A Scale-adaptive Vision Model Links C. elegans Neuronal Morphology to Behavior for Neurotoxicity Assessment

Abstract

Neurological disorders are a leading cause of global disability and are increasingly linked to environmental chemical exposures. Yet neurotoxicity assessment still relies on hand-scored morphological readouts that are subjective and poorly predictive of behavioral outcomes. Caenorhabditis elegans provides a genetically tractable, 3R-compliant alternative, but quantifying neuronal phenotypes from confocal microscopy at scale remains computationally challenging: existing vision foundation models, trained on natural or radiological images, cannot resolve the sparse signals and multi-scale lesions of neuronal imaging. Here, we introduce a dedicated self-supervised vision model for C. elegans dopaminergic neurons, together with CeNeuMorph, a multi-grained confocal benchmark of 27,117 annotated images. Specifically, moving beyond standard Masked Autoencoders, we propose a scale-adaptive masked image modeling strategy that jointly learns representations across resolutions and patch sizes under a fixed token budget. By decoupling structural semantic learning from rigid grid constraints, the model effectively resolves the full spectrum of neurodegenerative lesions - ranging from fine dendritic beading to gross soma shrinkage - within a tractable computational framework. Finally, our model surpasses both generalist and biomedical foundation models across classification, segmentation and detection tasks. Fusing visual features with morphological descriptors enables prediction of dopamine-dependent behavioral deficits ($R^2=0.498$). Screening 180 agrochemicals, we identify the benzimidazole moiety as a previously unrecognized determinant of dopaminergic neurotoxicity. Together, the work demonstrates how scale-adaptive self-supervised learning can connect morphology to function for a scalable alternative to mammalian in vivo models for neurotoxicity assessment and drug discovery.