Phenotypic Characterization of Speed-Associated Gait Changes in Mice Reveals Modular Organization of Locomotor Networks

Studies of locomotion in mice suggest that circuits controlling the alternating between left and right limbs may have a modular organization with distinct locomotor circuits being recruited at different speeds. It is not clear, however, whether such a modular organization reflects specific behavioral outcomes expressed at different speeds of locomotion. Here, we use detailed kinematic analyses to search for signatures of a modular organization of locomotor circuits in intact and genetically modified mice moving at different speeds of locomotion. We show that wild-type mice display three distinct gaits: two alternating, walk and trot, and one synchronous, bound. Each gait is expressed in distinct ranges of speed with phenotypic inter-limb and intra-limb coordination. A fourth gait, gallop, closely resembled bound in most of the locomotor parameters but expressed diverse inter-limb coordination. Genetic ablation of commissural V0V neurons completely removed the expression of one alternating gait, trot, but left intact walk, gallop, and bound. Ablation of commissural V0V and V0D neurons led to a loss of walk, trot, and gallop, leaving bound as the default gait. Our study provides a benchmark for studies of the neuronal control of locomotion in the full range of speeds. It provides evidence that gait expression depends upon selection of different modules of neuronal ensembles.

[1]  Richard J. Batka,et al.  The Need for Speed in Rodent Locomotion Analyses , 2014, Anatomical record.

[2]  Ronald M. Harris-Warrick,et al.  Frequency-dependent recruitment of V2a interneurons during fictive locomotion in the mouse spinal cord , 2011, Nature communications.

[3]  Ole Kiehn,et al.  Functional organization of V2a‐related locomotor circuits in the rodent spinal cord , 2010, Annals of the New York Academy of Sciences.

[4]  E1‐Ngn2/Cre is a new line for regional activation of Cre recombinase in the developing CNS , 2004, Genesis.

[5]  O. Kiehn,et al.  Transmitter‐phenotypes of commissural interneurons in the lumbar spinal cord of newborn mice , 2009, The Journal of comparative neurology.

[6]  J. Fetcho,et al.  Spinal Interneurons Differentiate Sequentially from Those Driving the Fastest Swimming Movements in Larval Zebrafish to Those Driving the Slowest Ones , 2009, The Journal of Neuroscience.

[7]  O. Kiehn,et al.  Glutamatergic Mechanisms for Speed Control and Network Operation in the Rodent Locomotor CPG , 2010, Front. Neural Circuits.

[8]  E. Lein,et al.  Functional organization of the hippocampal longitudinal axis , 2014, Nature Reviews Neuroscience.

[9]  Current Biology , 2012, Current Biology.

[10]  K. A. Clarke,et al.  Gait Analysis in the Mouse , 1999, Physiology & Behavior.

[11]  K. Kullander,et al.  Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice , 2012, Nature.

[12]  Ole Kiehn,et al.  Segmental, Synaptic Actions of Commissural Interneurons in the Mouse Spinal Cord , 2007, The Journal of Neuroscience.

[13]  Sébastien Vigneau,et al.  Multiple origins of Cajal-Retzius cells at the borders of the developing pallium , 2005, Nature Neuroscience.

[14]  Turgay Akay,et al.  V3 Spinal Neurons Establish a Robust and Balanced Locomotor Rhythm during Walking , 2008, Neuron.

[15]  R. Harris-Warrick,et al.  Electrophysiological Characterization of V2a Interneurons and Their Locomotor-Related Activity in the Neonatal Mouse Spinal Cord , 2010, The Journal of Neuroscience.

[16]  Demetris K. Roumis,et al.  Functional Specialization of Mouse Higher Visual Cortical Areas , 2011, Neuron.

[17]  Marc Jamon,et al.  The adaptation of limb kinematics to increasing walking speeds in freely moving mice 129/Sv and C57BL/6 , 2009, Behavioural Brain Research.

[18]  O. Kiehn Locomotor circuits in the mammalian spinal cord. , 2006, Annual review of neuroscience.

[19]  W. B. Lindquist,et al.  Continuous shifts in the active set of spinal interneurons during changes in locomotor speed , 2008, Nature Neuroscience.

