Abstract
Rotenone is a naturally-occurring isoflavone that is used as a pesticide. Rotenone is also administered to rats to induce nigrostriatal dopaminergic neuron loss in an established model of Parkinson’s Disease (PD). However, the molecular mechanisms linking rotenone action to the emergence of PD-like phenotypes are poorly understood. Here, we characterize rotenone-induced gene dysregulation in the striatum. Male Lewis rats at 12–14 months received rotenone injected at 3 mg/kg, i.p. once daily for nine days. Behavioral effects of rotenone were verified using the bar test for catalepsy. RNA sequencing was carried out on RNA extracted from the striatum of rats receiving the full course of Rotenone treatment and vehicle-treated controls. Illumina PE150 sequencing to 30 M clusters per sample revealed several hundred differentially expressed genes (DEGs) at FDR < 5%. These included Dopa decarboxylase (Ddc), which encodes an important enzyme in dopamine production, and Angiopoietin 2 (Angpt2), a gene previously implicated in analysis of post-mortem PD brain. Pathway analysis of top findings identified the Circadian Clock System as enriched with rotenone DEGs. Circadian and sleep dysfunction is a known feature of PD. We validated the differential expression of two circadian genes via quantitative PCR: downregulation of Period 3 (Per3) and upregulation of the aryl hydrocarbon receptor nuclear translocator-like (Arntl). Overall this study represents a first look at striatal dysregulation of gene expression in the established rotenone PD model and indicates that further study of circadian gene dysregulation in this model may be fruitful. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12031-026-02506-z.