Ischemic stroke is the leading cause of adult disability. The rewiring of surviving neurons is the fundamental process for functional recovery. Accumulating evidence implicates astrocytes in synapses and neural circuits formation, but few studies have further studied how to enhance the effects of astrocytes on synapse and circuits after stroke and its impacts on post-stroke functional recovery. In this study, we made use of chemogenetics to specifically activate astrocytic Gi signaling in the peri-infarcted sensorimotor cortex at different time epochs in a mouse model of photothrombotic stroke. We found that early activation of astrocytic hM4Di after stroke by CNO modulates astrocyte activity and upregulates synaptogenic molecules including thrombospondin-1 (TSP1) as revealed by bulk RNA-sequencing, but no significant improvement was observed in dendritic spine density and behavioral performance in grid walking test. Interestingly, when the manipulation was initiated at the subacute phase of stroke, the recovery of spine density and motor function could be effectively promoted, accompanied by increased TSP1 expression. Our data highlight the important role of astrocytes in synapse remodeling during the repair phase of stroke and suggest astrocytic Gi signaling activation as a potential strategy for synapse regeneration, circuit rewiring, and functional recovery.

中文翻译：

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星形胶质细胞 Gi 信号传导的化学遗传学激活促进中风后脊柱形成和运动功能恢复

缺血性中风是成人残疾的主要原因。存活神经元的重新布线是功能恢复的基本过程。越来越多的证据表明星形胶质细胞参与突触和神经回路的形成，但很少有研究进一步研究如何增强星形胶质细胞对中风后突触和神经回路的影响及其对中风后功能恢复的影响。在这项研究中，我们利用化学遗传学在光血栓性中风小鼠模型的不同时间段特异性激活梗塞周围感觉运动皮层的星形胶质细胞Gi信号传导。我们发现，如体 RNA 测序所示，中风后星形胶质细胞 hM4Di 的早期激活可调节星形胶质细胞活性并上调包括血小板反应蛋白-1 (TSP1) 在内的突触分子，但在树突棘密度和网格行走中的行为表现方面没有观察到显着改善测试。有趣的是，当中风亚急性期开始操作时，可以有效促进脊柱密度和运动功能的恢复，同时TSP1表达增加。我们的数据强调了星形胶质细胞在中风修复阶段突触重塑中的重要作用，并表明星形胶质细胞 Gi 信号激活是突触再生、电路重新布线和功能恢复的潜在策略。