Direction-specific processing in the cerebellar oculomotor vermis during saccades

About This Grant

Project Summary/Abstract The cerebellum is essential for ensuring precise and coordinated movements. Central to this function is the cerebellar cortex, which integrates sensory and motor signals carried by mossy fiber projections. These signals are transformed by Purkinje cells (P-cells), the sole output neurons of the cortical circuit, into simple spike activity that fine-tunes motor commands in real time. Despite extensive knowledge of the relevant anatomy, we still do not know how mossy fiber inputs are dynamically transformed within the cortical circuit to generate P-cell simple spikes. This gap persists largely due to the challenges of recording and manipulating the activity of targeted cell types and pathways within the cerebellum of awake, behaving animals. The oculomotor system offers a unique model to address this problem. The brainstem premotor neurons driving saccades are well characterized, as are their mossy fiber projections to the oculomotor vermis (OMV, lobules VIc and VII). Mossy fibers from both the nucleus reticularis tegmenti pontis (NRTP) and the paramedian pontine reticular formation (PPRF) project bilaterally, with the NRTP relaying desired saccade amplitude from the superior colliculus and the PPRF providing corollary discharges of motor commands to motoneurons. However, how the OMV processes these signals to regulate saccades remains unknown. Our recent experiments revealed that P-cell-specific optogenetic stimulation affects saccades in direction-dependent ways. Stimulation during contraversive saccades reduces velocity at short latency. In contrast, stimulation during ipsiversive saccades produces a delayed effect, manifesting as prolonged deceleration. These latency differences cannot be explained by interactions with mossy fiber saccadic burst signals, which are time-locked to saccade onset. Instead, our findings suggest that the OMV cortical circuit processes mossy fiber inputs differently for each direction, leading to differences in how and when P-cell simple spike activity influences saccade dynamics. Specifically, we hypothesize that the OMV functions as a feedforward controller for contraversive saccades and as a temporal integrator within a negative feedback loop that governs the termination of ipsiversive saccades. The implementation of these direction-dependent mechanisms is unclear. P-cells project to the deep cerebellar nuclei and back to the cortical circuit via axon collaterals, suggesting two possibilities: delays may arise from downstream brainstem circuits or an internal switching mechanism within the OMV that modulates mossy fiber processing. To resolve this issue, we will use optogenetics to perturb PPRF mossy fiber inputs to the OMV while simultaneously recording P-cell activity. While this approach is well-established in rodent models, it has not yet been applied in non-human primates, providing a novel opportunity to determine how the OMV processes saccade-related signals and resolves direction-specific differences.