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).

Reviewing Editor

  1. Indira M Raman, Northwestern University, United States

Version history

  1. Received: April 2, 2015
  2. Accepted: October 2, 2015
  3. Accepted Manuscript published: October 3, 2015 (version 1)
  4. Version of Record published: November 10, 2015 (version 2)

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

  • 9,527
    Page views
  • 1,409
    Downloads
  • 101
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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

Further reading

    1. Neuroscience
    Christian Brodbeck, Proloy Das ... Jonathan Z Simon
    Tools and Resources

    Even though human experience unfolds continuously in time, it is not strictly linear; instead, it entails cascading processes building hierarchical cognitive structures. For instance, during speech perception, humans transform a continuously varying acoustic signal into phonemes, words, and meaning, and these levels all have distinct but interdependent temporal structures. Time-lagged regression using temporal response functions (TRFs) has recently emerged as a promising tool for disentangling electrophysiological brain responses related to such complex models of perception. Here we introduce the Eelbrain Python toolkit, which makes this kind of analysis easy and accessible. We demonstrate its use, using continuous speech as a sample paradigm, with a freely available EEG dataset of audiobook listening. A companion GitHub repository provides the complete source code for the analysis, from raw data to group level statistics. More generally, we advocate a hypothesis-driven approach in which the experimenter specifies a hierarchy of time-continuous representations that are hypothesized to have contributed to brain responses, and uses those as predictor variables for the electrophysiological signal. This is analogous to a multiple regression problem, but with the addition of a time dimension. TRF analysis decomposes the brain signal into distinct responses associated with the different predictor variables by estimating a multivariate TRF (mTRF), quantifying the influence of each predictor on brain responses as a function of time(-lags). This allows asking two questions about the predictor variables: 1) Is there a significant neural representation corresponding to this predictor variable? And if so, 2) what are the temporal characteristics of the neural response associated with it? Thus, different predictor variables can be systematically combined and evaluated to jointly model neural processing at multiple hierarchical levels. We discuss applications of this approach, including the potential for linking algorithmic/representational theories at different cognitive levels to brain responses through computational models with appropriate linking hypotheses.

    1. Neuroscience
    Louise Schenberg, Aïda Palou ... Mathieu Beraneck
    Research Article

    The functional complementarity of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) allows for optimal combined gaze stabilization responses (CGR) in light. While sensory substitution has been reported following complete vestibular loss, the capacity of the central vestibular system to compensate for partial peripheral vestibular loss remains to be determined. Here, we first demonstrate the efficacy of a 6-week subchronic ototoxic protocol in inducing transient and partial vestibular loss which equally affects the canal- and otolith-dependent VORs. Immunostaining of hair cells in the vestibular sensory epithelia revealed that organ-specific alteration of type I, but not type II, hair cells correlates with functional impairments. The decrease in VOR performance is paralleled with an increase in the gain of the OKR occurring in a specific range of frequencies where VOR normally dominates gaze stabilization, compatible with a sensory substitution process. Comparison of unimodal OKR or VOR versus bimodal CGR revealed that visuo-vestibular interactions remain reduced despite a significant recovery in the VOR. Modeling and sweep-based analysis revealed that the differential capacity to optimally combine OKR and VOR correlates with the reproducibility of the VOR responses. Overall, these results shed light on the multisensory reweighting occurring in pathologies with fluctuating peripheral vestibular malfunction.