Study Rationale:
The motor symptoms of Parkinson's disease (PD) result from the degeneration of the dopamine producing neurons in a brain area called the substantia nigra pars compacta (SNc). Recent findings suggest that the SNc is diverse and is comprised of dopamine neurons with distinct properties. How these dopamine neuron “subtypes” contribute to movement and how they are affected in PD, and how they are modified by deep brain stimulation (DBS)remains unknown.
Hypothesis:
We will determine whether 1) the SNc is comprised of pro-motor and anti-motor dopamine neuron subtypes and 2) selective loss of pro-motor neurons in PD causes an imbalance in dopamine neuron subtypes that underlies the motor symptoms of PD.
Study Design:
We will separate these neurons into their distinct genetic subtypes, which will allow us to study their specific physiological, anatomical, and functional properties. We will also determine the molecular and circuit mechanisms underlying the dysfunction of dopamine neurons in a mouse model of PD (LRRK2 model). Additionally, we will explore whether deep brain stimulation of dopamine neuron inputs contributes to the therapeutic efficacy of this treatment.
Impact on Diagnosis/Treatment of Parkinson's Disease:
First, our work will identify which dopamine neuron subtypes degenerate and which circuits are dysregulated in PD. This knowledge will be important for understanding the pattern of SNc neuron loss in PD and efficacy of deep brain stimulation in patients. By using a LRRK2 model, our studies also will identify the molecular targets of the hyperactive LRRK2 enzyme, which will be critical for the optimization of LRRK2 inhibitor drugs and their application in patients.
Next Steps for Development:
Definition of pro- and anti-motor dopamine circuitry could be to used to inform the development of electrical, pharmacological, and chemogenetic approaches for the rescue of circuit function in people with PD.