Decoding the organization of spinal circuits that control locomotion

Key Points

  • Locomotion is a complex motor act that, to a large degree, is controlled by neuronal circuits in the spinal cord. Using a systems neuroscience approach in several model systems of non-limbed and limbed animals, important advances have been made in revealing the functional organization of the spinal locomotor networks.

  • The key circuit elements in the spinal locomotor networks are the rhythm-generating circuits and the pattern-generating circuits, which include circuits that control bilateral muscle activity, and circuits that control flexor–extensor muscles in limbed animals.

  • Comparison of the network organization of the key circuit elements in limbed and non-limbed animals reveals both commonalities and differences in organization.

  • The commonalities extend to the basic components of inhibitory left–right alternating circuits and excitatory neurons involved in rhythm generation.

  • The differences include left–right alternating circuitries that have multiple components in legged animals compared with the control of axial muscles in fish where one component dominates, rhythm-generating neurons that originate from developmentally diverse progenitors in fish and mice, and elaborated reciprocal network circuits involved in the flexor–extensor coordination that is found in legged animals, which do not have direct counterparts in non-legged animals.

  • Locomotor networks, whether they control swimming or over-ground locomotion, are built around modules of rhythm- and pattern-generating modules.

  • Functional network reorganization occurs with changes in the speed of locomotion or changes in gait. This reconfiguration takes places both at the level of rhythm generation and at the level of pattern generation.

  • The exact mechanisms of rhythm generation are not generally understood across phyla but seem to depend on an interplay between active membrane properties and network properties.

  • Proprioception suggests an important role for phase switching during locomotion.

  • The combination of electrophysiological and molecular genetic approaches has revealed details of the organization of large-scale spinal networks in limbed animals in considerably different ways than previous research has suggested and has allowed for comparison with network organization in leg-less animals with more limited numbers of cells in the spinal cord. Although these fundamental motor networks have begun to be decoded, there are still unresolved issues regarding their functional organization.

Abstract

Unravelling the functional operation of neuronal networks and linking cellular activity to specific behavioural outcomes are among the biggest challenges in neuroscience. In this broad field of research, substantial progress has been made in studies of the spinal networks that control locomotion. Through united efforts using electrophysiological and molecular genetic network approaches and behavioural studies in phylogenetically diverse experimental models, the organization of locomotor networks has begun to be decoded. The emergent themes from this research are that the locomotor networks have a modular organization with distinct transmitter and molecular codes and that their organization is reconfigured with changes to the speed of locomotion or changes in gait.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Organization of neuronal control of locomotion in vertebrates.
Figure 2: Multiple left–right coordination circuits.
Figure 3: Organizational and molecular delineation of rhythm-generating circuits.
Figure 4: Multiple levels of flexor–extensor antagonism.
Figure 5: Proprioceptive input directs stance and swing phase transitions.

References

  1. 1

    Drew, T. & Marigold, D. S. Taking the next step: cortical contributions to the control of locomotion. Curr. Opin. Neurobiol. 33, 25–33 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Takakusaki, K. Neurophysiology of gait: from the spinal cord to the frontal lobe. Mov. Disord. 28, 1483–1491 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Garcia-Rill, E. The basal ganglia and the locomotor regions. Brain Res. 396, 47–63 (1986).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Grillner, S. & Robertson, B. The basal ganglia downstream control of brainstem motor centres — an evolutionarily conserved strategy. Curr. Opin. Neurobiol. 33, 47–52 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Garcia-Rill, E., Hyde, J., Kezunovic, N., Urbano, F. J. & Petersen, E. The physiology of the pedunculopontine nucleus: implications for deep brain stimulation. J. Neural Transmission 122, 225–235 (2015).

    CAS  Article  Google Scholar 

  6. 6

    Ryczko, D. & Dubuc, R. The multifunctional mesencephalic locomotor region. Curr. Pharm. Design 19, 4448–4470 (2013).

    CAS  Article  Google Scholar 

  7. 7

    Dubuc, R. et al. Initiation of locomotion in lampreys. Brain Res. Rev. 57, 172–182 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Orlovsky, G. N., Deliagina, T. G. & Grillner, S. Neuronal Control of Locomotion. From Mollusc to Man (Oxford Univ. Press, 1998).

    Google Scholar 

  9. 9

    Jordan, L. M., Liu, J., Hedlund, P. B., Akay, T. & Pearson, K. G. Descending command systems for the initiation of locomotion in mammals. Brain Res. Rev. 57, 183–191 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Kiehn, O. Locomotor circuits in the mammalian spinal cord. Annu. Rev. Neurosci. 29, 279–306 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Grillner, S. The motor infrastructure: from ion channels to neuronal networks. Nat. Rev. Neurosci. 4, 573–586 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Brown, T. The intrinsic factors in the act of progression in mammals. Proc. R. Soc. Lond. B 84, 308–319 (1911).

