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 cells and brainstem cells is considered as solely indirect and to involve intermediary brain regions. However, direct connections between dopamine and brainstem cells were uncovered, and these promote locomotion in basal vertebrates. In mammals, such connections could play a key role in locomotor control. In Parkinson's disease, the loss of such connections could be involved in walking deficits. However, we still do not know which cells are targeted by dopamine in the brainstem, and what is the role of these cells in the control of walking. Our goal is to identify in mice the locomotor role of brainstem cells sensitive to dopamine. First, using genetic techniques that make cells sensitive to light or to synthetic drugs, we will examine whether switching on dopamine sensitive cells in the brainstem is sufficient to initiate or speed up walking. We will determine whether switching off those cells impairs gait or stops walking. Second, using a brain imaging method, we will examine whether dopamine is released in brainstem locomotor circuits when mice walk. We will determine whether brainstem cells sensitive to dopamine are activated when mice walk. Third, to understand how these cells produce their behavioural effects, we will use high-resolution examination of brain anatomy to visualize brainstem cells sensitive to dopamine, their inputs and outputs, which will appear in different colors. The proposed project will provide new knowledge on the mechanisms through which walking is controlled by dopamine-sensitive cells in the brainstem. This knowledge is essential to understand why walking commands are impaired by the loss of dopaminergic cells in Parkinson's disease, and thereby to find new strategies to improve walking in such disease.