Rubrocerebellar Feedback Loop Isolates the Interposed Nucleus as an Independent Processor of Corollary Discharge Information in Mice

Abstract

Understanding cerebellar contributions to motor coordination requires deeper insight into how the output structures of the cerebellum, the cerebellar nuclei, integrate their inputs and influence downstream motor pathways. The magnocellular red nucleus (RNm), a brainstem premotor structure, is a major target of the interposed nucleus (IN), and has also been described in previous studies to send feedback collaterals to the cerebellum. Because such a pathway is in a key position to provide motor efferent information to the cerebellum, satisfying predictions about the use of corollary discharge in cerebellar computations, we studied it in mice of both sexes. Using anterograde viral tracing, we show that innervation of cerebellum by rubrospinal neuron collaterals is remarkably selective for the IN compared with the cerebellar cortex. Optogenetic activation of the pathway in acute mouse brain slices drove IN activity despite small amplitude synaptic currents, suggesting an active role in IN information processing. Monosynaptic transsynaptic rabies tracing indicated the pathway contacts multiple cell types within the IN. By contrast, IN inputs to the RNm targeted a region that lacked inhibitory neurons. Optogenetic drive of IN inputs to the RNm revealed strong, direct excitation but no inhibition of RNm neurons. Together, these data indicate that the cerebellar nuclei are under afferent control independent of the cerebellar cortex, potentially diversifying its roles in motor control. The common assumption that all cerebellar mossy fibers uniformly collateralize to the cerebellar nuclei and cortex underlies classic models of convergent Purkinje influence on cerebellar output. Specifically, mossy fibers are thought to both directly excite nuclear neurons and drive polysynaptic feedforward inhibition via Purkinje neurons, setting up a fundamental computational unit. Here we present data that challenge this rule. A dedicated cerebellar nuclear afferent comprised of feedback collaterals from premotor rubrospinal neurons can directly modulate IN output independent of Purkinje cell modulation. In contrast to the IN-RNm pathway, the RNm-IN feedback pathway targets multiple cell types, potentially influencing both motor output pathways and nucleo-olivary feedback.

Structure of long-range direct and indirect spinocerebellar pathways as well as local spinal circuits mediating proprioception

“…Second, we find that CC neurons synapse only on GCs and do not collateralize to any other areas of the medulla or CN, in contrast to MF terminations that arise from the LRt, red nucleus, and basilar pontine nucleus, which are reported to collateralize to the CN (Sillitoe et al, 2012;Beitzel et al, 2017). Although teleosts have axon collaterals from the direct spinocerebellar pathway to the LRt, we find that CC neurons do not make axon collaterals to the LRt or anywhere else in the pons or medulla, consistent with findings in cats (Ekerot and Oscarsson, 1976;Szabo et al, 1990;Jiang et al, 2015).…”

“…A major contributor to the DSCT comes from CC neurons, whose soma reside in the medial aspect of the thoracic to upper lumbar spinal cord (Oscarsson, 1965;Baek et al, 2019). While SCT axons terminate as mossy fiber (MF) terminals on granule cells (GCs) in the vermis of the anterior zone (AZ, lobules I-V), the posterior zone (PZ, lobules VIII and anterior IX), and the copula pyramidis (Cop) (Arsenio Nunes and Sotelo, 1985;Bosco and Poppele, 2001;Reeber et al, 2011), it is unclear whether SCT neurons send axon collaterals to areas of the medulla or cerebellar nuclei (CN)(Medial, Interpositus, and Lateral) as is seen from other MF sources, thus allowing for integration with other ascending or descending pathways (Sillitoe et al, 2012;Beitzel et al, 2017). Axon collaterals to the lateral reticular nucleus (LRt) from the direct spinocerebellar pathway have been found in teleosts; however, it is unclear whether this occurs in mammals (Ekerot and Oscarsson, 1976;Szabo et al, 1990;Jiang et al, 2015).…”

Dynamics of the Cortico-Cerebellar Loop Fine-Tune Dexterous Movement

“…Since our pontocerebellar perturbations do not directly affect these other inputs, it is likely that activity in these other loops override the aberrant PN activity and entrain relatively normal activity in the DCN and cortex. For DCN, potential inputs include sensory streams, such as those from external cuneate nucleus (Huang et al, 2013) , or motor inputs, such as those from the red nucleus (Beitzel et al, 2017) . These inputs may act by directly influencing the DCN or by driving near normal Purkinje cell output from the cerebellar regions that they target.…”

Monosynaptic Inputs to Excitatory and Inhibitory Neurons of the Intermediate and Deep Layers of the Superior Colliculus

“…1A). Cell-type specificity of viral infection and spread was achieved using a Cre-dependent trans-complementation strategy (Wickersham et al, 2007;Wall et al, 2010;Watabe-Uchida et al, 2012;Kim et al, 2016;Beitzel et al, 2017). The majority of rabies "starter" neurons were located within the SCid (Fig.…”