Integrative transcriptomic, experimental, and Mendelian randomization evidence implicates CREB1 in chronic sleep...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Insomnia and anxiety often co-occur, but the molecular mechanisms connecting sleep loss, inflammation, and mood disorders are not fully understood.
• Identifying these molecular links is crucial for developing targeted treatments for anxiety and sleep disturbances.

Purpose of the Study:

• To identify inflammation-related molecular candidates involved in anxiety-like behaviors resulting from chronic sleep deprivation (CSD).
• To investigate the roles of CREB1 and CXCR4 in the neurobiological pathways affected by CSD.

Main Methods:

• Integrated transcriptomic data analysis, a rat model of CSD, and Mendelian randomization (MR).
• Analyzed peripheral blood gene expression datasets for insomnia and anxiety, intersected with inflammation-related genes.
• Validated findings in rats using EEG/EMG for sleep architecture, behavioral tests for anxiety, and amygdala tissue analysis for molecular markers.
• Employed two-sample MR using eQTLGen and FinnGen data to assess genetic associations.

Main Results:

• CSD disrupted sleep architecture and increased anxiety-like behaviors in rats.
• CSD elevated inflammatory markers (TNF-α, IL-6), microglial activation markers (Iba1), and signaling pathway components (p-NF-κB, p-ERK1/2) in the amygdala.
• CSD modulated CREB1 phosphorylation and BDNF levels, suggesting plasticity-related changes.
• MR analysis supported a genetic association between higher CREB1 expression and increased risk of anxiety disorders (OR=1.28, p=0.0089).

Conclusions:

• CREB1 is implicated as a molecular node connecting neuroinflammatory signaling to anxiety-like phenotypes following CSD.
• CXCR4 is a potential upstream neuroimmune candidate requiring further mechanistic validation.
• These findings provide insights into the molecular underpinnings of the insomnia-anxiety comorbidity.