    Article  Google Scholar 

  13. 13

    Grillner, S. in Hanbook of Physiology (ed. Brooks, V.) 1179–1236 (American Physiological Society, 1981).

    Google Scholar 

  14. 14

    Harris-Warrick, R. M. Neuromodulation and flexibility in Central Pattern Generator networks. Curr. Opin. Neurobiol. 21, 685–692 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Sillar, K. T., Combes, D. & Simmers, J. Neuromodulation in developing motor microcircuits. Curr. Opin. Neurobiol. 29, 73–81 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Sharples, S. A., Koblinger, K., Humphreys, J. M. & Whelan, P. J. Dopamine: a parallel pathway for the modulation of spinal locomotor networks. Front. Neural Circuits 8, 55 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Pearson, K. G. Generating the walking gait: role of sensory feedback. Prog. Brain Res. 143, 123–129 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Rossignol, S., Dubuc, R. & Gossard, J. P. Dynamic sensorimotor interactions in locomotion. Physiol. Rev. 86, 89–154 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Stuart, D. G. & Hultborn, H. Thomas Graham Brown (1882–1965), Anders Lundberg (1920–), and the neural control of stepping. Brain Res. Rev. 59, 74–95 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Grillner, S. & Jessell, T. M. Measured motion: searching for simplicity in spinal locomotor networks. Curr. Opin. Neurobiol. 19, 572–586 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Grillner, S. Biological pattern generation: the cellular and computational logic of networks in motion. Neuron 52, 751–766 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Sillar, K. T., Combes, D., Ramanathan, S., Molinari, M. & Simmers, J. Neuromodulation and developmental plasticity in the locomotor system of anuran amphibians during metamorphosis. Brain Res. Rev. 57, 94–102 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Buchanan, J. T. Contributions of identifiable neurons and neuron classes to lamprey vertebrate neurobiology. Prog. Neurobiol. 63, 441–466 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Roberts, A., Li, W. C., Soffe, S. R. & Wolf, E. Origin of excitatory drive to a spinal locomotor network. Brain Res. Rev. 57, 22–28 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    El Manira, A. Dynamics and plasticity of spinal locomotor circuits. Curr. Opin. Neurobiol. 29, 133–141 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Roberts, A., Li, W. C. & Soffe, S. R. How neurons generate behavior in a hatchling amphibian tadpole: an outline. Front. Behav. Neurosci. 4, 16 (2010).

    PubMed  PubMed Central  Google Scholar 

  27. 27

    Kiehn, O. Development and functional organization of spinal locomotor circuits. Curr. Opin. Neurobiol. 21, 100–109 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Jankowska, E. Spinal interneuronal networks in the cat: elementary components. Brain Res. Rev. 57, 46–55 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Goulding, M. Circuits controlling vertebrate locomotion: moving in a new direction. Nat. Rev. Neurosci. 10, 507–518 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    McLean, D. L. & Dougherty, K. J. Peeling back the layers of locomotor control in the spinal cord. Curr. Opin. Neurobiol. 33, 63–70 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Stein, P. S. Molecular, genetic, cellular, and network functions in the spinal cord and brainstem. Ann. NY Acad. Sci. 1279, 1–12 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Gordon, I. T. & Whelan, P. J. Deciphering the organization and modulation of spinal locomotor central pattern generators. J. Exp. Biol. 209, 2007–2014 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    O'Donovan, M. J. et al. Mechanisms of excitation of spinal networks by stimulation of the ventral roots. Ann. NY Acad. Sci. 1198, 63–71 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Alvarez, F. J., Benito-Gonzalez, A. & Siembab, V. C. Principles of interneuron development learned from Renshaw cells and the motoneuron recurrent inhibitory circuit. Ann. NY Acad. Sci. 1279, 22–31 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Brownstone, R. M. & Wilson, J. M. Strategies for delineating spinal locomotor rhythm-generating networks and the possible role of Hb9 interneurones in rhythmogenesis. Brain Res. Rev. 57, 64–76 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Nishimaru, H. & Kakizaki, M. The role of inhibitory neurotransmission in locomotor circuits of the developing mammalian spinal cord. Acta Physiol. (Oxf.) 197, 83–97 (2009).

