Major depressive disorder (MDD) is a serious mental disorder, yet the mechanism by which circular RNAs (circRNAs) are involved in the pathogenesis of MDD by encoding proteins is unknown. Our previous study has shown that circFKBP8(5S,6) relies on its encoded protein, namely cFKBP8, to promote susceptibility to chronic unpredictable mild stress (CUMS) in mice, but the precise molecular mechanisms are unknown. Here we found that overexpression of circFKBP8(5S,6) or cFKBP8 in neurons of the prelimbic cortex (PrL) of CUMS mice down-regulated the expression levels of DRD3 and its downstream AMPK/ULK1 (Ser555) and AMPK/mTOR/ULK1 (Ser757) pathways, which resulted in down-regulation of neuronal autophagy levels. Interestingly, both the activation and overexpression of DRD3 ameliorated the exacerbation of depressive-like behaviors induced by circFKBP8(5S,6) or cFKBP8, activated both the AMPK/ULK1 (Ser555) pathway and the AMPK/mTOR/ULK1 (Ser757) pathway, and up-regulated neuronal autophagy levels. In conclusion, circFKBP8(5S,6) or cFKBP8 promotes susceptibility to CUMS in mice, at least in part, by down-regulating DRD3 expression and its downstream AMPK/mTOR/ULK1 signaling pathway-mediated neuronal autophagy.

No well-established biomarkers are available for the clinical diagnosis of major depressive disorder (MDD). Vitamin D-binding protein (VDBP) is altered in plasma and postmortem dorsolateral prefrontal cortex (DLPFC) tissues of MDD patients. Thereby, the role of VDBP as a potential biomarker of MDD diagnosis was further assessed. Total extracellular vesicles (EVs) and brain cell-derived EVs (BCDEVs) were isolated from the plasma of first-episode drug-naïve or drug-free MDD patients and well-matched healthy controls (HCs) in discovery (20 MDD patients and 20 HCs) and validation cohorts (88 MDD patients and 38 HCs). VDBP level in the cerebrospinal fluid (CSF) from chronic glucocorticoid-induced depressed rhesus macaques or prelimbic cortex from lipopolysaccharide (LPS)-induced depressed mice and wild control groups was measured to evaluate its relationship with VDBP in plasma microglia-derived extracellular vesicles (MDEVs). VDBP was significantly decreased in MDD plasma MDEVs compared to HCs, and negatively correlated with HAMD-24 score with the highest diagnostic accuracy among BCDEVs. VDBP in plasma MDEVs was decreased both in depressed rhesus macaques and mice. A positive correlation of VDBP in MDEVs with that in CSF was detected in depressed rhesus macaques. VDBP levels in prelimbic cortex microglia were negatively correlated with those in plasma MDEVs in depressed mice. The main results suggested that VDBP in plasma MDEVs might serve as a prospective candidate biomarker for MDD diagnosis.

Superparamagnetic iron oxide (SPIO) nanoparticles play an important role in mediating precise and effective magnetic neuro-stimulation and can help overcome limitations related to penetration depth and spatial resolution. However, nanoparticles readily diffuse in vivo, decreasing the spatial resolution and activation efficiency. In this study, we employed a microfluidic means to fabricate injectable microhydrogels encapsulated with SPIO nanoparticles, which significantly improved the stability of nanoparticles, increased the magnetic properties, and reinforced the stimulation effectivity. The fabricated magnetic microhydrogels were highly uniform in size and sphericity, enabling minimally invasive injection into brain tissue. The long-term residency in the cortex up to 22 weeks and the safety of brain tissue were shown using a mouse model. In addition, we quantitatively determined the magneto-mechanical force yielded by only one magnetic microhydrogel using a video-based method. The force was found to be within 7–8 pN under 10 Hz magnetic stimulation by both theoretical simulation and experimental measurement. Lastly, electrophysiological measurement of brain slices showed that the magnetic microhydrogels offer significant advantages in terms of neural activation relative to dissociative SPIO nanoparticles. A universal strategy is thus offered for performing magnetic neuro-stimulation with an improved prospect for biomedical translation.