Ischemia, resulting from reduced blood supply due to arterial constriction or blockages, leads to oxygen and nutrient deprivation, impacting various body systems and contributing to numerous diseases. Despite extensive research on ischemia, molecular studies with spatial and temporal specificity are limited. Our study utilized single-cell genomics to investigate hypoxia-induced changes in the mouse brain at 30 and 60 minutes of exposure, aiming to map cellular trajectories, ontologies, and expression patterns in a cell-specific manner.

Material and methods:
We developed a mouse model of hypoxia using the thread-plug method. Experimental groups were exposed to hypoxia for 30 minutes (T_30) and 60 minutes (T_60), with a sham surgery group as control. After excising the cerebral cortex, we performed nuclear isolation and library construction for spatio-temporal analysis of cortical cells. Data analysis included differential gene expression, trajectory analysis, examination of gene regulatory networks, and hallmark analysis.

Single-cell genomics analysis revealed 12 distinct cell populations with different transcriptomic profiles. Spatio-temporal distinctions in cell signaling were observed, showing a switch from Ras GTPase signaling to calmodulin and calcium-dependent signaling between the two hypoxia levels. In the T_30 group, distal axons and growth cones were transcriptionally active, while in the T_60 group, cell edges and post-synaptic areas were more active. The synaptic vesicle cycle was implicated in transcriptional changes across the T_30 and T_60 groups.

Our single-cell genomics study provides new insights into cellular dynamics during hypoxia. The identified cell populations and molecular pathways highlight potential targets for further research and the development of targeted therapies for ischemia.

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