Light-Dependent Circadian Rhythm Governs O-GlcNAc Cycling to Influence Cognitive Function in Adult Zebrafish

Area of Science:

• Neuroscience
• Chronobiology
• Molecular Biology

Background:

• The circadian cycle regulates numerous physiological processes, including brain function.
• Protein O-GlcNAcylation is a post-translational modification implicated in cellular regulation.

Purpose of the Study:

• To investigate the role of 24-hour protein O-GlcNAcylation rhythms in the zebrafish brain.
• To determine the impact of circadian disruption on O-GlcNAcylation and its relationship with neuronal function, learning, and memory.

Main Methods:

• Zebrafish models were used to study circadian rhythms by inverting the light-dark cycle and administering melatonin.
• Protein O-GlcNAcylation, O-GlcNAc transferase (OGT), and O-GlcNAcase (OGA) expression were analyzed.
• The effects of OGT inhibition using OSMI-1 on behavior and gene expression were assessed.

Main Results:

• Circadian rhythm disruption impaired O-GlcNAcylation rhythms and altered OGT/OGA expression in the zebrafish brain, significantly impacting learning and memory.
• Circadian cycling influenced O-GlcNAcylation of histone H2B, correlating with H3 trimethylation changes, which were disrupted by cycle alterations.
• OSMI-1 treatment disrupted wake-sleep patterns and inhibited key synaptic plasticity genes (c-fos, bdnf, calm1), reducing O-GlcNAcylated H2B and OGT binding to gene promoters.

Conclusions:

• Circadian cycling of the O-GlcNAc histone code is involved in regulating synaptic plasticity and brain function.
• Protein O-GlcNAcylation acts as a critical post-translational mechanism integrating circadian signals with neuronal function to control physiological rhythms.