Summary: A new study reveals how prenatal infections, known as “two-hit stress,” lead to behaviors like brain dysfunction and mental disorders. The researchers found that affected mice showed abnormal cerebellar activity, with increased microglial turnover and impaired connectivity throughout the brain.
In particular, microglial replacement therapy reversed these effects and provided a potential new approach to mental health treatment. Findings suggest that gender differences can affect stress resilience, highlighting the need for personalized treatment for psychiatric and neurodegenerative disorders.
Important facts
2 Effects of Hit Stress: Prenatal infection and childhood stress destroy cerebellar function. The role of microglia: Microglia turnover and increased neural loss contribute to brain dysfunction.
Source: Kyoto University
Having one traumatic experience is bad enough. If you’ve been constantly experiencing stress before birth, you may be in particularly tough times.
Our emotions can be affected by infections experienced in the mother’s uterus. This can result from two hit stress, followed by postpartum developmental social stress following infection during pregnancy.
A team of researchers at Kyoto University recently set out to understand the mechanisms that two hits contribute to brain dysfunction and mental disorders.
They conducted a comprehensive study of social and cognitive behaviors in mice exposed to such stress and paid particular attention to behaviors like anxiety.
Previously, the team demonstrated that acute cerebellar inflammation caused by bacterial infections induces neuroplasticity. We have demonstrated that this can lead to the development of brain hyperthermia and symptoms such as depression and autism. However, it remains unclear how the stress of two hits contributed to brain changes.
Subject mice in the current study were allowed to freely explore, revealing widespread behavioral differences between the two hit mice, correlated with cerebellar abnormalities. In particular, the researchers observed a significant increase in the number and turnover of microglia, the major immune cells found in the central nervous system.
The study also revealed neural loss in the cerebellar, reduced action potential firing in the remaining cerebellar neurons, and reduced functional connectivity throughout the brain.
“These results show cerebellar cognitive dysfunction in animals exposed to two-hit stress,” says team member Tanaka Kazuka. Exposure to such stress altered the microglia reactivity of the cerebellar in both male and female mice, leading to brain dysfunction and mental disorder-like behavior.
But that’s not all bad news. To rescue exposed mice, researchers used microglia supplementation to improve the effect of two-hit stress. Suppressing microglia is also effective, but overall microglia depletion usually weakens immunity and is susceptible to body infections.
“To address this limitation, our team performed cerebellar-specific microglial replacements, which worked very well,” says the corresponding author general.
This suggests that in some animals, gender differences appear in the cerebellum in response to chronic inflammatory stress under certain conditions.
As a result, personalized medicine for mental health may need to consider gender differences as an important factor, which could also be applicable to neurodegenerative diseases and aging treatments.
Overall, these findings offer new pathways for understanding the biological mechanisms behind mental disorders and have the potential to change both scientific approaches and social attitudes to help those affected.
About this neuroscience and stress research news
Author: Whitney Havel
Source: Kyoto University
Contact: Whitney Havel – Kyoto University
Image: Image credited to Neuroscience News
Original research: Open access.
“Connecting reactive microglia by persistent peripheral stress following maternal immune activation and trapping cerebellar cognition” Communication Biology
Abstract
Following maternal immune activation, subtle stress binds to produce reactive microglia, trapping cerebellar cognition
Functional changes in microglia occur in the brain exposed to external stress during early development.
Pathophysiological findings of neurodevelopmental disorders, such as schizophrenia and autism spectrum disorder, suggest cerebellar dysfunction. However, there is no link between stress-induced microglial reactivity and cerebellar dysfunction.
Here we investigate the developmental immune environment of a translated mouse model combining two risk factors: maternal infection and repeated social defeat stress (2HIT).
The insulting synergistic effect of inflammatory stress has been discovered, leading to an increase in microglia, particularly in the cerebellum of both sexes. Microglia turnover rates correlate with Purkinje neuronal loss in 2HIT mice.
Highly multiplexed imaging mass cell measurements identify cellular transitions to TREM2(+) stress-related microglia in the cerebellum. Single-cell intercellular clustering reveals the association of IL-6 and TGFβ signaling with MicrogLial cell transitions.
Reduced excitability of remaining Purkinje cells, functional incongruence of the entire brain, and behavioral abnormalities indicate cerebellar-cognitive dysfunction in two-hit animals.
