Summary: A new study reveals how prenatal infections followed by early-life stress—known as “two-hit stress”—can lead to brain dysfunction and psychiatric-like behaviors. Researchers found that affected mice showed abnormal cerebellar activity, increased microglial turnover, and impaired brain-wide connectivity.
Notably, microglia replacement therapy successfully reversed these effects, offering a potential new approach for mental health treatments. The findings suggest that sex differences may influence stress resilience, highlighting the need for personalized treatments for psychiatric and neurodegenerative disorders.
Key Facts
- Two-Hit Stress Impact: Prenatal infection and early-life stress disrupt cerebellar function.
- Microglia’s Role: Increased microglial turnover and neuronal loss contribute to brain dysfunction.
- Potential Therapy: Microglia replacement reversed stress-induced abnormalities in mice.
Source: Kyoto University
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.
About this neuroscience and stress research news
Author: Whitney Hubbell
Source: Kyoto University
Contact: Whitney Hubbell – Kyoto University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition” by Momoka Hikosaka et al. Communications Biology
Abstract
Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition
The functional alteration of microglia arises in brains exposed to external stress during early development.
Pathophysiological findings of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder suggest cerebellar functional deficits. However, the link between stress-induced microglia reactivity and cerebellar dysfunction is missing.
Here, we investigate the developmental immune environment in translational mouse models that combine two risk factors: maternal infection and repeated social defeat stress (2HIT).
We find the synergy of inflammatory stress insults, leading to microglial increase specifically in the cerebellum of both sexes. Microglial turnover correlates with the Purkinje neuron loss in 2HIT mice.
Highly multiplexed imaging-mass-cytometry identifies a cell transition to TREM2(+) stress-associated microglia in the cerebellum. Single-cell-proteomic clustering reveals IL-6- and TGFβ-signaling association with microglial cell transitions.
Reduced excitability of remaining Purkinje cells, cerebellum-involved brain-wide functional dysconnectivity, and behavioral abnormalities indicate cerebellar cognitive dysfunctions in 2HIT animals, which are ameliorated by both systemic and cerebellum-specific microglia replacement.
