Shining light into the black box of spinal locomotor networks

Rhythmic activity is responsible for numerous essential motor functions including locomotion, breathing and chewing. In the case of locomotion, it has been realized for some time that the spinal cord contains sufficient circuitry to produce a sophisticated stepping pattern. However, the central pattern generator for locomotion in mammals has remained a ‘black box’ where inputs to the network were manipulated and the outputs interpreted. Over the last decade, new genetic approaches and techniques have been developed that provide ways to identify and manipulate the activity of classes of interneurons. The use of these techniques will be critically discussed and related to current models of network function.

[1]  E. Callaway,et al.  Photostimulation using caged glutamate reveals functional circuitry in living brain slices. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Rossignol,et al.  Recovery of locomotion after chronic spinalization in the adult cat , 1987, Brain Research.

[3]  J. Eccles,et al.  The recording of potentials from motoneurones with an intracellular electrode , 1952, The Journal of physiology.

[4]  Linying Wu,et al.  Locomotor-like rhythms in a genetically distinct cluster of interneurons in the mammalian spinal cord. , 2005, Journal of neurophysiology.

[5]  R. Brownstone,et al.  An in vitro functionally mature mouse spinal cord preparation for the study of spinal motor networks , 1999, Brain Research.

[6]  K. Svoboda,et al.  Genetic Dissection of Neural Circuits , 2008, Neuron.

[7]  Hynek Wichterle,et al.  Functional Properties of Motoneurons Derived from Mouse Embryonic Stem Cells , 2004, The Journal of Neuroscience.

[8]  E. Jankowska Interneuronal relay in spinal pathways from proprioceptors , 1992, Progress in Neurobiology.

[9]  E. Bamberg,et al.  Channelrhodopsin-2, a directly light-gated cation-selective membrane channel , 2003, Proceedings of the National Academy of Sciences of the United States of America.

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

[11]  Brian Randell,et al.  Reliability Issues in Computing System Design , 1978, CSUR.

[12]  P. Jonas,et al.  Corelease of two fast neurotransmitters at a central synapse. , 1998, Science.

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

[14]  A. Lansner,et al.  The cortex as a central pattern generator , 2005, Nature Reviews Neuroscience.

[15]  O. Kiehn,et al.  Development in neonatal rats of the sensory resetting of the locomotor rhythm induced by NMDA and 5-HT , 1997, Experimental Brain Research.

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

[17]  Jack L. Feldman,et al.  In vitro brainstem-spinal cord preparations for study of motor systems for mammalian respiration and locomotion , 1987, Journal of Neuroscience Methods.

[18]  Feng Zhang,et al.  Multimodal fast optical interrogation of neural circuitry , 2007, Nature.

[19]  Thomas M Jessell,et al.  Development The decade of the developing brain , 2000, Current Opinion in Neurobiology.

[20]  S. Grillner The motor infrastructure: from ion channels to neuronal networks , 2003, Nature Reviews Neuroscience.

[21]  R. Wyman,et al.  MOTOR OUTPUT PATTERNS DURING RANDOM AND RHYTHMIC STIMULATION OF LOCUST THORACIC GANGLIA. , 1965, Biophysical journal.

[22]  Ole Kiehn,et al.  Activity of Renshaw Cells during Locomotor-Like Rhythmic Activity in the Isolated Spinal Cord of Neonatal Mice , 2006, The Journal of Neuroscience.

[23]  E. Jankowska Spinal interneuronal systems: identification, multifunctional character and reconfigurations in mammals , 2001, The Journal of physiology.

[24]  Toshiaki Endo,et al.  Asymmetric operation of the locomotor central pattern generator in the neonatal mouse spinal cord. , 2008, Journal of neurophysiology.

[25]  Alfredo Fontanini,et al.  Network homeostasis: a matter of coordination , 2009, Current Opinion in Neurobiology.

[26]  R. Brownstone,et al.  Heterogeneity of V2‐derived interneurons in the adult mouse spinal cord , 2007, The European journal of neuroscience.

[27]  P A Getting,et al.  Emerging principles governing the operation of neural networks. , 1989, Annual review of neuroscience.

[28]  Alan Roberts,et al.  Early functional organization of spinal neurons in developing lower vertebrates , 2000, Brain Research Bulletin.

[29]  P. Whelan,et al.  Locomotor networks are targets of modulation by sensory transient receptor potential vanilloid 1 and transient receptor potential melastatin 8 channels , 2009, Neuroscience.

[30]  Hans Hultborn,et al.  Thomas Graham Brown (1882–1965), Anders Lundberg (1920–), and the neural control of stepping , 2008, Brain Research Reviews.

