A quantitative framework for whole-body coordination reveals specific deficits in freely walking ataxic mice

Abstract

The coordination of movement across the body is a fundamental, yet poorly understood aspect of motor control. Mutant mice with cerebellar circuit defects exhibit characteristic impairments in locomotor coordination; however, the fundamental features of this gait ataxia have not been effectively isolated. Here we describe a novel system (LocoMouse) for analyzing limb, head, and tail kinematics of freely walking mice. Analysis of visibly ataxic Purkinje cell degeneration (pcd) mice reveals that while differences in the forward motion of individual paws are fully accounted for by changes in walking speed and body size, more complex 3D trajectories and, especially, inter-limb and whole-body coordination are specifically impaired. Moreover, the coordination deficits in pcd are consistent with a failure to predict and compensate for the consequences of movement across the body. These results isolate specific impairments in whole-body coordination in mice and provide a quantitative framework for understanding cerebellar contributions to coordinated locomotion.

Article and author information

Author details

  1. Ana S Machado

    Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  2. Dana M Darmohray

    Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  3. Joao Fayad

    Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  4. Hugo G Marques

    Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  5. Megan R Carey

    Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal
    For correspondence
    megan.carey@neuro.fchampalimaud.org
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All procedures were reviewed and performed in accordance with the Champalimaud Centre for the Unknown Ethics Committee guidelines, and approved by the Portuguese Direcção Geral de Veterinária (Ref. No. 0421/000/000/2015).

Copyright

© 2015, Machado et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 9,786
    views
  • 1,521
    downloads
  • 168
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ana S Machado
  2. Dana M Darmohray
  3. Joao Fayad
  4. Hugo G Marques
  5. Megan R Carey
(2015)
A quantitative framework for whole-body coordination reveals specific deficits in freely walking ataxic mice
eLife 4:e07892.
https://doi.org/10.7554/eLife.07892

Share this article

https://doi.org/10.7554/eLife.07892

Further reading

    1. Neuroscience
    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.

    1. Neuroscience
    Gáspár Oláh, Rajmund Lákovics ... Gábor Tamás
    Research Article

    Human-specific cognitive abilities depend on information processing in the cerebral cortex, where the neurons are significantly larger and their processes longer and sparser compared to rodents. We found that, in synaptically connected layer 2/3 pyramidal cells (L2/3 PCs), the delay in signal propagation from soma to soma is similar in humans and rodents. To compensate for the longer processes of neurons, membrane potential changes in human axons and/or dendrites must propagate faster. Axonal and dendritic recordings show that the propagation speed of action potentials (APs) is similar in human and rat axons, but the forward propagation of excitatory postsynaptic potentials (EPSPs) and the backward propagation of APs are 26 and 47% faster in human dendrites, respectively. Experimentally-based detailed biophysical models have shown that the key factor responsible for the accelerated EPSP propagation in human cortical dendrites is the large conductance load imposed at the soma by the large basal dendritic tree. Additionally, larger dendritic diameters and differences in cable and ion channel properties in humans contribute to enhanced signal propagation. Our integrative experimental and modeling study provides new insights into the scaling rules that help maintain information processing speed albeit the large and sparse neurons in the human cortex.