1. Exploring the role of neuronal-enriched extracellular vesicle miR-93 and interoception in major depressive disorder.
- Author
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Burrows K, Figueroa-Hall LK, Stewart JL, Alarbi AM, Kuplicki R, Hannafon BN, Tan C, Risbrough VB, McKinney BA, Ramesh R, Victor TA, Aupperle R, Savitz J, Teague TK, Khalsa SS, and Paulus MP
- Subjects
- Female, Humans, Male, Brain metabolism, Brain diagnostic imaging, Brain physiopathology, Case-Control Studies, Magnetic Resonance Imaging, Neurons metabolism, Depressive Disorder, Major metabolism, Depressive Disorder, Major physiopathology, Depressive Disorder, Major genetics, Extracellular Vesicles genetics, Extracellular Vesicles metabolism, Interoception physiology, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
Major depressive disorder (MDD) is associated with interoceptive processing dysfunctions, but the molecular mechanisms underlying this dysfunction are poorly understood. This study combined brain neuronal-enriched extracellular vesicle (NEEV) technology and serum markers of inflammation and metabolism with Functional Magnetic Resonance Imaging (fMRI) to identify the contribution of gene regulatory pathways, in particular micro-RNA (miR) 93, to interoceptive dysfunction in MDD. Individuals with MDD (n = 41) and healthy comparisons (HC; n = 35) provided blood samples and completed an interoceptive attention task during fMRI. EVs were separated from plasma using a precipitation method. NEEVs were enriched by magnetic streptavidin bead immunocapture utilizing a neural adhesion marker (L1CAM/CD171) biotinylated antibody. The origin of NEEVs was validated with two other neuronal markers - neuronal cell adhesion molecule (NCAM) and ATPase Na+/K+ transporting subunit alpha 3 (ATP1A3). NEEV specificities were confirmed by flow cytometry, western blot, particle size analyzer, and transmission electron microscopy. NEEV small RNAs were purified and sequenced. Results showed that: (1) MDD exhibited lower NEEV miR-93 expression than HC; (2) within MDD but not HC, those individuals with the lowest NEEV miR-93 expression had the highest serum concentrations of interleukin (IL)-1 receptor antagonist, IL-6, tumor necrosis factor, and leptin; and (3) within HC but not MDD, those participants with the highest miR-93 expression showed the strongest bilateral dorsal mid-insula activation during interoceptive versus exteroceptive attention. Since miR-93 is regulated by stress and affects epigenetic modulation by chromatin re-organization, these results suggest that healthy individuals but not MDD participants show an adaptive epigenetic regulation of insular function during interoceptive processing. Future investigations will need to delineate how specific internal and external environmental conditions contribute to miR-93 expression in MDD and what molecular mechanisms alter brain responsivity to body-relevant signals., (© 2024. The Author(s).)
- Published
- 2024
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