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bioRxiv · 10.64898/2026.08.08.743593

Juvenile influenza can impair myelin development and adult behavior through chemokine signaling in mice

Malacon, K.·Shamardani, K.·Artandi, S.·Ni, L.·Zernicka-Glover, N. K.·Rogers, A.·Yalcın, B.·Castaneda, E. H.·Pham, T.·Iwasaki, A.·Blish, C. A.·Geraghty, A. C.·Monje, M.
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Abstract

Brain development, especially developmental myelination, continues through young adulthood. Concordantly, children may be particularly vulnerable to neural-immune challenges. To investigate the consequences of major childhood immune challenges, juvenile mice were exposed to respiratory influenza (H1N1) infection. White matter-specific microglial reactivity accompanied by oligodendrocyte loss was evident until two months following infection. Mice exhibited hyperlocomotion and impaired attention, but not anxiety-like behavior, at one month following infection. Linking the oligodendroglial and behavioral deficits, genetic disruption of oligodendrocyte development at the same juvenile timepoint recapitulated this behavioral phenotype. Microglial reactivity and oligodendrocyte numbers normalized by young adulthood. However, myelin development was disrupted, with persistently decreased myelinated axon density and reduced myelin sheath thickness. Hyperlocomotion resolved, but anxiety-related behaviors emerged at two months after infection. At 6 months, anxiety resolved but cognitive deficits persisted. Elevated CSF chemokines and microglial chemokine expression prompted testing the role of the multi-chemokine receptor CCR3. CCR3 inhibition rescued these cellular and behavioral aberrations after juvenile H1N1 infection. Together, these findings underscore the potential for disruption of myelin development and lasting cognitive and neuropsychiatric sequelae following major immune challenges during the juvenile period and highlight chemokine signaling as an important therapeutic target.

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Malacon, K., Shamardani, K., Artandi, S., Ni, L., Zernicka-Glover, N. K., Rogers, A., Yalcın, B., Castaneda, E. H., Pham, T., Iwasaki, A., Blish, C. A., Geraghty, A. C., Monje, M.. 2026-08-17. Juvenile influenza can impair myelin development and adult behavior through chemokine signaling in mice. https://doi.org/10.64898/2026.08.08.743593

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