    CAS  Article  Google Scholar 

  37. 37

    Stepien, A. E. & Arber, S. Probing the locomotor conundrum: descending the 'V' interneuron ladder. Neuron 60, 1–4 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Fetcho, J. R. The utility of zebrafish for studies of the comparative biology of motor systems. J. Exp. Zool. B Mol. Dev. Evol. 308, 550–562 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Nissen, U. V., Mochida, H. & Glover, J. C. Development of projection-specific interneurons and projection neurons in the embryonic mouse and rat spinal cord. J. Comp. Neurol. 483, 30–47 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Matsuyama, K., Kobayashi, S. & Aoki, M. Projection patterns of lamina VIII commissural neurons in the lumbar spinal cord of the adult cat: an anterograde neural tracing study. Neuroscience 140, 203–218 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Stokke, M. F., Nissen, U. V., Glover, J. C. & Kiehn, O. Projection patterns of commissural interneurons in the lumbar spinal cord of the neonatal rat. J. Comp. Neurol. 446, 349–359 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Bannatyne, B. A., Edgley, S. A., Hammar, I., Jankowska, E. & Maxwell, D. J. Networks of inhibitory and excitatory commissural interneurons mediating crossed reticulospinal actions. Eur. J. Neurosci. 18, 2273–2284 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Weber, I., Veress, G., Szucs, P., Antal, M. & Birinyi, A. Neurotransmitter systems of commissural interneurons in the lumbar spinal cord of neonatal rats. Brain Res. 1178, 65–72 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Restrepo, C. E. et al. Transmitter-phenotypes of commissural interneurons in the lumbar spinal cord of newborn mice. J. Comp. Neurol. 517, 177–192 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Jankowska, E., Krutki, P. & Matsuyama, K. Relative contribution of Ia inhibitory interneurones to inhibition of feline contralateral motoneurones evoked via commissural interneurones. J. Physiol. 568, 617–628 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Butt, S. J. & Kiehn, O. Functional identification of interneurons responsible for left-right coordination of hindlimbs in mammals. Neuron 38, 953–963 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Quinlan, K. A. & Kiehn, O. Segmental, synaptic actions of commissural interneurons in the mouse spinal cord. J. Neurosci. 27, 6521–6530 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Pierani, A. et al. Control of interneuron fate in the developing spinal cord by the progenitor homeodomain protein Dbx1. Neuron 29, 367–384 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Lanuza, G. M., Gosgnach, S., Pierani, A., Jessell, T. M. & Goulding, M. Genetic identification of spinal interneurons that coordinate left-right locomotor activity necessary for walking movements. Neuron 42, 375–386 (2004). The first study to genetically manipulate a transcription-defined population of spinal neurons in the mouse spinal cord.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Talpalar, A. E. et al. Dual-mode operation of neuronal networks involved in left–right alternation. Nature 500, 85–88 (2013). Using mouse genetics in a behavioural context, this study shows that two separate neuronal populations — which are characterized by the expression of specific molecular markers — control alternating gait. These separate circuits are necessary for alternation at slow and fast speeds of locomotion.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Bellardita, C. & Kiehn, O. Phenotypic characterization of speed-aasociated gait changes in mice reveals modular organization of locomotor networks. Curr. Biol. 25, 1426–1436 (2015). A comprehensive characterization of speed-associated gait changes in mice and the loss of specific gaits after genetic ablation of commissural neurons.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Serradj, N. & Jamon, M. The adaptation of limb kinematics to increasing walking speeds in freely moving mice 129/Sv and C57BL/6. Behav. Brain Res. 201, 59–65 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Shevtsova, N. A. et al. Organization of left–right coordination of neuronal activity in the mammalian spinal cord: insights from computational modelling. J. Physiol. 593, 2403–2426 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Zhang, Y. et al. V3 spinal neurons establish a robust and balanced locomotor rhythm during walking. Neuron 60, 84–96 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Borowska, J. et al. Functional subpopulations of V3 interneurons in the mature mouse spinal cord. J. Neurosci. 33, 18553–18565 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Vallstedt, A. & Kullander, K. Dorsally derived spinal interneurons in locomotor circuits. Ann. NY Acad. Sci. 1279, 32–42 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Andersson, L. S. et al. Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice. Nature 488, 642–646 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Roberts, A., Li, W. C. & Soffe, S. R. Roles for inhibition: studies on networks controlling swimming in young frog tadpoles. J. Comp. Physiol. A Neuroethol. Sens. Neural. Behav. Physiol. 194, 185–193 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Li, W. C., Soffe, S. R. & Roberts, A. The spinal interneurons and properties of glutamatergic synapses in a primitive vertebrate cutaneous flexion reflex. J. Neurosci. 23, 9068–9077 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Li, W. C., Sautois, B., Roberts, A. & Soffe, S. R. Reconfiguration of a vertebrate motor network: specific neuron recruitment and context-dependent synaptic plasticity. J. Neurosci. 27, 12267–12276 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Mahmood, R., Restrepo, C. E. & El Manira, A. Transmitter phenotypes of commissural interneurons in the lamprey spinal cord. Neuroscience 164, 1057–1067 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Satou, C., Kimura, Y. & Higashijima, S. Generation of multiple classes of V0 neurons in zebrafish spinal cord: progenitor heterogeneity and temporal control of neuronal diversity. J. Neurosci. 32, 1771–1783 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    McLean, D. L., Masino, M. A., Koh, I. Y., Lindquist, W. B. & Fetcho, J. R. Continuous shifts in the active set of spinal interneurons during changes in locomotor speed. Nat. Neurosci. 11, 1419–1429 (2008). This study shows speed-related neuronal switching.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    McLean, D. L., Fan, J., Higashijima, S., Hale, M. E. & Fetcho, J. R. A topographic map of recruitment in spinal cord. Nature 446, 71–75 (2007). This study demonstrated speed-related recruitment pattern of spinal interneurons and the specific role of ventral excitatory neurons in controlling slow swimming.