Optogenetic investigation into the role of the subthalamic nucleus in motor control

Abstract

BackgroundThe subthalamic nucleus (STN) is a major regulator of intended movements. The STN is controlled by both excitatory and inhibitory inputs. Dysregulation of the STN contributes to motor deficiency in Parkinsons disease (PD). Both STN-lesioning and high-frequency electrical stimulation of the STN improve motor symptoms in PD. However, despite a pivotal clinical target, the natural role of the STN in motor regulation has remained elusive. In fact, controlled excitatory or inhibitory manipulations have been poorly explored. By controlled regulation, new functional knowledge of the STN can be reached. ObjectiveTo uncover the role of the STN in several aspects of motor function during non-pathological conditions. MethodsThe Pitx2-Cre mouse model has been described as a transgenic tool to direct genetic targeting events to the STN. Here, Pitx2-Cre mice were used to direct optogenetic excitation and inhibition to the STN. The impact of each type of stimulation on motor output was recorded and compared. ResultsOptogenetic excitation of the STN triggered action potentials in a key component of the basal ganglia. Optogenetic excitation of the STN in the freely-moving animal reduced vertical and horizontal movement, induced immediate grooming and caused loss of motor coordination. In contrast, optogenetic inhibition increased general locomotion and reduced natural grooming. Opposite rotations were observed upon unilateral excitation and inhibition of the STN. ConclusionsOptogenetic excitation and inhibition of the STN give rise to opposite motor responses in several parameters relevant to voluntary motor control that are commonly disturbed in PD.