Having one traumatic experience is bad enough. If you’ve constantly experienced stress since before birth, you may be in for an especially tough time. Our emotions may be influenced by infections experienced in the mother’s womb. This can result from two-hit stress, where an infection during pregnancy is followed by social stress during postpartum development.
A team of researchers at Kyoto University recently set out to understand the mechanisms behind which two-hit stress contributes to brain dysfunction and mental disorders. They conducted a comprehensive investigation of the social and cognitive behaviors of mice that have been exposed to such stress, paying particular attention to anxiety-like behaviors.
Previously, this team demonstrated that acute inflammation in the cerebellum caused by a bacterial infection induces neural plasticity, which in turn may lead to hyper-excitability in the brain and the onset of depressive and autism-like symptoms. Yet exactly how two-hit stress contributes to changes in the brain had remained unclear.
Subject mice in the current investigation were allowed to freely explore, revealing extensive behavioral differences in two-hit mice, correlating with abnormalities in the cerebellum. In particular, the researchers observed a significant increase in the number and turnover of microglia, the primary immune cells found in the central nervous system. The study also revealed neuronal loss in the cerebellum, a reduction in the action potential firing of remaining cerebellar neurons, and a decrease in brain-wide functional connectivity.
“These results indicate cerebellar cognitive dysfunctions in animals exposed to two-hit stress,” says team member Momoka Hikosaka. The exposure to such stress altered the microglial reactivity in the cerebella of both male and female mice, leading to cerebellar dysfunction and behaviors resembling psychiatric disorders.
But it’s not all bad news. To rescue the exposed mice, the researchers used microglia replacement to ameliorate the effects of two-hit stress. Suppressing microglia can also be effective, but systemic depletion of microglia typically weakens immunity, making the body more susceptible to infections.
“To address this limitation, our team performed cerebellum-specific microglia replacement, which worked remarkably well,” says corresponding author Gen Ohtsuki, adding, “We were impressed to observe that the female mice showed notably higher stress resilience.”
This suggests that in some animals, sex differences in response to chronic inflammatory stress emerge in the cerebellum under certain conditions. Consequently, personalized medicine for mental health may require considering sex differences as an important factor, which could also be applied to neurodegenerative diseases and aging treatment.
Overall, these findings provide new pathways for understanding the biological mechanisms behind mental disorders, and have the potential to transform both scientific approaches and societal attitudes toward helping those affected.