CREB1 Emerges as Molecular Link Between Chronic Sleep Deprivation and Anxiety
People who carry genetic variants that boost expression of the CREB1 gene face a 28 percent higher risk of developing anxiety, according to a new study that triangulates three independent lines of evidence. The finding, published in Progress in Neuro-Psychopharmacology & Biological Psychiatry, positions CREB1 as a central molecular bridge between chronic sleep loss and pathological anxiety, with inflammation as the likely intermediary.
The transcriptomic screen
The research team, led by Zhujiang Bai and colleagues at Hainan Medical University in China, began by reanalyzing public gene expression datasets from people with insomnia and people with anxiety disorders. They searched for genes that were dysregulated in both conditions, reasoning that shared molecular signatures might reveal a common biological pathway.
The screen yielded 37 differentially expressed genes common to insomnia and anxiety. When the team ran enrichment analysis on this set, the signal was unmistakable: the genes were overwhelmingly enriched for inflammation-related biological processes. This computational finding set the stage for the team to test the connection in the lab.
The experimental model
To probe causality, the researchers turned to a rat model of chronic sleep deprivation. Rats subjected to prolonged sleep loss showed marked increases in inflammatory markers including tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in the amygdala, a brain region central to fear and emotional processing.
Microglial activation, measured by Iba1 expression, was elevated as well. Beyond general inflammation, the team tracked specific signaling proteins. Levels of phosphorylated NF-kappaB p65, phosphorylated ERK1/2, and phosphorylated CREB1 were all significantly increased in the amygdala of sleep-deprived animals. Total CREB1 protein remained unchanged, indicating that sleep deprivation drives post-translational activation of CREB1 rather than changes in its overall abundance.
The team also observed increases in brain-derived neurotrophic factor (BDNF) and the chemokine receptor CXCR4, which they identified as a potential upstream neuroimmune candidate linking sleep loss to CREB1 activation. CXCR4 could not be tested further in the human genetic arm of the study due to data limitations.
The genetic evidence
The most striking evidence comes from Mendelian randomization, a genetic epidemiology technique that uses naturally occurring gene variants as instrumental variables to estimate causal effects. The team used expression quantitative trait loci (eQTL) for CREB1 from the eQTLGen consortium and outcome data from FinnGen, a large Finnish biobank.
Genetically predicted higher CREB1 expression was associated with a 28 percent increase in anxiety risk (odds ratio 1.28, 95 percent confidence interval 1.06 to 1.54, p = 0.0089). Because inherited genetic variants are fixed at conception and not easily confounded by lifestyle or environmental factors, Mendelian randomization provides stronger evidence for a causal relationship than observational studies alone.
Why it matters
Chronic sleep deprivation affects an estimated one-third of adults worldwide and is a well-established risk factor for anxiety disorders, which represent the most common class of mental health conditions globally. Yet the molecular mechanisms linking poor sleep to heightened anxiety have remained poorly understood.
The convergence of transcriptomic, experimental, and genetic evidence on CREB1 offers a mechanistic explanation. The protein, a transcription factor, regulates the expression of genes involved in neuronal plasticity, stress responses, and inflammation. The present study suggests that chronic sleep loss triggers a neuroimmune cascade in the amygdala involving CXCR4, NF-kappaB signaling, and ERK phosphorylation, ultimately resulting in CREB1 activation and downstream changes that promote anxiety.
If confirmed, these findings could point toward novel therapeutic targets. Drugs that modulate CREB1 activity or interrupt the upstream inflammatory cascade might one day offer new options for patients whose anxiety is tied to sleep disruption.
Limits
Mendelian randomization can suggest causality but cannot prove it at the molecular level. The eQTL data reflect CREB1 expression in blood rather than directly in brain tissue, and the FinnGen cohort is predominantly of European ancestry, which limits generalizability. The CXCR4 hypothesis, while biologically plausible, could not be tested with human genetic data and remains supported only by the rodent experiments. Replication in additional cohorts and direct brain tissue studies will be needed.
Bottom line
Three converging lines of evidence point to CREB1 activation as a molecular link between chronic sleep deprivation and anxiety, with inflammation as a key mediator. The finding opens a new avenue for understanding how poor sleep reshapes brain circuitry and raises the possibility of targeting this pathway therapeutically.
Source
Bai Z, Ye W, Chen Z, Shen W, Sun Z. CREB1 mediates chronic sleep deprivation-induced anxiety via neuroimmune mechanisms. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2026. DOI: 10.1016/j.pnpbp.2026.111827. PMID: 42419627.