Project 170829

This application addresses one disability of people with spinal cord injuries and diseases: the inability to walk. The spinal cord of mammals (including humans) contains a network of nerve cells which produces the basic pattern of walking in the absence of connection with the brain. Details of the mechanisms of this network have been elusive. During walking, there is very strict alternation between muscles that flex and those that extend every joint. This alternation is critical for the production of coordinated movement. If flexor and extensor muscles are active at the same time, the joint would not bend, and there will be no movement. Muscles receive their commands from specialised nerve cells called "motor neurons," which receive alternating commands from other spinal cord nerve cells, called interneurons. There are two basic types of nerve cells providing the alternating on and off commands to motor neurons - excitatory and inhibitory interneurons. I propose to study these two types of nerve cells in order to understand how the motor neurons (and hence the muscles) are activated during walking and how sensory information from the limbs uses these two types of interneurons to ensure that appropriate muscle contraction takes place with changing limb position. These experiments will be done using genetically-modified mice and advanced microscopy techniques which together allow visualisation of the activity of identified interneurons, and manipulation of this activity. By combining many different techniques, we will be able to study the role of these neurons in producing coordinated movement. By the conclusion of the 5-year granting period, we will have a greater understanding of how the spinal cord controls the activation pattern of muscles, and how sensory information interacts with this fundamental network. This knowledge will assist in the development of strategies to improve the function of people living with spinal cord injuries and diseases.

using genetically-modified mice and advanced microscopy to study spinal cord locomotor networks