永井 裕崇

Chronic social stress induces neuronal dysfunctions in the medial prefrontal cortex (mPFC) for emotional and cognitive disturbances. However, the subcellular mechanism remains elusive. Here we examined ultrastructural and multi-omics changes in the mPFC in a mouse model of social defeat stress. Acute stress induced dendritic membrane deformation with mitochondrial swelling in mPFC neurons, leading to dendritic atrophy after chronic stress. Synaptic, but not bulk tissue, proteomes in the mPFC differentiated naïve and stressed mice and further uncovered two distinct states in stressed mice. Proteins involved in mitochondrial metabolic functions mostly decreased with chronic stress regardless of the synaptic proteomic state. By contrast, proteins responsible for mitochondrial homeostasis increased in stressed mice with a specific synaptic proteomic state associated with behavioral resilience to chronic stress. These findings suggest that the balance between mitochondrial metabolic dysfunction and its maintenance at mPFC synapses determines stress susceptibility in mice.

Chronic social stress induces emotional and cognitive disturbances and is a risk for mental illness. Reduced neuronal activity in the medial prefrontal cortex (mPFC) underlies these behavioral abnormalities. However, the subcellular origin and process of this neuronal change remain elusive. Here we examined ultrastructural and multi-omics changes in the mPFC with social stress in mice. Social stress caused the loss of dendritic branches with morphological alterations of mitochondria and induced synaptic shrinkage selectively at mitochondria-containing synapses. Social stress deteriorated mitochondrial functions at synapses with altered mitochondrial proteome and central metabolism in the mPFC. Pharmacological manipulation targeting mitochondria attenuated the synaptic shrinkage and depression-related behaviors. These findings show that chronic social stress alters the central metabolism at mPFC synapses, leading to neuronal pathology and depression-related behaviors.

Aging causes cognitive and motivational declines, but the biological basis remains elusive. Here we analyzed distinct behavioral effects of aging in C57BL6N (B6N) and C57BL/6J (B6J) strains. In this study, mice first learned a visual discrimination task to obtain food rewards by responding to the correct one of two visual stimuli. Then, they learned a response direction task of responding to either left or right for food rewards. Attentional set-shifting, behavioral flexibility between the tasks, is known to depend on working memory. Aged B6N mice showed motivational declines in both tasks. By contrast, task motivation was intact in aged B6J mice, but some of them showed a deficit in attentional set-shifting. We also analyzed synaptic proteomes in the medial prefrontal cortex, a brain region crucial for attentional set-shifting. Young and aged B6J mice showed differential expression of many synaptic proteins, some of which increased only in a subset of the aged mice with attentional set-shifting intact. These findings suggest that different biological mechanisms related to genetic and synaptic factors underlie motivation and cognitive declines with aging.