Olfactory bulb-initiated α-synucleinopathy induces visual abnormalities via remote occipital network dysfunction

Visual abnormalities are common in Lewy body diseases (LBDs), yet Lewy pathology is often sparse in the visual cortex, suggesting that dysfunction of anatomically remote networks may contribute to impaired visual processing. Here we report that α-synuclein (αSyn) expression initiated in the olfactory bulb induces visual abnormalities through remote network dysfunction despite no readily detectable local αSyn in the visual cortex. An adeno-associated virus expressing the A53T mutant αSyn was injected into the right olfactory bulb of mice. αSyn expression remained largely confined to olfactory- and limbic-associated cortices and was not readily detectable in the visual cortex with multiple αSyn and phospho-αSyn antibodies. αSyn-expressing mice exhibited abnormal performance in the visual cliff test and impaired visual discrimination, whereas locomotor activity, anxiety-like behavior, and olfactory performance were not detectably altered. Whole-brain phospho-S6 mapping suggested increased activity in olfactory/limbic-associated cortices and bilateral visual cortices, together with reduced activity in the thalamic reticular nucleus, and these regional changes were confirmed by c-Fos histology. Wide-field calcium imaging showed strengthened functional connectivity across the dorsal cortex, with prominent enhancement in occipital networks. These findings demonstrate a dissociation between αSyn distribution and distal circuit dysfunction, and support large-scale limbic/insular and thalamocortical reorganization as a network-level mechanism linking focal αSyn pathology to remote visual dysfunction. This study advances our pathophysiological understanding of distributed neurological dysfunction in α-synucleinopathies.