Dopaminergic (DA) neurons of the Substantia Nigra (SN) regulate voluntary motor movement. These neurons are severely affected in Parkinson’s disease (PD), where their demise leads to disease-typical decline in motor functions (Parkinsonism). While numerous genes regulating formation and differentiation of DA neurons during development are known, little is known about genes and epigenetic modulators that control, in adults, their complex structure and functions. Several genes associated with familial PD are known, but there is little information on genetic factors that, through influencing DA neurons in adults, could be candidates for modulating onset, severity, and progression of Parkinsonism and the individual response to dopamine replacement therapy in sporadic forms of PD. We therefore propose to identify new modulators of SN dopaminergic neuron structure and function using the mouse as a model system. Our approach combines mouse genetics, transcriptomic and epigenomic profiling, neuropathology, and cellular studies to achieve this goal. We believe this multi-disciplinary approach is necessary for the analysis of complex traits such as the properties of DA neurons. We propose to use mouse genetic reference populations, in particular Collaborative Cross and Chromosome Substitution mice, to identify genetic modulators that control DA neurons, and to validate new candidate modulators in neuronal cellular models. We expect our results to shed new light on SN DA neuron function and integrity in the adult mammalian brain. The identification of novel genetic modulators of these neurons could lead to a deeper understanding of one of the most evolutionary preserved neural systems of the mammalian nervous system, and pave the way for the identification of factors that, in humans, are associated with the modulation of Parkinsonian motor symptoms, thus opening new venues for individualized therapies.