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bioRxiv · 10.64898/2026.06.04.730118

Functional ultrasound imaging reveals pathway-specific visual system reorganization in young Cln3-/- mice

Yin, F.·Ding, Y.·Chang, H. E.·Prifti, V.·Feng, J.·Freedman, E. G.·Foxe, J. J.·Doyley, M. M.·Wang, K. H. J.
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Abstract

CLN3 disease, or juvenile Batten disease, is a neurodegenerative lysosomal storage disorder in which visual impairment is typically the earliest clinical manifestation. Although retinal pathology has been extensively studied, functional alterations within central visual pathways remain poorly understood. Here, we used functional ultrasound (fUS) imaging to characterize visually evoked activity across central visual circuits in young Cln3 knockout (Cln3-/-) mice before the onset of severe retinal degeneration. Visually evoked hemodynamic responses were quantified in regions spanning the geniculostriate and extrageniculate visual pathways, including cortical, thalamic, and midbrain regions. To assess regional pathological burden, accumulation of subunit c of mitochondrial ATP synthase (SCMAS), a pathological marker of CLN3 disease, was examined using immunohistochemistry. We found that Cln3-/- mice exhibited pathway-specific alterations in visually evoked activity. Regions along the extrageniculate pathway, including the midbrain, posterior thalamus, and anterior secondary visual cortex, showed enhanced activation relative to wild-type controls. In contrast, activation within the geniculostriate pathway was reduced in the anterior thalamus and remained unchanged in the primary and posterior secondary visual cortex. SCMAS accumulation was elevated across all examined visual regions in Cln3-/- mice relative to wild-type controls, with greater accumulation observed in geniculostriate regions than in extrageniculate regions. These findings demonstrate early pathway-specific functional and pathological alterations in the visual system of Cln3-/- mice, suggesting pathway-level reorganization of central visual processing. This study advances understanding of central visual dysfunction in CLN3 disease and highlights fUS imaging as a sensitive approach for detecting early functional abnormalities in neurodegenerative disorders.

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Yin, F., Ding, Y., Chang, H. E., Prifti, V., Feng, J., Freedman, E. G., Foxe, J. J., Doyley, M. M., Wang, K. H. J.. 2026-06-09. Functional ultrasound imaging reveals pathway-specific visual system reorganization in young Cln3-/- mice. https://doi.org/10.64898/2026.06.04.730118

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