社会ストレスによる細胞内変化とその意義

抄録

Excessive or chronic social stress induces emotional and cognitive disturbancesand is a risk for mental illness. Reduced neuronal activity in the medialprefrontal cortex (mPFC) underlies these behavioral abnormalities. However, thesubcellular origin and process of this neuronal change remain elusive. Here weexamined ultrastructural alterations of mPFC neurons after social defeat stressin mice by serial electron microscopy and expansion microscopy. Social stresscaused the loss of dendritic branches as well as morphological abnormality ofsubcellular structures, including mitochondria in remaining dendrites withvaricosity-like membrane deformation. Social stress induced synaptic shrinkageselectively at mitochondria-containing synapses. Furthermore, multi-omics andfunctional analyses revealed that social stress deteriorated mitochondrialfunctions with decreased mitochondrial proteins at synapses. Pharmacologicalmanipulation targeting mitochondria attenuated the synaptic shrinkage anddepression-related behaviors. Together, these findings illustrate the importanceof synaptic subcellular organelle in the synaptic pathology underlying stressand depression.