Beyond the cold: New insights for neuroprotection and neurorecovery from functional genomics

Hibernating animals are a remarkable model for natural neuroprotection, demonstrating profound ischemia tolerance in diverse in vivo and ex vivo models. Recent advances in functional genomics, transcriptomics, proteomics, and metabolomics have enabled detailed dissection of these resilience pathways in brain tissue and cell models derived from hibernating species, such as the Arctic ground squirrel. Major adaptations include shifts from glycolytic to lipid-based and oxidative metabolism, upregulation of antioxidant networks, dynamic regulation of mitochondrial structure and function, and extensive cytoskeletal remodeling to support plasticity. Studies using -omics technologies further highlight critical roles for molecular chaperones, post-transcriptional control, and non-coding regulatory DNA in orchestrating hibernation phenotypes. Functional screens and pre-clinical studies link these pathways to enhanced neuronal survival under metabolic stress in vivo. Lessons from naturally resilient species hold promise for developing more effective neuroprotective and neurorecovery therapies in human stroke and brain injury. Future translational success will require precise, multi-pathway therapeutic strategies that recapitulate the coordinated resilience programs observed in hibernators.