我们将确定胶质外泌体对靶神经元转录组学特征的影响。该项目将揭示更深入地了解不同大脑区域中依赖于外泌体的神经元-胶质细胞通讯的普遍性及其与神经性能和神经可塑性的功能相关性。这与髓鞘疾病特别相关，其中轴突由于缺乏少突胶质细胞-神经元通信而退化。建立大脑中神经胶质外泌体转移的时空图符合优先计划的目标，旨在解决大脑活动的局部决定因素，并将细胞通讯的创新概念整合到神经胶质研究网络中。

Oligodendrocytes myelinate axons and in addition maintain axonal integrity by providing support to neurons. We have shown that oligodendrocytes secrete nano-sized vesicles termed exosomes, which mediate bidirectional neuron-glia communication. However, their impact on brain physiology is largely unresolved. Exosomes are released by oligodendrocytes upon neurotransmitter signalling and internalized by neurons via endocytosis delivering a variety of biomolecules, including RNA, from oligodendrocytes to neurons. Cultured neurons that have received exosomes are more resilient to stress suggesting that oligodendroglial exosomes mediate neuroprotection. Modification of exosomes to carry reporter enzymes such as Cre recombinase is utilized to illustrate transfer of exosomes and their cargo to target neurons allowing the identification of target neurons in the brain. In this project, we aim to determine the brain regions, where exosome transfer from oligodendrocytes to neurons is prevalent, and the specific neuronal subpopulations targeted by exosomes. Our strategy utilizes tamoxifen-inducible CreERT2-mediated recombination of target cells to trace exosome transfer in the brain of reporter mice. In addition, the coupling of exosome transfer to neural electrical activity will be assessed. Exosome transfer from NG2-cells to neurons and mature oligodendrocytes to neurons will be compared regarding their targeting characteristics revealing potentially distinct functional implications. Furthermore, we will determine the influence of glial exosomes on the transcriptomic profile of target neurons. The project will reveal deeper insight into the prevalence of exosome-dependent neuron-glia communication in distinct brain regions and its functional relevance for neural performance and neural plasticity. This is particularly relevant for myelin diseases, where axons degenerate as a result of lacking oligodendrocyte-neuron communication. Establishing a spatio-temporal map of glial exosome transfer in the brain complies with the goals of the Priority Program aiming to resolve local determinants of brain activity and furthermore integrates an innovative concept of cell communication into the glia research network.