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Goetz, C., Pivetta, C. & Arber, S. Distinct limb and trunk premotor circuits establish laterality in the spinal cord. Neuron 85, 131–144 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Buchanan, J. T. & Grillner, S. Newly identified 'glutamate interneurons' and their role in locomotion in the lamprey spinal cord. Science 236, 312–314 (1987). The first demonstration of excitatory locomotor-related neurons in the lamprey spinal cord.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Li, W. C., Roberts, A. & Soffe, S. R. Locomotor rhythm maintenance: electrical coupling among premotor excitatory interneurons in the brainstem and spinal cord of young Xenopus tadpoles. J. Physiol. 587, 1677–1693 (2009). This study demonstrated the presence and connectivity of a network of excitatory neurons in the brainstem and spinal cord underlying rhythm generation in young tadpoles.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Li, W. C., Soffe, S. R., Wolf, E. & Roberts, A. Persistent responses to brief stimuli: feedback excitation among brainstem neurons. J. Neurosci. 26, 4026–4035 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Dale, N. & Roberts, A. Dual-component amino-acid-mediated synaptic potentials: excitatory drive for swimming in Xenopus embryos. J. Physiol. 363, 35–59 (1985). Electrophysiological demonstration of excitatory last-order neurons in the young tadpole spinal cord.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Parker, D. & Grillner, S. The activity-dependent plasticity of segmental and intersegmental synaptic connections in the lamprey spinal cord. Eur. J. Neurosci. 12, 2135–2146 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Moult, P. R., Cottrell, G. A. & Li, W. C. Fast silencing reveals a lost role for reciprocal inhibition in locomotion. Neuron 77, 129–140 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Shalem, O., Sanjana, N. E. & Zhang, F. High-throughput functional genomics using CRISPR–Cas9. Nat. Rev. Genet. 16, 299–311 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Hagglund, M., Borgius, L., Dougherty, K. J. & Kiehn, O. Activation of groups of excitatory neurons in the mammalian spinal cord or hindbrain evokes locomotion. Nat. Neurosci. 13, 246–252 (2010). By using optogenetics, this was the first direct demonstration that activation of glutamatergic neurons in the mammalian spinal cord can evoke locomotor-like activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Hagglund, M. et al. Optogenetic dissection reveals multiple rhythmogenic modules underlying locomotion. Proc. Natl Acad. Sci. USA 110, 11589–11594 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Cazalets, J. R. & Bertrand, S. Ubiquity of motor networks in the spinal cord of vertebrates. Brain Res. Bull. 53, 627–634 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Cazalets, J. R., Borde, M. & Clarac, F. Localization and organization of the central pattern generator for hindlimb locomotion in newborn rat. J. Neurosci. 15, 4943–4951 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Zhong, G., Shevtsova, N., Rybak, I. & Harris-Warrick, R. Neuronal activity in the isolated mouse spinal cord during spontaneous deletions in fictive locomotion: insights into locomotor CPG organization. J. Physiol. 590, 4735–4759 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Kiehn, O. & Kjaerulff, O. Spatiotemporal characteristics of 5-HT and dopamine-induced rhythmic hindlimb activity in the in vitro neonatal rat. J. Neurophysiol. 75, 1472–1482 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Grillner, S. & Zangger, P. The effect of dorsal root transection on the efferent motor pattern in the cat's hindlimb during locomotion. Acta Physiol. Scand. 120, 393–405 (1984).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Machado, T. A., Pnevmatikakis, E., Paninski, L., Jessell, T. M. & Miri, A. Primacy of flexor locomotor pattern revealed by ancestral reversion of motor neuron identity. Cell 162, 338–350 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Dominici, N. et al. Locomotor primitives in newborn babies and their development. Science 334, 997–999 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Hinckley, C. A. et al. Spinal locomotor circuits develop using hierarchical rules based on motorneuron position and identity. Neuron 87, 1008–1021 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Crone, S. A. et al. Genetic ablation of V2a ipsilateral interneurons disrupts left-right locomotor coordination in mammalian spinal cord. Neuron 60, 70–83 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat. Rev. Genet. 1, 20–29 (2000). Comprehensive review that outline the early molecular code for spinal neurons.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Al-Mosawie, A., Wilson, J. M. & Brownstone, R. M. Heterogeneity of V2-derived interneurons in the adult mouse spinal cord. Eur. J. Neurosci. 26, 3003–3015 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Lundfald, L. et al. Phenotype of V2-derived interneurons and their relationship to the axon guidance molecule EphA4 in the developing mouse spinal cord. Eur. J. Neurosci. 26, 2989–3002 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Crone, S. A., Zhong, G., Harris-Warrick, R. & Sharma, K. In mice lacking V2a interneurons, gait depends on speed of locomotion. J. Neurosci. 29, 7098–7109 (2009). This study along with reference 83 show that the lack of excitatory V2a neurons in mice leads to changes in the left–right coordination without affecting the rhythm generation. V2a neurons regulate left–right alteration in a speed-dependent manner.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Stepien, A. E., Tripodi, M. & Arber, S. Monosynaptic rabies virus reveals premotor network organization and synaptic specificity of cholinergic partition cells. Neuron 68, 456–472 (2010). Study that describes the use of the monosynaptically restricted trans-synaptic labelling technique to reveal premotor networks in the spinal cord.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Dougherty, K. J. & Kiehn, O. Firing and cellular properties of V2a interneurons in the rodent spinal cord. J. Neurosci. 30, 24–37 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Zhong, G. et al. Electrophysiological characterization of V2a interneurons and their locomotor-related activity in the neonatal mouse spinal cord. J. Neurosci. 30, 170–182 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Zhong, G., Sharma, K. & Harris-Warrick, R. M. Frequency-dependent recruitment of V2a interneurons during fictive locomotion in the mouse spinal cord. Nat. Commun. 2, 274 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Dougherty, K. J. et al. Locomotor rhythm generation linked to the output of spinal Shox2 excitatory interneurons. Neuron 80, 920–933 (2013). Through the use of various genetic techniques to identify, chronically silence and optogenetically control populations of glutamatergic interneurons, this study identified glutamatergic SHOX2+ neurons as constituent members of the locomotor rhythm generator in mammals.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93