[31]  R. Harris-Warrick,et al.  Activity of Hb9 Interneurons during Fictive Locomotion in Mouse Spinal Cord , 2009, The Journal of Neuroscience.

[32]  Michael J. O'Donovan,et al.  Imaging the spatiotemporal organization of neural activity in the developing spinal cord , 2008, Developmental neurobiology.

[33]  E. Callaway,et al.  A Genetic Method for Selective and Quickly Reversible Silencing of Mammalian Neurons , 2002, The Journal of Neuroscience.

[34]  Serge Rossignol,et al.  Neural Control of Stereotypic Limb Movements , 2011 .

[35]  Whole cell recordings from visualized neurons in the inner laminae of the functionally intact spinal cord. , 2009, Journal of neurophysiology.

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

[37]  Michael J. O'Donovan,et al.  Primary Afferent Synapses on Developing and Adult Renshaw Cells , 2006, The Journal of Neuroscience.

[38]  Margaret L. T. Poon Induction of swimming in lamprey by L-DOPA and amino acids , 1980, Journal of comparative physiology.

[39]  D. McCrea,et al.  Organization of mammalian locomotor rhythm and pattern generation , 2008, Brain Research Reviews.

[40]  S. Grillner,et al.  How detailed is the central pattern generation for locomotion? , 1975, Brain Research.

[41]  P. Whelan,et al.  Dopaminergic Modulation of Spinal Neuronal Excitability , 2007, The Journal of Neuroscience.

[42]  David Parker,et al.  Neuronal network analyses: premises, promises and uncertainties , 2010, Philosophical Transactions of the Royal Society B: Biological Sciences.

[43]  R. W. Draft,et al.  Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system , 2007, Nature.

[44]  S. Rossignol,et al.  The locomotion of the low spinal cat. II. Interlimb coordination. , 1980, Acta physiologica Scandinavica.

[45]  D. McCrea,et al.  Modelling spinal circuitry involved in locomotor pattern generation: insights from the effects of afferent stimulation , 2006, The Journal of physiology.

[46]  Ole Kiehn,et al.  Projection patterns of commissural interneurons in the lumbar spinal cord of the neonatal rat , 2002, The Journal of comparative neurology.

[47]  P. Whelan CONTROL OF LOCOMOTION IN THE DECEREBRATE CAT , 1996, Progress in Neurobiology.

[48]  Ethan K. Scott,et al.  Optogenetic dissection of a behavioral module in the vertebrate spinal cord , 2009, Nature.

[49]  Karl Deisseroth,et al.  Integration of light-controlled neuronal firing and fast circuit imaging , 2007, Current Opinion in Neurobiology.

[50]  Michael J. O'Donovan,et al.  Noncholinergic excitatory actions of motoneurons in the neonatal mammalian spinal cord. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[51]  D. Morin,et al.  Genesis of spontaneous rhythmic motor patterns in the lumbosacral spinal cord of neonate mouse. , 1998, Brain research. Developmental brain research.

[52]  S. Rossignol,et al.  On the initiation of the swing phase of locomotion in chronic spinal cats , 1978, Brain Research.

[53]  Astrid A Prinz,et al.  Computational approaches to neuronal network analysis , 2010, Philosophical Transactions of the Royal Society B: Biological Sciences.

[54]  B. Schmidt,et al.  Regional distribution of the locomotor pattern-generating network in the neonatal rat spinal cord. , 1997, Journal of neurophysiology.

[55]  J. Buchanan Contributions of identifiable neurons and neuron classes to lamprey vertebrate neurobiology , 2001, Progress in Neurobiology.

[56]  R. Harris-Warrick,et al.  Two-photon calcium imaging of network activity in XFP-expressing neurons in the mouse. , 2007, Journal of neurophysiology.

[57]  T. Brown The intrinsic factors in the act of progression in the mammal , 1911 .

[58]  Dirk Bucher Central Pattern Generators , 2009 .

[59]  P. Whelan,et al.  Deciphering the organization and modulation of spinal locomotor central pattern generators , 2006, Journal of Experimental Biology.

[60]  A. Selverston,et al.  Invertebrate central pattern generator circuits , 2010, Philosophical Transactions of the Royal Society B: Biological Sciences.

[61]  Michael J. O'Donovan,et al.  Blockade and Recovery of Spontaneous Rhythmic Activity after Application of Neurotransmitter Antagonists to Spinal Networks of the Chick Embryo , 1998, The Journal of Neuroscience.

[62]  T. Jessell,et al.  The Homeodomain Factor Lbx1 Distinguishes Two Major Programs of Neuronal Differentiation in the Dorsal Spinal Cord , 2002, Neuron.

