Subthalamic Nucleus Modulation of the Pontine Nuclei and Its Targeting of the Cerebellar Cortex

Abstract

The subthalamic nucleus (STN) has been implicated in motor and nonmotor tasks, and is an effective target of deep brain stimulation for the treatment of Parkinson's disease, likely in part because of the STN's projections outside of the basal ganglia to other brain regions. While there is some evidence of a disynaptic connection between the STN and the cerebellum via the pontine nuclei (PN), how the STN modulates the activity of the neurons in the PN remains unknown. Here we addressed this question using a combination of anatomical tracings, optogenetics, and in vivo electrophysiology in both wild-type (WT) and transgenic mice of both sexes. Approximately half of recorded neurons in the PN, which were located primarily in the medial area, responded with short latency to both single pulses and trains of optogenetic stimulation of channelrhodopsin (ChR2)-expressing STN axons in awake, head-restrained mice. Furthermore, the increase in the activity of PN neurons correlated with the strength of activation of STN axons, suggesting that the STN projections to the PN could, in principle, encode information in a graded manner. In addition, transsynaptic retrograde tracing confirmed that the STN sends disynaptic projections to the cerebellar cortex. These results suggest that the STN sends robust functional projections to the PN, which then propagate to the cerebellum, and have important implications for understanding motor control of normal conditions, and Parkinsonian symptoms, where this pathway may have a role in the therapeutic efficacy of STN deep brain stimulation.SIGNIFICANCE STATEMENT The primary excitatory nucleus in the basal ganglia, the subthalamic nucleus, is known to play a role in pathways modulating movement. The pontine nuclei are the main precerebellar nuclei, which transmit signals through their axonal projections to the cerebellum as mossy fibers. The pathway we have functionally characterized in this paper represents an additional cortex-independent pathway capable of relaying information between the basal ganglia and cerebellum. The effectiveness of subthalamic nucleus deep brain stimulation in Parkinson's disease suggests that this pathway could be explored as an avenue of investigation for therapeutic purposes.

Keywords: cerebellum; in vivo electrophysiology; optogenetics; pontine nuclei; subthalamic nucleus; transsynaptic retrograde viral tracer.