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Project

Leveraging activity and guidance cues to promote targeting of CST outgrowth

Funder: Craig H Neilsen Foundation

Funding period
USD 600 K
Funding amount
Abstract
The overall aim of this proposal is to develop a novel strategy to study repair the corticospinal tract (CST) and restore motor function after cervical SCI. Whereas weakness occurs with damage to the corticospinal motor system in humans, there is a disproportionate loss of motor skills; most severely impacting hand/upper limb control. People with cervical SCI indicate that restoration of hand control is a high priority because it allows for greater independence in daily living. We take the unique perspective for cervical SCI repair to study the corticomotoneuronal (CM) connection between motor cortex neurons and motoneurons. CM connections are central to hand function in humans and higher primates. Rodents do not possess significant numbers of CM connections, which hampers study of the corticospinal motor system. Importantly, we have recently shown that deletion of the gene for the guidance molecule Plexin A1 in mice results in the presence of CM connections in substantial numbers to impact both the physiology of the CST and control of the forepaw.Aim 1 leverages this new mouse model to study the mechanisms underlying hyperreflexia. For the first time we can begin to identify how the CM connection is affected by an injury that leads to impaired control of motoneuron excitability and how it, in turn, affects motoneuronal and other injury-related changes. We will determine the impact of activity-dependent competitive interactions between the CM connection and the 1a afferent fiber connection directly on motoneurons, which is a key neuron type mediating hyperreflexia after SCI.Aim 2 explores a novel strategy to repair the CST by targeting CST axonal outgrowth directly to motoneurons. Whereas genetic and other strategies have been developed to enhance CST axon growth capacity, how to direct axonal outgrowth to key postsynaptic targets is largely unexplored. The logic of this aim combines our neuromodulatory approach to promote CST axonal sprouting with guidance gene deletion after injury to help CST axons sprout and establish synaptic connections onto motoneurons. We combine chronic electrical stimulation of the motor cortex and viral deletion of the gene for PlexinA1 (PlxA1) in mature PlxA1fl/fl mice following cervical injury. We hypothesize that this will lead to greater numbers of monosynaptic contacts between the CST and motoneurons.Aim 3 will determine if combined PlexinA1 gene deletion and motor cortex stimulation after SCI improves motor recovery. We will use a C4 contusion model. We hypothesize that the presence of CM connections will improve the injured animal’s performance in motor tasks.Successful completion of the proposed studies will reveal, for the first time, important new insights into the biology of the CM connection in health and after injury. In this way, we hope begin to devise CST repair strategies to engineer this important synaptic connection in people with cervical spinal cord injuries to promote hand function. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Neurosciences

  • RCDC

    Spinal Cord Injury

  • RCDC

    Genetics

  • RCDC

    Neurodegenerative

  • HRCS HC

    Neurological

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science