Sleep deprivation and neuronal hyperexcitation share molecular fingerprints, large-scale transcriptomic analysis finds
A systematic analysis of publicly available brain gene expression data has found that sleep deprivation produces a molecular fingerprint nearly indistinguishable from that of acute neuronal hyperexcitation. Researchers at Fujita Health University in Japan report that 73% of cross-model comparisons showed significant positive overlap in gene expression patterns between sleep-deprived brains and brains experiencing seizure-like hyperexcitation. The findings, published in Neuropsychopharmacology Reports, provide a mechanistic bridge linking insufficient sleep to the molecular states underlying epilepsy, bipolar mania, and other disorders of brain excitability.
What they found
The research team, led by Markos Michail Chatzigiannis, Hideo Hagihara, and Tsuyoshi Miyakawa, analyzed 32 publicly available transcriptomic datasets from sleep-deprived mice alongside 23 datasets from neuronal hyperexcitation models (chemically or electrically induced seizures). Using the Running Fisher algorithm to systematically compare expression profiles across datasets, they found:
- 73% of cross-model comparisons showed significant positive transcriptomic overlap (p ≤ 0.05), meaning sleep deprivation and hyperexcitation share a consistent molecular profile across multiple brain regions and experimental conditions.
- The overlap was strongest with acute hyperexcitation. Datasets collected within 1–12 hours of seizure induction showed the highest transcriptomic similarity to sleep deprivation. Datasets from 24 hours or later showed weaker overlap, suggesting that sleep loss most closely mimics the early, active phase of hyperexcitation rather than chronic or recovery stages.
- Immediate early genes (IEGs) dominated the shared signature. Key overexpressed genes common to both conditions included Egr1, Fos, and Arc,all transcription factors and plasticity-related genes that are rapidly turned on in response to neuronal activity. These genes are central to synaptic plasticity, learning, and memory, and their sustained upregulation during sleep deprivation suggests the brain remains in a hyperexcitable, plasticity-active state.
- Inflammation-associated genes were also shared. Ptgs2 (which encodes COX-2, a target of anti-inflammatory drugs like celecoxib) and Junb (another IEG with roles in inflammation) were consistently elevated in both conditions, pointing to a neuroinflammatory component of the shared signature.
- Different cell types contributed distinct components. Microglia showed enrichment of stress and immune-response genes, neurons expressed IEGs and plasticity-related signatures, endothelial cells upregulated metabolism-associated genes, and astrocytes contributed additional signals. This cell-type specificity indicates that the shared hyperexcitation-like state is not limited to neurons but involves a coordinated glial and vascular response.
Why it matters
Sleep deprivation has long been recognized as a clinical trigger for seizures in people with epilepsy and for manic episodes in bipolar disorder. But the molecular basis of this phenomenon has remained poorly defined. The current study offers a direct answer: sleep loss pushes brain gene expression toward a state that is transcriptomically homologous to acute hyperexcitation.
“Although sleep deprivation is clinically associated with numerous neuropsychiatric disorders, its underlying molecular correlates remain unclear,” the authors write. This study begins to fill that gap by identifying specific genes and pathways, IEGs, neuroinflammation, metabolism, that constitute a shared molecular language between the two states.
For clinicians, the findings reinforce the view that sleep is not simply restorative in a metabolic or energetic sense; it actively regulates the excitation-inhibition balance at the transcriptional level. For researchers, the shared signature provides potential biomarker targets, panels of IEGs and inflammatory genes whose expression levels could serve as molecular readouts of sleep debt and hyperexcitation risk.
The study was supported by the Japan Society for the Promotion of Science (grants JP20H00522 and JP25K00903) and the MEXT Promotion of Distinctive Joint Research Center Program.
Limitations
The analysis was performed entirely on mouse brain tissue. While the core transcriptional machinery is broadly conserved between rodents and humans, confirmation in human brain tissue or cerebrospinal fluid biomarkers is needed before the findings can be translated into clinical tools.
As a meta-analysis of preexisting datasets, the study cannot definitively establish causal direction. It is possible that sleep deprivation drives hyperexcitation, that an underlying hyperexcitable state predisposes individuals to both poor sleep and seizure activity, or that both conditions share a common upstream trigger. Experimental perturbation studies, in which gene expression is measured before, during, and after controlled sleep deprivation in the same animals, would help resolve this question.
Bottom line
Sleep deprivation reshapes the brain’s transcriptional landscape into a pattern that closely mimics acute neuronal hyperexcitation, characterized by activation of immediate early genes, neuroinflammatory pathways, and metabolic changes across multiple cell types. The finding provides a molecular framework for understanding why insufficient sleep can trigger seizures, worsen psychiatric symptoms, and carry risks beyond fatigue, it may actively drive a pro-excitatory, pro-inflammatory brain state.
Source
Chatzigiannis MM, Hagihara H, Miyakawa T. Sleep deprivation and neuronal hyperexcitation share transcriptomic signatures. Neuropsychopharmacol Rep. 2026;46(3):e70150. DOI: 10.1002/npr2.70150