[20]  O Kiehn,et al.  Distribution of Networks Generating and Coordinating Locomotor Activity in the Neonatal Rat Spinal Cord In Vitro: A Lesion Study , 1996, The Journal of Neuroscience.

[21]  Patrick J. Whelan,et al.  Shining light into the black box of spinal locomotor networks , 2010, Philosophical Transactions of the Royal Society B: Biological Sciences.

[22]  Ole Kiehn,et al.  Change in the balance of excitatory and inhibitory midline fiber crossing as an explanation for the hopping phenotype in EphA4 knockout mice , 2011, The European journal of neuroscience.

[23]  R. Harris-Warrick,et al.  In Mice Lacking V2a Interneurons, Gait Depends on Speed of Locomotion , 2009, The Journal of Neuroscience.

[24]  Rémi Hackert,et al.  Gait parameters of treadmill versus overground locomotion in mouse , 2007, Behavioural Brain Research.

[25]  Jessica Ausborn,et al.  Separate Microcircuit Modules of Distinct V2a Interneurons and Motoneurons Control the Speed of Locomotion , 2014, Neuron.

[26]  Turgay Akay,et al.  Behavioral and electromyographic characterization of mice lacking EphA4 receptors. , 2006, Journal of neurophysiology.

[27]  Ole Kiehn,et al.  A transgenic mouse line for molecular genetic analysis of excitatory glutamatergic neurons , 2010, Molecular and Cellular Neuroscience.

[28]  T. Jessell,et al.  Genetic Identification of Spinal Interneurons that Coordinate Left-Right Locomotor Activity Necessary for Walking Movements , 2004, Neuron.

[29]  N. Heglund,et al.  Speed, stride frequency and energy cost per stride: how do they change with body size and gait? , 1988, The Journal of experimental biology.

[30]  S. Itohara,et al.  Spinal Glutamatergic Neurons Defined by EphA4 Signaling Are Essential Components of Normal Locomotor Circuits , 2014, The Journal of Neuroscience.

[31]  Toshiaki Endo,et al.  Genetic Ablation of V2a Ipsilateral Interneurons Disrupts Left-Right Locomotor Coordination in Mammalian Spinal Cord , 2008, Neuron.

[32]  Serge Rossignol,et al.  Treadmill Locomotion in the Intact and Spinal Mouse , 2003, The Journal of Neuroscience.

[33]  T. Jessell,et al.  Control of Interneuron Fate in the Developing Spinal Cord by the Progenitor Homeodomain Protein Dbx1 , 2001, Neuron.

[34]  M. Goulding Circuits controlling vertebrate locomotion: moving in a new direction , 2009, Nature Reviews Neuroscience.

[35]  M Hildebrand,et al.  Symmetrical gaits of horses. , 1965, Science.

[36]  S. Grillner,et al.  Measured motion: searching for simplicity in spinal locomotor networks , 2009, Current Opinion in Neurobiology.

[37]  Ole Kiehn,et al.  Organization of left–right coordination in the mammalian locomotor network , 2002, Brain Research Reviews.

[38]  O Kiehn,et al.  Crossed Rhythmic Synaptic Input to Motoneurons during Selective Activation of the Contralateral Spinal Locomotor Network , 1997, The Journal of Neuroscience.

[39]  Georg B. Keller,et al.  Sensorimotor Mismatch Signals in Primary Visual Cortex of the Behaving Mouse , 2012, Neuron.

[40]  Ole Kiehn,et al.  Role of EphA4 and EphrinB3 in Local Neuronal Circuits That Control Walking , 2003, Science.

[41]  O. Kiehn,et al.  Dual-mode operation of neuronal networks involved in left–right alternation , 2013, Nature.

[42]  O. Kiehn Development and functional organization of spinal locomotor circuits , 2011, Current Opinion in Neurobiology.

[43]  Ole Kiehn,et al.  Locomotor Rhythm Generation Linked to the Output of Spinal Shox2 Excitatory Interneurons , 2013, Neuron.

[44]  Sabine Renous,et al.  Symmetrical and asymmetrical gaits in the mouse: patterns to increase velocity , 2004, Journal of Comparative Physiology A.