Multimodal MRI signatures and concurrent myelin remodeling alterations in the anterior cingulate cortex correlate with the antidepressant-like effects of 18β-glycyrrhetinic acid in CSDS mice.

Background

The anterior cingulate cortex (ACC) regulates emotion, and its dysfunction is associated with depression. 18β-glycyrrhetinic acid (18β-GA) exerts robust antidepressant effects; however, its roles in neural circuit remodeling of the ACC and underlying molecular mechanisms remain unclear. This study investigated its phenotypic changes within the ACC in chronic social defeat stress (CSDS) mice using multimodal MRI, histopathology and molecular assays.

Methods

Male C57BL/6J mice with CSDS depression model received 18β-GA treatment. We detected ACC neuroimaging alterations via multimodal MRI, and assessed BDNF, myelin-related molecules and myelin morphology. Hippocampal changes were also analyzed to explore the ACC-hippocampus emotional circuit.

Results

CSDS induced severe structural and functional deficits in the ACC, including gray matter atrophy, decreased FA, increased ReHo and disrupted functional connectivity between the ACC and limbic regions. 18β-GA-related effects coincided with ameliorated ACC imaging deficits, improved network homeostasis, attenuated stress-induced myelin injury, preserved myelin integrity, and elevated BDNF together with myelin-related molecular markers, pointing to parallel myelin-remodeling-associated phenotypic shifts. Consistent molecular and myelin changes were found in the hippocampus, indicating remodeling of the ACC-hippocampus emotional circuit.

Conclusion

18β-GA is accompanied by restored BDNF abundance, alleviated myelin lesions and normalized ACC neural circuits, which coincides with the alleviation of depressive-like phenotypes. Multimodal MRI parameters of the ACC, especially FA combined with myelin histopathological features, serve as promising biomarkers for evaluating the efficacy of 18β-GA. This study provides correlational evidence for BDNF-associated myelin remodeling alterations under chronic stress in depression-like mouse models and preclinical pharmacological evidence for the antidepressant use of 18β-GA.