The cerebellum is critical for fine-tuning movement. Inhibitory Purkinje cells are a predominant influence on the sole output of the cerebellum, the cerebellar nuclei. A good deal is known about how inhibitory influence from Purkinje neurons shapes nuclear output. One might expect that cerebellar nuclear cells could only fire during Purkinje cell pauses, however Purkinje cell-nuclear cell activity are not always inversely related, suggesting other inputs may drive cerebellar output. Here, we will test the hypothesis that the interposed nucleus (IN) can be driven by excitatory afferents but that Purkinje neurons set the gain of this input. Several nuances of precerebellar afferent anatomy will be utilized to explore this hypothesis. Evidence from retrograde tracing studies suggests that the glutamatergic premotor area, the red nucleus (RN), which innervates motor structures in the spinal cord, also innervates the IN to the exclusion of the cerebellar cortex. These RN-to-IN afferents differ from canonical pontine mossy fiber inputs, which mainly collateralize to innervate both the IN and overlying cortex. These differences point to a differential role the RN has in modulating IN firing rate. Here we will test the anatomical, physiological and behavioral substrates that underlie the function of the rubrocerebellar circuitry to cerebellar nuclear processing. The first goal of this proposal is to test how RN afferents are integrated with cortical driven inhibition to modulate IN output. The second goal of this proposal is to examine the role of rubrocerebellar afferents in coordinating inter-limb movements during gait. Both the IN and RN have been shown separately to be involved in limb coordination but there is no evidence as to the specific role of rubrocerebellar afferents. Lastly, we will examine what information rubrocerebellar afferents are sending to the IN. The two major inputs to the RN originate from the IN itself and primary motor cortex), however what innervates rubrocerebellar cells specifically is unknown. Together, these experiments will be the first to examine the role of a specific afferent in modulating cerebellar nuclear activity. Our studies will help elucidate the mechanisms by which the cerebellar nuclei integrate incoming sensory and motor information to execute precisely timed movement.
Deficits in sensorimotor integration are implicated in numerous neurological disorders including dystonia, ataxia, schizophrenia and autism. These studies will expand our understanding of normal sensorimotor integration in the cerebellum, informing future investigations of these and other disorders.
| Beitzel, Christy S; Houck, Brenda D; Lewis, Samantha M et al. (2017) Rubrocerebellar Feedback Loop Isolates the Interposed Nucleus as an Independent Processor of Corollary Discharge Information in Mice. J Neurosci 37:10085-10096 |
