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Introduction: Spontaneous recovery after stroke occurs in both human and animals. However, the underlying molecular mechanisms driving spontaneous recovery are still unclear. This study investigates the molecular mechanisms driving spontaneous recovery after unilateral experimental stroke using RNA sequencing (RNAseq).Methods: Ischemic stroke was induced in C57BL/6J adult male mice by transient MCAO. Neurological score, vertical pole, and rotating horizontal beam test were performed at baseline and post stroke days (PD) 4, 8, and 14. All mice were sacrificed at PD15 and processed for immunohistochemistry or Hi-seq. Infarcts were visualized by T2WI at PD2 using 7T MR scanner or histology at PD15. All stroke mice included in the study have comparable cortico-striatal infarcts and exhibit similar prestroke baseline performance and PD4 deficits. These mice were further categorized into spontaneously recovered and non-recovered groups based on their rotating beam performance during recovery.Results: Out of 35 stroke mice with abovementioned similar conditions, 9 (26%) were categorized into spontaneously recovered group and 26 (74%) were categorized into non-recovered group. Hierarchical clustering analysis supported this categorization. At PD14, the spontaneously recovered group exhibited significant improvement in beam performance in distance traveled and speed (p<0.001). Using Ingenuity Pathway Analysis, the comparison of RNAseq transcriptome between ipsilesional and contralesional primary motor cortex (iM1 and cM1) in spontaneously recovered and non-recovered stroke mice revealed significant differential molecular pathways, including glutamate, calcium, and neurotrophin signaling pathways.Conclusions: Our study demonstrates that stroke mice with similar cortico-striatal infarct size can exhibit significant differences in their behavioral recovery outcome. The transcriptome profile in iM1-cM1 network at 2 weeks post-stroke highlighted several molecular pathways that were significantly different between spontaneously recovered and non-recovered mice. Validation of key molecular candidates from the RNAseq data would provide insights into the molecular mechanisms mediating spontaneous recovery after stroke.