To understand normal brain function as well as diseases of the brain it is necessary to understand how an assembly of nerve cells can generate the processing power required for different behaviors. The vertebrate spinal cord contains a central pattern generator or CPG that can produce the rhythmic movements of locomotion in the absence of peripheral and descending inputs. CPGs serve as relatively simple model systems for understanding how neuronal assemblies produce complex functions. While the organization of the constituent interneurons in the 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. Here we propose to identify and characterize neuronal populations in the mammalian locomotor network. We will focus on neuronal populations in segmental left-right coordination and groups of excitatory neurons that might be directly involved in rhythm generation. We will focus on these interneurons because they play key roles in CPG function. We will use in vitro preparations of prenatal and postnatal rodents for this purpose and apply a range of powerful new physiological and genetic approaches, which are adapted specifically for the proposed projects. The proposed work will provide a comprehensive anatomical, electrophysiological, pharmacological and molecular characterization of locomotor related interneurons and their connectivity. Such information will comprise 1 of the first characterizations of the roles of neuronal populations in the production of behavior by the mammalian spinal cord. Because CPG function is localized to the spinal cord and is critical for spinal control of walking, our work is of strong relevance to the ongoing effort to re-establish locomotor function in patients with spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040795-07
Application #
7189036
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Kleitman, Naomi
Project Start
2001-03-09
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
7
Fiscal Year
2007
Total Cost
$236,808
Indirect Cost
Name
Karolinska Institute
Department
Type
DUNS #
350582235
City
Stockholm
State
Country
Sweden
Zip Code
171 7-7
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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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