Diverse inhibitory projections from the cerebellar interposed nucleus.

Elena N Judd,Abigail L Person,Samantha M Lewis

doi:10.7554/elife.66231

Abstract

The cerebellum consists of parallel circuit modules that contribute to diverse behaviors, spanning motor to cognitive. Recent work employing cell-type-specific tracing has identified circumscribed output channels of the cerebellar nuclei (CbN) that could confer tight functional specificity. These studies have largely focused on excitatory projections of the CbN, however, leaving open the question of whether inhibitory neurons also constitute multiple output modules. We mapped output and input patterns to intersectionally restricted cell types of the interposed and adjacent interstitial nuclei in mice. In contrast to the widespread assumption of primarily excitatory outputs and restricted inferior olive-targeting inhibitory output, we found that inhibitory neurons from this region ramified widely within the brainstem, targeting both motor- and sensory-related nuclei, distinct from excitatory output targets. Despite differences in output targeting, monosynaptic rabies tracing revealed largely shared afferents to both cell classes. We discuss the potential novel functional roles for inhibitory outputs in the context of cerebellar theory.

Highlights

The cerebellum plays a critical role in refining motor control through learning
Viral expression of Int-Vgat neurons labeled axonal varicosities which were immunopositive for antibodies against Gad65/67, but never Vglut2, consistent with a GABAergic phenotype for these projections (Figure 1E, Figure 1—figure supplement 2; analyzed in the inferior olive (IO), spinal trigeminal nucleus, interpolar (SPVi), pontine grey (PG), red nucleus (RN), and vestibular nuclei)
Consistent with previous work, we found that the putative excitatory output neurons of Int collateralize to regions of the contralateral brainstem, spinal cord, and thalamus and more restrictedly to the caudal ipsilateral brainstem, including to regions recently shown to control forelimb musculature

Summary

Introduction

The cerebellum plays a critical role in refining motor control through learning. The cerebellar nuclei (CbN), which constitute the major outputs of the cerebellum, are proposed to relay predictive computations of the cerebellar cortex and store well-learned patterns, placing them in a central position to implement cerebellar control (Eccles and Szentágothai, 1967Ohyama et al, 2003; Chan-Palay, 1977). Monosynaptic rabies transsynaptic tracing (Kim et al, 2016; Wickersham et al, 2010) restricted to excitatory premotor neuron populations through the selective expression of Cre recombinase under the Slc17a6 (Vglut2) promoter (Gong et al, 2007) and inhibitory neurons through Cre expression controlled under the Slc32a1 (Vgat) promoter revealed reproducible patterns of presynaptic inputs largely shared across cell types Taken together, these experiments provide new insight into input/output organization of the intermediate cerebellum, suggest potential functional diversity of parallel channels, and provide anatomical targets for functional studies aimed at evaluating these putative roles

Results

Discussion

Materials and methods