Multi-behavioral phenotyping in zebrafish identifies a novel disruptor of non-associative learning with environmental and human relevance
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The vertebrate nervous system is vulnerable to chemical toxicity and the widespread release of chemicals into the environment outstrips the capacity to assess their safety. We devised a battery of automated behavior assays in larval zebrafish ( Danio rerio ), a 3R-compliant model amenable to higher-throughput chemical screens. The battery captures stereotypical visual and acoustic behaviors including habituation, a form of non-associative learning. Known pharmacological modulators of habituation in zebrafish evoked distinct behavioral patterns. By screening chemicals positive for ex vivo N-methyl-D-aspartate receptor (NMDAR) modulation, we identified chlorophene, a biocide that caused sedation, paradoxical excitation, and reduced habituation in zebrafish. Using in silico target predictions and pharmacological interventions, we discovered that chlorophene acts via gamma-aminobutyric acid A receptors (GABAARs), a previously unknown target site. Orthogonal validation in cultured mouse cortical neurons and human stem cell-derived BrainSpheres confirmed chlorophene’s interaction with GABAARs. Together, multi-behavioral phenotyping in zebrafish can accelerate the identification of neurotoxicants and their underlying mode of action.
