Down-regulated miR-16-2 in peripheral blood is positively correlated with decreased bilateral insula volume in patients with major depressive disorder

Major depressive disorder (MDD) is a complex psychiatric disorder characterized by affective, cognitive, neuromorphological, and molecular abnormalities that may have a neurodevelopmental origin (Gong and He, 2015). According to data from the World Health Organization, MDD affected approximately 322 million people worldwide, and the number of patients increased by 18.4 % between 2005 and 2015; and MDD is predicted to top the list of disease burden globally by 2030 (Collaborators GDaIIaP, 2016; WHO, 2017). In contrast to highly hereditary mental illnesses such as autism and schizophrenia, depression has a relatively low heritability (approximately 37 %; 95 % CI = 31 %–42 %) but a comparatively high proportion of individual-specific environmental effects (63 %; 95 % CI = 58 %–67 %) (Sullivan et al., 2000). Accumulated evidence shows that epigenetics plays an important role in MDD (Urdinguio et al., 2009). As an important epigenetic factor, microRNAs are receiving intensive research interest in psychiatric disease studies. It has been reported that microRNAs can regulate >50 % of human genes (Lewis et al., 2005; Selbach et al., 2008), which include those that regulate neurogenesis and synaptic plasticity, and susceptibility genes that are involved in the pathogenesis of depression (Enatescu et al., 2016).

Accumulating evidence shows that microRNA-16 (miR-16) targets the serotonin transporter (SERT), regulating the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Baudry et al., 2010). Chronic treatment with fluoxetine (Prozac) increases miR-16 levels in serotonergic raphe nuclei, which in turn decreases SERT expression, resulting in reduced 5-HT reuptake and achieving an antidepressant effect (Baudry et al., 2010). Studies in both mice and humans have shown that miR-16 can regulate SERT (Moya et al., 2013). Researchers have found that miR-16 expression is significantly down-regulated in the cerebrospinal fluid (CSF), dermal fibroblasts, and serum of patients with MDD (Launay et al., 2011; Garbett et al., 2015; Song et al., 2015; Gheysarzadeh et al., 2018). Our previous study also showed that microRNA-16-2-3p (miR-16-2) was down-regulated in the peripheral blood of MDD patients but not in healthy controls (HCs) (Wang et al., 2022). It is worth noting that miR-16 and miR-16-2 are identical mature miRNAs derived from different precursors, indicating that they have the same biological functions (Gao et al., 2011). These findings indicate that miR-16-2 may have a significant role in the pathogenesis and neuronal mechanisms underlying depressive symptoms and may be involved in the pathophysiology or etiology of diseases with an elusive genetic basis.

Shi et al. found that dysregulated miRNA in individuals with MDD can contribute to the decrease of specific brain areas, resulting in corresponding clinical symptoms, which provided a new perspective on how underlying epigenetic factors influence the pathophysiology of MDD (S. Qi et al., 2018). Several areas of reported grey matter deficits have been identified as prominently contributing to the pathogenesis of MDD, including the hippocampus, insula, prefrontal and orbitofrontal cortex (OFC), anterior cingulate, and temporal lobes (Schmaal et al., 2016; Schmaal et al., 2017; Lai, 2013). Additionally, patients with MDD exhibit decreased grey matter volume (GMV) in the dorsolateral prefrontal cortex (DLPFC), left superior temporal gyrus (STG_L), amygdala, and caudate nucleus (Gong and He, 2015; Schmaal et al., 2017). Given these findings, it is hypothesized that miR-16-2 may be associated with alterations in GMV in the brain.

To verify this hypothesis, we examined the expression of miR-16-2 in the peripheral blood of MDD patients and HCs using reverse transcription quantitative polymerase chain reaction (RT-qPCR) in this study. We also explored the relationship between miR-16-2 expression, clinical symptoms, and altered GMV in the brains of MDD patients, as well as the diagnostic and predictive value of miR-16-2 in MDD.

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