While the organization of the constituent interneurons in the central pattern generator (CPG) controlling swimming in non-limbed animals is known in great detail, little is known about the cellular organization of CPGs controlling walking in limbed mammals. This application proposes to identify and characterize a key feature of the mammalian locomotor network, namely the CPG-circuits involved in left/right alternation. Commissural interneurons or CINs that project axons to the opposite site of the cord are by necessity included in this circuit. These interneurons will be the focus of this investigation because their specific projection pattern and their well-defined role in locomotion makes CPG-CINs uniquely identifiable. The scientific goals of this project will be obtained using in vitro preparations of early postnatal rats and a range of unique approaches, which we have been developed specifically for this project. The proposed work will provide a comprehensive anatomical and electrophysiological characterization of locomotor related CINs and their connectivity. There are six specific aims: 1) anatomical identification of subpopulations of CINs; 2) determination of activity patterns of CINs and their phase relations to the locomotor pattern; 3) electrophysiological identification of projections from CINs to contralateral motoneurons; 4) electrophysiological identification of projections from CINs to last order interneurons in the pathway to contralateral motoneurons; 5) determination of projections between CINs on opposite sides of the spinal cord; 6) characterization of transmitter-modulated bursting properties of CINs. Such information will represent one of the first characterizations of the role of a neuronal population in the production of behavior by the mammalian spinal cord. By comparing these results with work performed in non-mammalian vertebrates the work also specifically will assess whether new organizational principles emerged for the construction of vertebrate CPGs as the behavioral task changed from non-limbed swimming to limbed walking. Because CPG function is localized to the spinal cord and is critical for spinal control of walking, the planned work is of strong relevance to the ongoing effort to re-establish locomotor function in patients with spinal cord injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZNS1-SRB-L (01))
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Chen, Daofen
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University of Copenhagen
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Restrepo, Carlos E; Margaryan, Gayane; Borgius, Lotta et al. (2011) Change in the balance of excitatory and inhibitory midline fiber crossing as an explanation for the hopping phenotype in EphA4 knockout mice. Eur J Neurosci 34:1102-12
Kiehn, Ole (2011) Development and functional organization of spinal locomotor circuits. Curr Opin Neurobiol 21:100-9
Kiehn, Ole; Dougherty, Kimberly J; Hagglund, Martin et al. (2010) Probing spinal circuits controlling walking in mammals. Biochem Biophys Res Commun 396:11-8
Hägglund, Martin; Borgius, Lotta; Dougherty, Kimberly J et al. (2010) Activation of groups of excitatory neurons in the mammalian spinal cord or hindbrain evokes locomotion. Nat Neurosci 13:246-52
Borgius, Lotta; Restrepo, C Ernesto; Leao, Richardson N et al. (2010) A transgenic mouse line for molecular genetic analysis of excitatory glutamatergic neurons. Mol Cell Neurosci 45:245-57
Dougherty, Kimberly J; Kiehn, Ole (2010) Firing and cellular properties of V2a interneurons in the rodent spinal cord. J Neurosci 30:24-37
Dougherty, Kimberly J; Kiehn, Ole (2010) Functional organization of V2a-related locomotor circuits in the rodent spinal cord. Ann N Y Acad Sci 1198:85-93
Restrepo, Carlos Ernesto; Lundfald, Line; Szabó, Gabor et al. (2009) Transmitter-phenotypes of commissural interneurons in the lumbar spinal cord of newborn mice. J Comp Neurol 517:177-92
Crone, Steven A; Quinlan, Katharina A; Zagoraiou, Laskaro et al. (2008) Genetic ablation of V2a ipsilateral interneurons disrupts left-right locomotor coordination in mammalian spinal cord. Neuron 60:70-83
Kiehn, Ole; Quinlan, Katharina A; Restrepo, Carlos Ernesto et al. (2008) Excitatory components of the mammalian locomotor CPG. Brain Res Rev 57:56-63

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