Sleep Deprivation and Neuronal Hyperexcitation Share Transcriptomic Signatures

Although sleep deprivation (SD) is clinically associated with numerous neuropsychiatric disorders, its underlying molecular correlates remain unclear. Because extended wakefulness is accompanied by increased neuronal activity and network firing, SD may be associated with a hyperactive neural state. This study aimed to test the hypothesis that SD shares transcriptomic signatures induced by neuronal hyperexcitation and to identify the gene pathways and cell types associated with these signatures. Publicly available transcriptomic datasets were analyzed, including 32 SD and 23 neuronal hyperexcitation transcriptomic datasets. These datasets were systematically compared using the Running Fisher algorithm across multiple mouse brain regions and rodent neuronal hyperexcitation models. The analysis revealed significant positive transcriptomic overlaps between SD and neuronal hyperexcitation models (p ≤ 0.05 in 73% of cross-model comparisons). In addition, neuronal hyperexcitation datasets collected within 1-12 h after seizure induction showed stronger transcriptomic similarity to SD than those collected 24 h or later. The shared transcriptomic signature was significantly enriched for pathways associated with neuronal plasticity, immune response, and inflammation. Key overexpressed genes common to both conditions included immediate early genes (IEGs) such as Egr1, Fos, and Arc, as well as inflammation-associated genes such as Ptgs2 and Junb. Comparisons between SD single-cell and neuronal hyperexcitation datasets indicated that the shared signature was most strongly enriched in microglia and neurons, with additional contributions from endothelial cells and astrocytes. Microglia showed enrichment of stress- and immune-response genes, neurons exhibited IEG and plasticity-related signatures, and endothelial cells expressed metabolism-associated genes. Together, these findings indicate that SD is associated with a transcriptomic state resembling acute neuronal hyperexcitation, characterized by activation of neuronal plasticity-, neuroinflammatory-, and metabolism-related pathways. This shared molecular signature provides a transcriptomic framework linking sleep loss to molecular processes implicated in neuropsychiatric disorders and suggests that acute neuronal hyperexcitation-related molecular processes may contribute to SD-associated brain dysfunction.