    Wilson, J. M. et al. Conditional rhythmicity of ventral spinal interneurons defined by expression of the Hb9 homeodomain protein. J. Neurosci. 25, 5710–5719 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Hinckley, C. A., Hartley, R., Wu, L., Todd, A. & Ziskind-Conhaim, L. Locomotor-like rhythms in a genetically distinct cluster of interneurons in the mammalian spinal cord. J. Neurophysiol. 93, 1439–1449 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Ziskind-Conhaim, L. & Hinckley, C. A. Hb9 versus type 2 interneurons. J. Neurophysiol. 99, 1044–1046 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Brocard, F., Tazerart, S. & Vinay, L. Do pacemakers drive the central pattern generator for locomotion in mammals? Neuroscientist 16, 139–155 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Bui, T. V. et al. Circuits for grasping: spinal dI3 interneurons mediate cutaneous control of motor behavior. Neuron 78, 191–204 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Kimura, Y. Okamura, Y. & Higashijima, S. alx, a zebrafish homolog of Chx10, marks ipsilateral descending excitatory interneurons that participate in the regulation of spinal locomotor circuits. J. Neurosci. 26, 5684–5697 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Eklof-Ljunggren, E. et al. Origin of excitation underlying locomotion in the spinal circuit of zebrafish. Proc. Natl Acad. Sci. USA 109, 5511–5516 (2012). Using laser ablation of neurons in the larval zebrafish, this study show that the V2a neurons in zebrafish larvae are involved in producing swimming.

    Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Ljunggren, E. E., Haupt, S., Ausborn, J., Ampatzis, K. & El Manira, A. Optogenetic activation of excitatory premotor interneurons is sufficient to generate coordinated locomotor activity in larval zebrafish. J. Neurosci. 34, 134–139 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Bagnall, M. W. & McLean, D. L. Modular organization of axial microcircuits in zebrafish. Science 343, 197–200 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Ampatzis, K., Song, J., Ausborn, J. & El Manira, A. Separate microcircuit modules of distinct v2a interneurons and motoneurons control the speed of locomotion. Neuron 83, 934–943 (2014). This study shows that separate excitatory neurons that are directly presynaptic to motor neurons are recruited in a speed-dependent manner, which matches motor neuron recruitment.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Ampatzis, K., Song, J., Ausborn, J. & El Manira, A. Pattern of innervation and recruitment of different classes of motoneurons in adult zebrafish. J. Neurosci. 33, 10875–10886 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Marder, E. & Bucher, D. Central pattern generators and the control of rhythmic movements. Curr. Biol. 11, R986–R996 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Feldman, J. L. & Del Negro, C. A. & Gray, P. A. Understanding the rhythm of breathing, so near, yet so far. Annu. Rev. Physiol. 75, 423–452 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Kiehn, O., Johnson, B. R. & Raastad, M. Plateau properties in mammalian spinal interneurons during transmitter-induced locomotor activity. Neuroscience 75, 263–273 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Hochman, S. & McCrea, D. A. Effects of chronic spinalization on ankle extensor motoneurons. III. Composite Ia EPSPs in motoneurons separated into motor unit types. J. Neurophysiol. 71, 1480–1490 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Reith, C. A. & Sillar, K. T. A role for slow NMDA receptor-mediated, intrinsic neuronal oscillations in the control of fast fictive swimming in Xenopus laevis larvae. Eur. J. Neurosci. 10, 1329–1340 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Wallen, P. & Grillner, S. N-methyl-D-aspartate receptor-induced, inherent oscillatory activity in neurons active during fictive locomotion in the lamprey. J. Neurosci. 7, 2745–2755 (1987).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Li, W. C., Roberts, A. & Soffe, S. R. Specific brainstem neurons switch each other into pacemaker mode to drive movement by activating NMDA receptors. J. Neurosci. 30, 16609–16620 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Cowley, K. C., Zaporozhets, E., Maclean, J. N. & Schmidt, B. J. Is NMDA receptor activation essential for the production of locomotor-like activity in the neonatal rat spinal cord? J. Neurophysiol. 94, 3805–3814 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Beato, M., Bracci, E. & Nistri, A. Contribution of NMDA and non-NMDA glutamate receptors to locomotor pattern generation in the neonatal rat spinal cord. Proc. Biol. Sci. 264, 877–884 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Dai, Y., Jordan, L. M. & Fedirchuk, B. Modulation of transient and persistent inward currents by activation of protein kinase C in spinal ventral neurons of the neonatal rat. J. Neurophysiol. 101, 112–128 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Tazerart, S., Viemari, J. C., Darbon, P., Vinay, L. & Brocard, F. Contribution of persistent sodium current to locomotor pattern generation in neonatal rats. J. Neurophysiol. 98, 613–628 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Zhong, G., Masino, M. A. & Harris-Warrick, R. M. Persistent sodium currents participate in fictive locomotion generation in neonatal mouse spinal cord. J. Neurosci. 27, 4507–4518 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Ziskind-Conhaim, L., Wu, L. & Wiesner, E. P. Persistent sodium current contributes to induced voltage oscillations in locomotor-related hb9 interneurons in the mouse spinal cord. J. Neurophysiol. 100, 2254–2264 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Brocard, F. et al. Activity-dependent changes in extracellular Ca2+ and K+ reveal pacemakers in the spinal locomotor-related network. Neuron 77, 1047–1054 (2013). Locomotor-like activity in the isolated neonatal rodent spinal cord reduces the level of extracellular calcium and increases the extracellular potassium concentration as a consequence of neuronal activity. The study shows that these changes trigger persistent sodium-dependent pacemaker activities in interneurons located in the region of the locomotor network and suggest that such properties are dynamically modulated during locomotion.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Richter, D. W. & Smith, J. C. Respiratory rhythm generation in vivo. Physiology 29, 58–71 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Endo, T. & Kiehn, O. Asymmetric operation of the locomotor central pattern generator in the neonatal mouse spinal cord. J. Neurophysiol. 100, 3043–3054 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Hochman, S. & Schmidt, B. J. Whole cell recordings of lumbar motoneurons during locomotor-like activity in the in vitro neonatal rat spinal cord. J. Neurophysiol. 79, 743–752 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Hultborn, H. Transmission in the pathway of reciprocal Ia inhibition to motoneurones and its control during the tonic stretch reflex. Prog. Brain Res. 44, 235–255 (1976).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Wang, Z., Li, L., Goulding, M. & Frank, E. Early postnatal development of reciprocal Ia inhibition in the murine spinal cord. J. Neurophysiol. 100, 185–196 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Talpalar, A. E. et al. Identification of minimal neuronal networks involved in flexor-extensor alternation in the mammalian spinal cord. Neuron 71, 1071–1084 (2011). This study identified a minimal network composed of inhibitory reciprocally connected Ia interneurons as responsible for out-of-phase activation of antagonistic muscles across a joint.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Geertsen, S. S., Stecina, K., Meehan, C. F., Nielsen, J. B. & Hultborn, H. Reciprocal Ia inhibition contributes to motoneuronal hyperpolarisation during the inactive phase of locomotion and scratching in the cat. J. Physiol. 589, 119–134 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Pratt, C. A. & Jordan, L. M. Ia inhibitory interneurons and Renshaw cells as contributors to the spinal mechanisms of fictive locomotion. J. Neurophysiol. 57, 56–71 (1987).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Deliagina, T. G. & Orlovsky, G. N. Activity of Ia inhibitory interneurons during fictitious scratch reflex in the cat. Brain Res. 193, 439–447 (1980).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Wilson, J. M., Blagovechtchenski, E. & Brownstone, R. M. Genetically defined inhibitory neurons in the mouse spinal cord dorsal horn: a possible source of rhythmic inhibition of motoneurons during fictive locomotion. J. Neurosci. 30, 1137–1148 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Tripodi, M., Stepien, A. E. & Arber, S. Motor antagonism exposed by spatial segregation and timing of neurogenesis. Nature 479, 61–66 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Angel, M. J., Jankowska, E. & McCrea, D. A. Candidate interneurones mediating group I disynaptic EPSPs in extensor motoneurones during fictive locomotion in the cat. J. Physiol. 563, 597–610 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Bannatyne, B. A. et al. Excitatory and inhibitory intermediate zone interneurons in pathways from feline group I and II afferents: differences in axonal projections and input. J. Physiol. 587, 379–399 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Moran-Rivard, L. et al. Evx1 is a postmitotic determinant of v0 interneuron identity in the spinal cord. Neuron 29, 385–399 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Zhou, Y., Yamamoto, M. & Engel, J. D. GATA2 is required for the generation of V2 interneurons. Development 127, 3829–3838 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Gosgnach, S. et al. V1 spinal neurons regulate the speed of vertebrate locomotor outputs. Nature 440, 215–219 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Zhang, J. et al. V1 and v2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion. Neuron 82, 138–150 (2014). Using mouse genetics and physiology, this study showed that flexor–extensor alternation in rodents depends on the combined activity of inhibitory V1 and V2b neurons, two molecularly defined groups of neurons in the mammalian spinal cord that include Renshaw cells and Ia-INs.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Britz, O. et al. A genetically defined asymmetry underlies the inhibitory control of flexor-extensor locomotor movements. eLife 4, e04718 (2015).

