2022 Fiscal Year Annual Research Report
母体免疫活性化による子供の小脳発達と機能の障害の解析
| Project/Area Number |
22J10152
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| Allocation Type | Single-year Grants |
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| Research Institution | Okinawa Institute of Science and Technology Graduate University |
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Principal Investigator |
Mi Yang 沖縄科学技術大学院大学, 科学技術研究科, 特別研究員(DC2)
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| Project Period (FY) |
2022-04-22 – 2024-03-31
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| Keywords | Neuroimmunity / Cerebellum / Neurodevelopment / Autism |
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| Outline of Annual Research Achievements |
Maternal immune activation (MIA) triggered by viral infection during pregnancy induces developmental defects in the fetal cerebral cortex dependent on the Th17/IL-17 pathway, leading to autism spectrum disorder (ASD)-like symptoms. However, the impact of MIA on cerebellum, the brain structure most constantly found abnormal in ASD, is far from clear.
The main goal of this project is to provide evidence that MIA interrupts offspring cerebellar development through a specific maternal cytokine signaling and helps to better characterize cerebellar neuropathology in human ASD.
Here we found that MIA impairs murine fetal cerebellum development. MIA induces developmental alterations of excitatory cerebellar nuclei excitatory neurons (eCNs) in the fetal cerebellum, both in the mid and late stages of pregnancy.
Importantly, the administration of Interferon beta (IFN-β), a major cytokine produced in MIA, into pregnant mice decreases eCNs in the fetal cerebellum. These data suggest that MIA-mediated upregulation of IFN-β leads to defective cerebellar nuclei development, providing new insights into the association of abnormal cytokine signaling in the cerebellum with ASD. In the future, these finds could stimulate further studies aimed at better understanding the immune-neural interaction, which may ultimately inform the development of strategies to reduce the adverse effects of MIA on the fetal cerebellum.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
The major goal of this project is to provide evidence that MIA interrupts offspring cerebellar development through specific maternal cytokine signaling pathways.
Using single-cell RNA sequencing, we have determined that MIA causes developmental defects in the cerebellum in particular cell clusters. Subsequently, we have further confirmed that maternal signaling plays a key role in the induction of these fetal cerebellar abnormalities.
The next and final step in completing this project is to study changes in adult offspring at the behavioral and morphological levels. And then I will focus on publication as the original plan.
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| Strategy for Future Research Activity |
To further confirm that the cerebellar nuclei changes caused by MIA are persistent, adult offspring of MIA will be examined focusing on cerebellar morphology and associated motor behavior.
By using interferon α receptor (ifnar) knockout mice, we will confirm the involvement of maternal IFN-β signaling in MIA-induced cerebellar alterations, both at the cellular and behavioral levels.
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