Neuronal networks within the spinal cord organize and drive rhythmic movements like walking and swimming. These circuits represent the central pattern generator (CPG) that controls both the rhythm and the pattern of the locomotor activity. The organization of these circuits has recently begun to be revealed due to the state-of- art combination of complementary genetic, molecular and physiological methods. The overall goal of this project is to dissect the organization of the spinal CPG with focus on the organization of flexor-extensor alternating and left-right coordinating circuits. All work will be done on identifiable classes of spinal interneurons labeled by genetic markers in transgenic mice and/or classified by anatomic or electrophysiological labeling needed to obtain a unified picture of the CPG organization. We propose to identify the functional connectome and the interactions between these fundamental components of the CPG. The experiments performed will use a combination of electrophysiological, imaging, and molecular biology techniques complemented with advanced computer modeling. The three PIs involved in this project have strong background and experience in spinal cord studies and unique expertise in physiological, genetic and molecular methods (Martyn Goulding and Ole Kiehn) and computational modeling (Ilya Rybak).
The Specific Aims of the project include: investigation of activity patterns and connectivity of the genetically identified spinal interneurons responsible for left-right coordinaton during locomotion (Aim 1), investigation of the genetically identified spinal interneurons and thei connectivity responsible for flexor-extensor alternation and their interactions with the circuits providing left-right coordination (Aim 2), development of a comprehensive computational model of spinal cord circuits (Aim 3). The proposed multidisciplinary approach based on the state-of-art methods and close collaboration between the three leading labs will investigate and analyze the specific contributions of left-right and flexor-extensor coordinating neuronal circuits and their interactions to the generation and control of the locomotor pattern and provide important insights into the neural organization of the mammalian spinal cord, leading to new strategies to treat spinal cord injury and degeneration spinal cord disorders.

Public Health Relevance

Neural networks in the mammalian spinal cord can generate locomotor activity without supra-spinal input that is often disabled after spinal cord injury. This study will provide a comprehensive understanding of how the locomotor network is organized with particular focus on circuits providing flexor-extensor alternation and left- right coordinatio, which together represent the essence of neural control of locomotion. With such enhanced understanding, the new therapeutic tools may be developed to effectively target spinal neurons and circuits, facilitating a recovery of motor function after injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS090919-02
Application #
8925170
Study Section
Special Emphasis Panel (ZRG1-IFCN-T (02))
Program Officer
Chen, Daofen
Project Start
2014-09-15
Project End
2019-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
2
Fiscal Year
2015
Total Cost
$624,136
Indirect Cost
$76,911
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bellardita, Carmelo; Caggiano, Vittorio; Leiras, Roberto et al. (2017) Spatiotemporal correlation of spinal network dynamics underlying spasms in chronic spinalized mice. Elife 6:
Sternfeld, Matthew J; Hinckley, Christopher A; Moore, Niall J et al. (2017) Speed and segmentation control mechanisms characterized in rhythmically-active circuits created from spinal neurons produced from genetically-tagged embryonic stem cells. Elife 6:
Flynn, Jamie R; Conn, Victoria L; Boyle, Kieran A et al. (2017) Anatomical and Molecular Properties of Long Descending Propriospinal Neurons in Mice. Front Neuroanat 11:5
Tuncdemir, Sebnem N; Wamsley, Brie; Stam, Floor J et al. (2016) Early Somatostatin Interneuron Connectivity Mediates the Maturation of Deep Layer Cortical Circuits. Neuron 89:521-35
Kiehn, Ole (2016) Decoding the organization of spinal circuits that control locomotion. Nat Rev Neurosci 17:224-38
Shevtsova, Natalia A; Rybak, Ilya A (2016) Organization of flexor-extensor interactions in the mammalian spinal cord: insights from computational modelling. J Physiol 594:6117-6131
Danner, Simon M; Wilshin, Simon D; Shevtsova, Natalia A et al. (2016) Central control of interlimb coordination and speed-dependent gait expression in quadrupeds. J Physiol 594:6947-6967
Rybak, Ilya A; Dougherty, Kimberly J; Shevtsova, Natalia A (2015) Organization of the Mammalian Locomotor CPG: Review of Computational Model and Circuit Architectures Based on Genetically Identified Spinal Interneurons(1,2,3). eNeuro 2:
Molkov, Yaroslav I; Bacak, Bartholomew J; Talpalar, Adolfo E et al. (2015) Mechanisms of left-right coordination in mammalian locomotor pattern generation circuits: a mathematical modeling view. PLoS Comput Biol 11:e1004270
Britz, Olivier; Zhang, Jingming; Grossmann, Katja S et al. (2015) A genetically defined asymmetry underlies the inhibitory control of flexor-extensor locomotor movements. Elife 4:

Showing the most recent 10 out of 13 publications