Altered reactivity to threatening stimuli in Drosophila models of Parkinson’s disease, revealed by a trial-based assay

Abstract

The fruit fly Drosophila melanogaster emerges as an affordable, genetically tractable model of behavior and brain diseases. However, despite the surprising level of evolutionary conservation from flies to humans, significant genetic and circuit-level differences hinder the interpretability of fruit fly models for human disease. Therefore, to facilitate fly-to-human translation with more direct behavior-level comparison, we surveyed the rarely-exploited, rich behavioral repertoire of fruit flies with genetic alterations relevant to Parkinson’s disease (PD). Flies displayed variable behaviors, including freezing, slowing and running, in response to predator-mimicking passing shadows used as threatening stimuli in a single-animal trial-based assay. We found that the expression of human mutant Parkin in flies resulted in reduced walking speed and decreased reactivity to passing shadows. Flies with dopamine receptor mutations showed similar alterations, consistent with the motor and cognitive deficits typical in humans with PD. However, Drosophila overexpressing the human form of α-synuclein manifested in only moderate phenotypical alterations, suggesting that other fruit fly models may be favored in PD research. We also found age-dependent trends in behavioral choice across the fly lifespan, while dopamine receptor mutant flies maintained their decreased general reactivity throughout all age groups. Our data demonstrate that single-trial behavioral analysis can reveal subtle behavioral changes in mutant flies that can be used to further our understanding of disease pathomechanisms and help gauge the validity of genetic Drosophila models of neurodegeneration.