Drosophila model of depression-like behavior: systematic investigation of external stress parameters and intrinsic susceptibility

Currently, Drosophila is widely used to study brain diseases. Unfortunately, Drosophila still lacks a mature and stable model for research on depression. This study addressed this issue by systematically exploring external stress and intrinsic susceptibility factors (Drosophila strains, adult/larval forms) that may influence the establishment and reproducibility of the stress-induced model. On this basis, the parameters are optimized. The results indicate Drosophila strains and forms are critical factors influencing model establishment, while external stress is the primary cause affecting the model's mortality rate. Compared with the other four strains, Canton-S are the most susceptible to chronic unpredictable mild stress (CUMS). Larval forms exhibit lower reactivity to external stress compared to adults. Parameter variations greatly influence model mortality rates from cold/heat/starvation stress. The model methodology validation study conducted subsequently through assessments of face, construct, and predictive validity demonstrates that the model exhibits face (neurobehavioral differences), structural (neurotransmitter changes in the Drosophila brain), and predictive (behavioral changes after fluoxetine treatment) validity. Additionally, spatial behavior experiments in Drosophila provide more realistic activity patterns compared to planar behavior, minimizing potential errors in interpreting lateral movements of the Drosophila, and it is recommended that this metric be included in model evaluation. This study presents a comprehensive set of methods for establishing and evaluating a depression-like behavior model and offers greater convenience for research on the pathogenesis of depression, as well as the screening, efficacy evaluation, and mechanistic studies of antidepressant drugs.