Figure 1. Research strategy for identifying changes in brain O-glycosylation in a depression model
A mouse model displaying depression-like behaviors was established by exposing animals to chronic variable stress (left). A multi-omics approach was then applied, using high-resolution mass spectrometry to analyze O-glycan composition and protein alterations across nine distinct brain regions (center). This analysis revealed a pronounced reduction in sialylation and downregulation of the glycosyltransferase St3gal1 in the prefrontal cortex, together with associated changes in synaptic proteins and inhibitory neuronal function (right). Through this integrated strategy, the study demonstrated a direct link between brain O-glycosylation abnormalities and depression-like behaviors.

Figure 2. Altered brain O-glycosylation in control and stressed mice
O-glycan expression patterns were compared across nine brain regions in control (CON) and chronic variable stress (CVS) mice (left). Region-specific glycosylation profiles were observed throughout the brain, with stress-induced changes most pronounced in the prefrontal cortex (PFC), cerebellar cortex (CC), olfactory bulb (OLB), and diencephalon (DIE) (right). These findings indicate that chronic stress disrupts O-glycosylation, particularly O-glycan sialylation, in specific brain regions, potentially contributing to depression-like behaviors.

Figure 3. Induction of depression-like behaviors by reduced St3gal1 expression in the mPFC
Injection of a virus suppressing St3gal1 expression (shSt3gal1) into the prefrontal cortex of normal mice induced depression-like behaviors. These mice exhibited increased latency to feed in a novel environment, reflecting heightened anxiety and reduced feeding motivation (NSFT, novelty-suppressed feeding test), as well as decreased sucrose preference, indicating anhedonia (SPT, sucrose preference test).

Figure 4. Alleviation of depression-like behaviors by restoring St3gal1 expression in the mPFC
Injection of a virus enhancing St3gal1 expression (St3gal1-GFP) into the medial prefrontal cortex (mPFC) of mice exposed to chronic variable stress (CVS) markedly alleviated depression-like behaviors. Stressed mice expressing GFP alone (CVS.GFP) showed prolonged latency to feed in a novel environment, indicating heightened anxiety and reduced feeding motivation (NSFT), as well as increased immobility, reflecting despair-like behavior or passive stress-coping behavior (TST). In contrast, mice with restored St3gal1 expression (CVS.St3gal1-GFP) exhibited significant behavioral improvement. These findings suggest that restoration of St3gal1 expression in the mPFC can mitigate depression-related behaviors.
(出典：いずれもIBS)