    Article  Google Scholar 

  136. 136

    Higashijima, S., Masino, M. A., Mandel, G. & Fetcho, J. R. Engrailed-1 expression marks a primitive class of inhibitory spinal interneuron. J. Neurosci. 24, 5827–5839 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Li, W. C., Higashijima, S., Parry, D. M., Roberts, A. & Soffe, S. R. Primitive roles for inhibitory interneurons in developing frog spinal cord. J. Neurosci. 24, 5840–5848 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Peng, C. Y. et al. Notch and MAML signaling drives Scl-dependent interneuron diversity in the spinal cord. Neuron 53, 813–827 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    Grillner, S. Williams, T. & Lagerbäck, P. A. The edge cell, a possible intraspinal mechanoreceptor. Science 223, 500–503 (1984).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    Grillner, S. & Rossignol, S. On the initiation of the swing phase of locomotion in chronic spinal cats. Brain Res. 146, 269–277 (1978). This study demonstrates that movement-activated receptors in the hip are important for initiating the swing phase during locomotion.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Kriellaars, D. J., Brownstone, R. M., Noga, B. R. & Jordan, L. M. Mechanical entrainment of fictive locomotion in the decerebrate cat. J. Neurophysiol. 71, 2074–2086 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Hultborn, H. et al. How do we approach the locomotor network in the mammalian spinal cord? Ann. NY Acad. Sci. 860, 70–82 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Conway, B. A., Hultborn, H. & Kiehn, O. Proprioceptive input resets central locomotor rhythm in the spinal cat. Exp. Brain Res. 68, 643–656 (1987).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144

    Akay, T., Tourtellotte, W. G., Arber, S. & Jessell, T. M. Degradation of mouse locomotor pattern in the absence of proprioceptive sensory feedback. Proc. Natl Acad. Sci. USA 111, 16877–16882 (2014). This study shows that mouse locomotor patterns are significantly changed after genetic elimination of proprioceptive feedback from muscle spindles and GTOs. Activity in muscle spindles alone affects swing-stance transition and the combination of muscle spindles and GTOs affects stance-swing phase transitions.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. 145

    Takeoka, A., Vollenweider, I., Courtine, G. & Arber, S. Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury. Cell 159, 1626–1639 (2014). This study shows that locomotor recovery after spinal cord injury is promoted by sensory feedback originating in muscle spindles. Mice that lack the muscle spindle sensory feedback exhibit disturbed descending circuits during recovery. The findings suggest that muscle spindle feedback facilitaties circuit reorganization after spinal cord injury.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    Ausborn, J., Mahmood, R. & El Manira, A. Decoding the rules of recruitment of excitatory interneurons in the adult zebrafish locomotor network. Proc. Natl Acad. Sci. USA 109, E3631–E3639 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    Marder, E. Neuromodulation of neuronal circuits: back to the future. Neuron 76, 1–11 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Lallemend, F. & Ernfors, P. Molecular interactions underlying the specification of sensory neurons. Trends Neurosci. 35, 373–381 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Zagoraiou, L. et al. A cluster of cholinergic premotor interneurons modulates mouse locomotor activity. Neuron 64, 645–662 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. 150

    Perry, S. et al. Firing properties of Renshaw cells defined by Chrna2 are modulated by hyperpolarizing and small conductance ion currents Ih and ISK. Eur. J. Neurosci. 41, 889–900 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  151. 151

