Elucidating the Role of Neural Activity in Midbrain Dopamine Neuron Degeneration

PROJECT SUMMARY/ABSTRACT Parkinson’s Disease (PD) is a debilitating neurodegenerative disease characterized by the progressive loss of substantia nigra pars compacta (SNc) dopamine neurons. The reasons for their selective vulnerability and the mechanisms that drive their degeneration remain unclear. There is mounting evidence that the activity of energetically-burdened SNc neurons is altered in PD, however the role of neural activity in the susceptibility of dopamine neurons is poorly understood. Additionally, while dopamine is known to be toxic to neurons that do not have a means of sequestering or metabolizing it, the role of dopamine itself in the degeneration of dopamine neurons in PD is not known. To investigate the role of activity in dopamine neuron selective vulnerability, we have developed novel mouse models in which we can chronically manipulate midbrain dopamine neuron activity using chemogenetics. With these models, we propose to determine how chronically manipulating activity and dopamine metabolism within dopamine neurons impacts their susceptibility to degeneration. These experiments will be the first to directly interrogate the role of neural activity in degeneration in a chronic, minimally-invasive manner. Furthermore, they will provide insight for future therapeutic strategies to protect dopamine neurons from degeneration in PD.