Grant: Project Grant

Brainstem cells generate the walking command sent to the spinal cord to activate the leg muscles. In Parkinson's disease, dopamine cells die in the brain, resulting in walking deficits. Classically, the connection between dopamine and brainstem cells is considered as solely indirect and to involve intermediary brain regions. However, direct connections between dopaminergic and brainstem cells were recently uncovered. These direct connections promote locomotion in basal vertebrates. In mammals, such connections could play a key role in locomotor control as well. In Parkinson's disease, the loss of such direct connections could be involved in the walking deficits. However, we still do not know the functional role of such direct connections in mammals. Our goal is to identify in mice the locomotor role of the direct connections between dopaminergic cells and brainstem cells. The brainstem cells targeted by the dopaminergic cells will be identified using high-resolution examination of brain anatomy, where the different cells will appear in different colors. Using in vivo optogenetics, we will determine whether turning on these direct dopaminergic connections is sufficient to initiate or speed up locomotion. Using in vivo chemogenetics, we will determine whether turning off these dopaminergic connections impairs gait or stop locomotion. Finally, the cellular mechanisms through which dopamine controls brainstem cells will be identified using patch-clamp electrodes able to detect the electric currents underlying brain cell activities. The proposed project will provide important new knowledge on the mechanisms through which the walking commands are controlled by dopamine in the brain. This knowledge is essential to understand why the walking commands are impaired by the loss of dopaminergic cells in Parkinson's disease. This will allow us to propose new strategies to improve locomotor function in Parkinson's disease and other locomotor disorders.