    Zeisel, A. et al. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347, 1138–1142 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    Ray, R. S. et al. Impaired respiratory and body temperature control upon acute serotonergic neuron inhibition. Science 333, 637–642 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Deisseroth, K. Optogenetics: 10 years of microbial opsins in neuroscience. Nat. Neurosci. 18, 1213–1225 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Azim, E., Jiang, J., Alstermark, B. & Jessell, T. M. Skilled reaching relies on a V2a propriospinal internal copy circuit. Nature 508, 357–363 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Esposito, M. S., Capelli, P. & Arber, S. Brainstem nucleus MdV mediates skilled forelimb motor tasks. Nature 508, 351–356 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Caggiano, V., Sur, M. & Bizzi, E. Rostro-caudal inhibition of hindlimb movements in the spinal cord of mice. PLoS ONE 9, e100865 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Fetcho, J. R. Imaging neuronal activity with calcium indicators in larval zebrafish. CSH Protoc. http://dx.doi.org/10.1101/pdb.prot4781 (2007).

  158. 158

    Hamel, E. J., Grewe, B. F., Parker, J. G. & Schnitzer, M. J. Cellular level brain imaging in behaving mammals: an engineering approach. Neuron 86, 140–159 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  159. 159

    Feierstein, C. E., Portugues, R. & Orger, M. B. Seeing the whole picture: A comprehensive imaging approach to functional mapping of circuits in behaving zebrafish. Neuroscience 296, 26–38 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Harris-Warrick, R. M. Voltage-sensitive ion channels in rhythmic motor systems. Curr. Opin. Neurobiol. 12, 646–651 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  161. 161

    Dale, N. & Kuenzi, F. Ionic currents, transmitters and models of motor pattern generators. Curr. Opin. Neurobiol. 7, 790–796 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  162. 162

    Grillner, S., Wallen, P., Hill, R., Cangiano, L. & El Manira, A. Ion channels of importance for the locomotor pattern generation in the lamprey brainstem-spinal cord. J. Physiol. 533, 23–30 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  163. 163

    Kiehn, O., Kjaerulff, O., Tresch, M. C. & Harris-Warrick, R. M. Contributions of intrinsic motor neuron properties to the production of rhythmic motor output in the mammalian spinal cord. Brain Res. Bull. 53, 649–659 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 164

    El Manira, A., Kyriakatos, A. & Nanou, E. Beyond connectivity of locomotor circuitry-ionic and modulatory mechanisms. Prog. Brain Res. 187, 99–110 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Kiehn, O. & Dougherty, K. in Neuroscience in the 21st Century (ed. Pfaff, D. W.) 1209–1237 (Springer, 2013).

    Google Scholar 

  166. 166

    Alaynick, W. A., Jessell, T. M. & Pfaff, S. L. SnapShot: spinal cord development. Cell 146, 178–178.e1 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The work in the Kiehn laboratory is supported by the Swedish Research Council, The European Research Council advanced grant, Ragnar and Torsten Söderbergs Foundation, Karolinska Institutet, NIH and Hjärnfonden. The author thanks colleagues for many inspiring discussions regarding themes discussed in this Review. The author thanks K. Dougherty for reading a previous version of this article.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ole Kiehn.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Glossary

Gait

A description of the pattern of limb movements. Different gaits have different patterns of movements and are often expressed as a function of the speed of locomotion.

Mesencephalic locomotor region

(MLR). A region in the midbrain where electrical stimulation initiates locomotion. The strength of stimulation regulates the speed of locomotion.

Commissural neurons

(CNs). Excitatory or inhibitory neurons that have axons crossing between the left side and the right side of the nervous system.

Transcription factor

A protein that binds to DNA and controls the transcription of DNA to RNA. Expressed in specific populations of neurons during development.

Monosynaptically restricted trans-synaptic labelling

An anatomical viral-based method in which a fluorescently labelled virus jumps one synapse from a target population of neurons to their immediate presynaptic partners. Used for detailed connectivity studies.

Rhythm-generating neurons

Excitatory neurons that are primarily involved in rhythm generation.

Pacemaker properties

Neuronal membrane properties that endow cells with the capability to produce endogenous bursting.

Renshaw cells

Inhibitory neurons that are excited via recurrent collaterals from motor neurons. They project back to motor neurons and inhibit them. They also inhibit reciprocal Ia interneurons.

Recurrent inhibition

Inhibitory cells that are activated by excitatory cells and that provide inhibition of other cells occasionally including the cell that provided the excitation.

Golgi tendon organs

(GTOs). Force-activated receptors in tendons.

Proprioception

The awareness of body and limb position. Mediated by proprioceptive movement-activated receptors in muscles, tendons and joints.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kiehn, O. Decoding the organization of spinal circuits that control locomotion. Nat Rev Neurosci 17, 224–238 (2016). https://doi.org/10.1038/nrn.2016.9

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing