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A groundbreaking study conducted by researchers at Kyoto University sheds light on how stress experienced before birth and during early development can significantly impact brain function and behavior. The study, recently published in Communications Biology, explores the effects of “two-hit stress”—a combination of prenatal infection and postnatal social stress—on mice, revealing profound changes in their brain structure and mental health.
The Impact of Two-Hit Stress
Previous studies have shown that acute inflammation in the cerebellum due to bacterial infection can induce neural plasticity, potentially leading to psychiatric conditions like depression and autism. However, the exact mechanisms through which two-hit stress alters brain function remained unclear until now.
To address this, Kyoto University researchers allowed subject mice to freely explore their environment, observing extensive behavioral differences in those exposed to two-hit stress. They discovered significant abnormalities in the cerebellum, the region of the brain responsible for motor coordination and cognitive function.
Key Findings
One of the most striking results was an increase in the number and activity of microglia—the brain’s primary immune cells—in the cerebellum. Additionally, the study found:
- Neuronal loss in the cerebellum
- Reduced action potential firing in cerebellar neurons
- Decreased brain-wide functional connectivity
“These results indicate cerebellar cognitive dysfunctions in animals exposed to two-hit stress,” explained study author Momoka Hikosaka. The study demonstrated that stress exposure altered microglial reactivity, leading to behaviors resembling psychiatric disorders.
Potential Treatments and Sex Differences
While these findings highlight the detrimental impact of two-hit stress, researchers also explored possible interventions. Microglia replacement therapy was found to be an effective way to counteract the damage. However, general microglial suppression poses a risk by weakening immunity, making the body more vulnerable to infections.
To address this, the researchers focused on cerebellum-specific microglia replacement, which yielded promising results. Notably, female mice exhibited higher resilience to stress compared to males, suggesting that sex differences play a crucial role in the brain’s response to chronic inflammation.
“Understanding these differences is crucial for developing personalized medicine approaches for mental health and neurodegenerative diseases,” noted corresponding author Gen Ohtsuki.
Future Implications
These findings offer new insights into the biological mechanisms underlying mental disorders and could influence both scientific research and societal attitudes toward mental health care. By considering sex differences in treatment approaches, future therapies may become more effective and tailored to individual needs.
Disclaimer
This study was conducted on mice, and while the findings provide valuable insights into brain function, further research is needed to determine whether similar effects occur in humans. Readers should consult medical professionals before drawing conclusions about human health based on this research.
For more details, refer to the original study: Momoka Hikosaka et al., Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition, Communications Biology (2025). DOI: 10.1038/s42003-025-07566-2.