[63]  T. Jessell,et al.  Conditional Rhythmicity of Ventral Spinal Interneurons Defined by Expression of the Hb9 Homeodomain Protein , 2005, The Journal of Neuroscience.

[64]  Yoshihiro Yoshihara,et al.  Pax6 and Engrailed 1 Regulate Two Distinct Aspects of Renshaw Cell Development , 2004, The Journal of Neuroscience.

[65]  J. C. Smith,et al.  Neural mechanisms generating locomotion studied in mammalian brain stem‐spinal cord in vitro , 1988, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

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

[67]  E. Adrian,et al.  Thomas Graham Brown, 1882-1965 , 1966, Biographical Memoirs of Fellows of the Royal Society.

[68]  P. Wallén,et al.  The neuronal correlate of locomotion in fish , 1980, Experimental Brain Research.

[69]  Ole Kiehn,et al.  Firing Properties of Identified Interneuron Populations in the Mammalian Hindlimb Central Pattern Generator , 2002, The Journal of Neuroscience.

[70]  S. Grillner Control of Locomotion in Bipeds, Tetrapods, and Fish , 1981 .

[71]  S. Higashijima,et al.  Zebrafish and motor control over the last decade , 2008, Brain Research Reviews.

[72]  Ilya A Rybak,et al.  Modeling the mammalian locomotor CPG: insights from mistakes and perturbations. , 2007, Progress in brain research.

[73]  A. Lundberg Multisensory control of spinal reflex pathways. , 1979, Progress in brain research.

[74]  Alan Roberts,et al.  Origin of excitatory drive to a spinal locomotor network , 2008, Brain Research Reviews.

[75]  Michael J. O'Donovan,et al.  The Role of Activity-Dependent Network Depression in the Expression and Self-Regulation of Spontaneous Activity in the Developing Spinal Cord , 2001, The Journal of Neuroscience.

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

[77]  A. Lundberg,et al.  The effect of DOPA on the spinal cord. 6. Half-centre organization of interneurones transmitting effects from the flexor reflex afferents. , 1967, Acta physiologica Scandinavica.

[78]  Y. Yanagawa,et al.  Mammalian motor neurons corelease glutamate and acetylcholine at central synapses. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[79]  E. Callaway,et al.  V1 spinal neurons regulate the speed of vertebrate locomotor outputs , 2006, Nature.

[80]  Michael J. O'Donovan,et al.  Properties of rhythmic activity generated by the isolated spinal cord of the neonatal mouse. , 2000, Journal of neurophysiology.

[81]  M. Goulding,et al.  Development of circuits that generate simple rhythmic behaviors in vertebrates , 2005, Current Opinion in Neurobiology.

[82]  Feng Zhang,et al.  Channelrhodopsin-2 and optical control of excitable cells , 2006, Nature Methods.

[83]  D. McCrea,et al.  Modelling spinal circuitry involved in locomotor pattern generation: insights from deletions during fictive locomotion , 2006, The Journal of physiology.

[84]  Bradley J. Baker,et al.  Wide-field and two-photon imaging of brain activity with voltage- and calcium-sensitive dyes , 2009, Philosophical Transactions of the Royal Society B: Biological Sciences.

[85]  D. Richter,et al.  Reverse physiology in Drosophila: identification of a novel allatostatin‐like neuropeptide and its cognate receptor structurally related to the mammalian somatostatin/galanin/opioid receptor family , 1999, The EMBO journal.

[86]  Christopher A Hinckley,et al.  Electrical Coupling between Locomotor-Related Excitatory Interneurons in the Mammalian Spinal Cord , 2006, The Journal of Neuroscience.

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

[88]  O. Kiehn,et al.  Central Pattern Generators Deciphered by Molecular Genetics , 2004, Neuron.

[89]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[90]  S. Rossignol,et al.  Phase dependent reflex reversal during walking in chronic spinal cats , 1975, Brain Research.

[91]  J. Fetcho,et al.  Using imaging and genetics in zebrafish to study developing spinal circuits in vivo , 2008, Developmental neurobiology.

[92]  J. Buchanan Identification of interneurons with contralateral, caudal axons in the lamprey spinal cord: synaptic interactions and morphology. , 1982, Journal of neurophysiology.

[93]  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.

[94]  E. Marder,et al.  Central pattern generators and the control of rhythmic movements , 2001, Current Biology.

[95]  Michael J. O'Donovan,et al.  Real-time imaging of neurons retrogradely and anterogradely labelled with calcium-sensitive dyes , 1993, Journal of Neuroscience Methods.

