Cerebellar control of gait and interlimb coordination

Abstract

Synaptic and intrinsic processing in Purkinje cells, interneurons and granule cells of the cerebellar cortex have been shown to underlie various relatively simple, single-joint, reflex types of motor learning, including eyeblink conditioning and adaptation of the vestibulo-ocular reflex. However, to what extent these processes contribute to more complex, multi-joint motor behaviors, such as locomotion performance and adaptation during obstacle crossing, is not well understood. Here, we investigated these functions using the Erasmus Ladder in cell-specific mouse mutant lines that suffer from impaired Purkinje cell output (Pcd), Purkinje cell potentiation (L7-Pp2b), molecular layer interneuron output (L7-Δγ2), and granule cell output (α6-Cacna1a). We found that locomotion performance was severely impaired with small steps and long step times in Pcd and L7-Pp2b mice, whereas it was mildly altered in L7-Δγ2 and not significantly affected in α6-Cacna1a mice. Locomotion adaptation triggered by pairing obstacle appearances with preceding tones at fixed time intervals was impaired in all four mouse lines, in that they all showed inaccurate and inconsistent adaptive walking patterns. Furthermore, all mutants exhibited altered front–hind and left–right interlimb coordination during both performance and adaptation, and inconsistent walking stepping patterns while crossing obstacles. Instead, motivation and avoidance behavior were not compromised in any of the mutants during the Erasmus Ladder task. Our findings indicate that cell type-specific abnormalities in cerebellar microcircuitry can translate into pronounced impairments in locomotion performance and adaptation as well as interlimb coordination, highlighting the general role of the cerebellar cortex in spatiotemporal control of complex multi-joint movements.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-014-0870-1) contains supplementary material, which is available to authorized users.

The sorting receptor Rer1 controls Purkinje cell function via voltage gated sodium channels

“…In mice with a PC-specific deletion of Na v 1.6 early ataxia and impaired Rotarod performance was observed at 6–8 wks26. Why our Rer1 ΔPC do not show motor coordination problems on the Rotarod is unclear, but could be due to the rather insensitive Rotarod29 or because of residual Na v 1.1 and 1.6 that correctly assemble and make it to the AIS in the absence of Rer1. Interestingly, motor learning as assessed from the learning curves on Rotarod and beam walk was not affected by the deletion of Rer1, similar to the tambaleante mice, where PCs are lost after 4–6 months24.…”

“…Yet, the development of motor phenotypes is clearly age-dependent, similar to other cerebellar mouse mutants27, probably because of initial compensation for loss of function. In contrast, the early complete loss of PCs at P15-30 in the Pcd mice results in early ataxia2829 and problems on the Rotarod already at P2030. In mice with a PC-specific deletion of Na v 1.6 early ataxia and impaired Rotarod performance was observed at 6–8 wks26.…”

Somatosensory Cortex Plays an Essential Role in Forelimb Motor Adaptation in Mice

“…These results are consistent with the idea that S1 is providing the updating signal (such as sensory prediction errors) to another region that houses the internal model. For example, recent work suggests that the cerebellum may contribute to the coordination and adaptation of limb movements (Hoogland et al, 2015; Vinueza Veloz et al, 2015), and thus may house an internal model that could be updated by S1.…”

The Roles of the Olivocerebellar Pathway in Motor Learning and Motor Control. A Consensus Paper

“…Since these modules will be used for evoking, optimizing and coordinating unconditioned reflexes of motor activity as well as for modifying the amplitude and timing of the same motor domains during conditioning, our brain, i.e., the cerebellum, uses the same outlets and reference frames for both short-term and long-term functions. Considering the high complexity in controlling movements with multiple degrees of freedom within a particular motor domain let alone in coordinating the activity across multiple motor domains [233], I would like to argue that this configuration is not only the most efficient way to organize the olivocerebellar system, but probably also the only way to do so. Moreover, given the wide and uniform distribution of this system in the animal kingdom, varying from fish and birds up to rodents and primates [234], and thus including all animals capable of adapting their motor timing, but excluding those with more rigid timing mechanisms such as insects that have a cerebellar-like structure lacking an inferior olive [235–237], it is evident from an evolutionary point of view that it was advantageous to combine learning and timing functions within the same olivocerebellar system.…”