Intermittent Hypoxia Induces Cognitive Dysfunction and Hippocampal Gene Expression Changes in a Mouse Model of...

Area of Science:

• Neuroscience
• Molecular Biology
• Sleep Medicine

Background:

• Obstructive sleep apnea syndrome (OSAS) involves cyclical oxygen desaturation and reoxygenation.
• Cognitive dysfunction is a known complication of OSAS, but its underlying mechanisms are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms by which intermittent hypoxia (IH), modeling OSAS, induces cognitive dysfunction.
• To analyze changes in hippocampal gene expression and identify key pathways affected by IH.

Main Methods:

• C57BL/6J mice were exposed to IH, sustained hypoxia (SH), or normoxia (control) for 28 days.
• Cognitive function was assessed using Y-maze and passive avoidance tests.
• Hippocampal gene expression was analyzed using RNA sequencing (RNA-seq) and RT-qPCR.

Main Results:

• IH exposure led to impaired memory and learning in passive avoidance tests compared to control and SH groups.
• RNA-seq revealed coordinated suppression of mitochondrial function genes and oxidative stress response pathways in the IH group.
• RT-qPCR confirmed decreased expression of Lars2, Hmcn1, and Vstm2l, and suppression of the KEAP1-NFE2L2 antioxidant pathway in the IH group.

Conclusions:

• IH induces cognitive dysfunction by suppressing the KEAP1-NFE2L2 antioxidant pathway and downregulating mitochondrial genes.
• These molecular changes result in oxidative stress and mitochondrial dysfunction, contributing to OSAS-related cognitive impairment.