[96]  A. Lundberg,et al.  The effect of DOPA on the spinal cord. 5. Reciprocal organization of pathways transmitting excitatory action to alpha motoneurones of flexors and extensors. , 1967, Acta physiologica Scandinavica.

[97]  S. Grillner,et al.  On the central generation of locomotion in the low spinal cat , 1979, Experimental Brain Research.

[98]  D. Morin,et al.  Hemisegmental localisation of rhythmic networks in the lumbosacral spinal cord of neonate mouse , 1998, Brain Research.

[99]  A. Roberts,et al.  Central Circuits Controlling Locomotion in Young Frog Tadpoles , 1998, Annals of the New York Academy of Sciences.

[100]  Elzbieta Jankowska,et al.  Networks of inhibitory and excitatory commissural interneurons mediating crossed reticulospinal actions , 2003, The European journal of neuroscience.

[101]  G. Feng,et al.  Next-Generation Optical Technologies for Illuminating Genetically Targeted Brain Circuits , 2006, The Journal of Neuroscience.

[102]  E. Marder,et al.  Similar network activity from disparate circuit parameters , 2004, Nature Neuroscience.

[103]  J. Friedman,et al.  Virus-Assisted Mapping of Neural Inputs to a Feeding Center in the Hypothalamus , 2001, Science.

[104]  Michael J. O'Donovan,et al.  Calcium imaging of rhythmic network activity in the developing spinal cord of the chick embryo , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[105]  J. Buchanan,et al.  Activities of identified interneurons, motoneurons, and muscle fibers during fictive swimming in the lamprey and effects of reticulospinal and dorsal cell stimulation. , 1982, Journal of neurophysiology.

[106]  O. Kiehn,et al.  Phenotype of V2‐derived interneurons and their relationship to the axon guidance molecule EphA4 in the developing mouse spinal cord , 2007, The European journal of neuroscience.

[107]  E. Jankowska,et al.  Functional differentiation and organization of feline midlumbar commissural interneurones , 2005, The Journal of physiology.

[108]  P. Stein,et al.  Spinal Motor Patterns in the Turtle a , 1998, Annals of the New York Academy of Sciences.

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

[110]  O. Kiehn,et al.  Physiological, anatomical and genetic identification of CPG neurons in the developing mammalian spinal cord , 2003, Progress in Neurobiology.

[111]  A. Lev-Tov,et al.  Localization of the spinal network associated with generation of hindlimb locomotion in the neonatal rat and organization of its transverse coupling system. , 1997, Journal of neurophysiology.

[112]  L. Vinay,et al.  Contribution of persistent sodium current to locomotor pattern generation in neonatal rats. , 2007, Journal of neurophysiology.

[113]  Karl Deisseroth,et al.  Improved expression of halorhodopsin for light-induced silencing of neuronal activity , 2008, Brain cell biology.

[114]  L. Zon,et al.  Notch and MAML Signaling Drives Scl-Dependent Interneuron Diversity in the Spinal Cord , 2007, Neuron.

[115]  L. Enquist,et al.  Central neuronal circuit innervating the rat heart defined by transneuronal transport of pseudorabies virus , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[116]  A. Selverston A Neural Infrastructure for Rhythmic Motor Patterns , 2005, Cellular and Molecular Neurobiology.

[117]  D. McCrea,et al.  Deletions of rhythmic motoneuron activity during fictive locomotion and scratch provide clues to the organization of the mammalian central pattern generator. , 2005, Journal of neurophysiology.

[118]  O. Kiehn,et al.  Functional Identification of Interneurons Responsible for Left-Right Coordination of Hindlimbs in Mammals , 2003, Neuron.

[119]  T. Suzue,et al.  Respiratory rhythm generation in the in vitro brain stem‐spinal cord preparation of the neonatal rat. , 1984, The Journal of physiology.

[120]  Ian R. Wickersham,et al.  Monosynaptic Restriction of Transsynaptic Tracing from Single, Genetically Targeted Neurons , 2007, Neuron.

[121]  K. Deisseroth,et al.  Parvalbumin neurons and gamma rhythms enhance cortical circuit performance , 2009, Nature.

[122]  L. Jordan,et al.  TTX-resistant NMDA receptor-mediated voltage oscillations in mammalian lumbar motoneurons. , 1994, Journal of neurophysiology.

[123]  M. Taussig The Nervous System , 1991 .

[124]  K. Pearson,et al.  Inhibition of flexor burst generation by loading ankle extensor muscles in walking cats , 1980, Brain Research.

[125]  M. Goulding,et al.  Postnatal phenotype and localization of spinal cord V1 derived interneurons , 2005, The Journal of comparative neurology.

[126]  D. Parker Complexities and uncertainties of neuronal network function , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.