Structural brain abnormalities in endothelial nitric oxide synthase‐deficient mice revealed by high‐resolution magnetic resonance imaging

• Published in: Brain and behavior 2022-11, Vol.12 (11), p.e2801-n/a
• Main Authors: George, Hannah, Mercer, Grace V., Stapleton, Darcie, Dawson, Laura, MacCallum, Phillip E., Spring, Shoshana, Sled, John G., Blundell, Jacqueline, Cahill, Lindsay S.
• Format: Article
• Language: English
• Subjects: Anxiety; Behavior; Brain; endothelial nitric oxide synthase; Females; Laboratories; Magnetic resonance imaging; Males; mouse; Nitric oxide; Original; Rodents; sex differences
• ISSN: 2162-3279; 2162-3279
• DOI: 10.1002/brb3.2801

Introduction Endothelial nitric oxide synthase (eNOS) produces nitric oxide, which is essential for a variety of physiological functions in the brain. Previous work has demonstrated the detrimental effects of eNOS deficiency on brain function in male eNOS knockout (eNOS KO) mice. However, the effect of eNOS deficiency on brain structure and any association between these effects and sex is unknown. Methods This study used three‐dimensional high‐resolution ex vivo magnetic resonance imaging and behavioral tests of anxiety and cognitive performance to investigate structure–function relationships in the brain of female and male eNOS KO mice in young adulthood. Results While there were no differences in anxiety‐like behavior or locomotion, there was a sex‐specific deficit in contextual fear memory retention in male, but not in female, eNOS mice compared to wild‐type controls. Moreover, we found that eNOS deficiency induced changes in multiple brain regions that are involved in learning and fear memory including the hippocampus, amygdala, hypothalamus, and areas of the cortex. Several of these MRI‐detectable neuroanatomical changes were dependent on sex. Conclusion The observation that eNOS deficiency impacts brain structure at an early age demonstrates the importance of eNOS for healthy brain development. Using behavioural tests of anxiety and cognitive function and high‐resolution ex vivo magnetic resonance imaging, we demonstrated the endothelial nitric oxide synthase deficiency in mice impacts brain structure and function in a sex dependent manner.