Neurophysiology of impaired gait in mouse models of Parkinson’s disease

Project Summary Walking is one of the most essential forms of mammalian behavior, but there is still only an incomplete understanding of the neural mechanisms that control gait performance at the level of individual limbs and steps. Several movement disorders including Parkinson’s disease (PD) are associated with impaired gait, and current therapies are often only partially effective at alleviating these motor symptoms. The basal ganglia are a set of subcortical nuclei that are strongly implicated in Parkinsonian motor symptoms. However, most efforts to link motor deficits with altered basal ganglia activity in PD animal models have focused on relatively low spatial resolution measures of motion such as movement initiation, termination, and whole-body speed. This leaves a large unmet need to study the neurophysiological basis of impaired gait in PD animal models with single-limb and step resolution. This project will examine how the dorsolateral striatum and substantia nigra pars reticulata, a major input and output nucleus of the basal ganglia, encode gait information in two complementary mouse PD models. Experiments will use high speed video, automated behavioral tracking, single-unit electrophysiology from genetically identified cell types, and optogenetic manipulations to mimic or rescue motor impairments in the unilateral 6-hydroxydopamine (6OHDA) and alpha-synuclein preformed fibril models of PD. This proposal is motivated by novel electrophysiological data suggesting that a sizable fraction of neurons in the striatum and substantia nigra are normally coupled to the cycle of limb movements during walking. Furthermore, lesioning dopamine with unilateral 6OHDA injections disrupts the normal balance of gait phase coding between direct and indirect pathway neurons in the striatum. Aim 1 will build on these preliminary results by identifying the neural signatures of impaired gait and other, more commonly studied measures of motion (start/stop and whole-body speed), in 6OHDA lesioned mice on and off dopamine replacement medication. Aim 2 will track the progression of gait impairments and movement-related neural activity changes in the alpha-synuclein preformed fibril model. Finally, Aim 3 will determine whether manipulating certain basal ganglia cell types can impair single-limb gait performance in healthy animals, or rescue gait in PD models. Together, this project will significantly advance our understanding of the basal ganglia’s role in encoding and controlling gait in PD animal models.