AbstractAimsThe aim was to investigate the effect of mood disorders on parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced motor disability, substantia nigra pars compacta (SNc) dopaminergic (DA) neurons loss. Also, the neural circuit mechanism was elucidated.MethodsThe depression‐like (physical stress, PS) and anxiety‐like (emotional stress, ES) mouse models were established by the three‐chamber social defeat stress (SDS). The features of Parkinson's disease were reproduced by MPTP injection. Viral‐based whole‐brain mapping was utilized to resolve the stress‐induced global changes in direct inputs onto SNc DA neurons. Calcium imaging and chemogenetic techniques were applied to verify the function of the related neural pathway.ResultsWe found that PS mice, but not ES mice, showed worse movement performance and more SNc DA neuronal loss than control mice after MPTP administration. The projection from the central amygdala (CeA) to the SNcDAwas significantly increased in PS mice. The activity of SNc‐projected CeA neurons was enhanced in PS mice. Activating or inhibiting the CeA‐SNcDApathway could mimic or block PS‐induced vulnerability to MPTP.ConclusionsThese results indicated that projections from CeA to SNc DA neurons contribute to SDS‐induced vulnerability to MPTP in mice.