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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)

 
68
Projects
USD 17.6 M
Aggregated funding amount
USD 259 K
Average funding amount
Project list item
Plasticity Of Reticulospinal Pathways Following Spinal Cord Injury

Craig H Neilsen Foundation to Frederic Bretzner

USD 300,000
2019 - 2021
Project list item
Molecular control over motor circuit remodeling

Craig H Neilsen Foundation to Edmund Roy Hollis, Nadjat Serradj

USD 300,000
2019 - 2021
Project list item
Novel and potent compounds that promote axon growth

Craig H Neilsen Foundation to Vance P. Lemmon, Sixue Chen, John Bixby, Hassan Al-Ali, Marc Giulianotti

USD 600,000
2019 - 2022
Project list item
Cervical Spinal Epidural Stimulation and Respiratory Recovery After SCI

Craig H Neilsen Foundation to Erica Dale, Erica Dale

USD 300,000
2019 - 2021
Project list item
Novel chemical approaches for specific targeting of CSPGs to restore function after SCI

Craig H Neilsen Foundation to Linda Carol Hsieh-Wilson, Elizabeth Jane Bradbury

USD 600,000
2019 - 2022
Project list item
Metabolic reprograming of glial cells promotes axon regeneration in the CNS

Craig H Neilsen Foundation to Yuanquan Song

USD 300,000
2019 - 2021
Project list item
Determining spinal alterations in sexual reflex control.

Craig H Neilsen Foundation to Lique Martina Coolen, James Walker Wiggins, Sid Gaikwad, James Walker Wiggins

USD 599,976
2019 - 2022
Project list item
Axonal mRNA transport and local translation as a potentially crucial mechanism for spinal cord axon

Craig H Neilsen Foundation to Jian Zhong

USD 300,000
2018 - 2020
Project list item
Intracortical neuroprosthesis to foster motor recovery after SCI

Craig H Neilsen Foundation to Marina Martinez, Numa Dancause, Marco Bonizzato

USD 295,832
2018 - 2020
Project list item
Property of vasoconstrictor thoracic sympathetic postganglionic neurons after SCI

Craig H Neilsen Foundation to Yaqing Li

USD 150,000
2018 - 2020
Project list item
Zinc chelation to promote axon regeneration after spinal cord injury

Craig H Neilsen Foundation to Sheri Lynn Peterson

USD 148,728
2018 - 2020
Project list item
Recovery of bladder function after SCI with opsin-based sensorimotor modulation

Craig H Neilsen Foundation to Jennifer DeBerry, Cary DeWitte, Candace Floyd

USD 299,683
2018 - 2020
Project list item
Combinatorial Therapies to Treat Breathing Impairments After Cervical SCI

Craig H Neilsen Foundation to Elisa Gonzalez-Rothi, Gordon Mitchell, Elisa Gonzalez-Rothi

USD 299,826
2017 - 2019
Project list item
CST neuron gene expression during axon regeneration enabled by PTEN deletion

Craig H Neilsen Foundation to Oswald Steward, Stanley Carmichael, Erin Gutilla, Karla McHale, Ardi Gunawan, Kelly Matsudaira Yee, Oswald Steward

USD 300,000
2017 - 2019
Project list item
Regeneration of respiratory neural circuitry following SCI

Craig H Neilsen Foundation to Angelo C Lepore, Michael Aron Lane, George Smith, Angelo C Lepore

USD 300,000
2017 - 2019
Project list item
Movement Asymmetries following Spinal Cord Injury

Craig H Neilsen Foundation to Yuming Lei

USD 150,000
2017 - 2019
Project list item
Regenerative strategies for autonomic recovery after spinal cord injury

Craig H Neilsen Foundation to Rahul Sachdeva

USD 150,000
2017 - 2019
Project list item
Promoting structural and functional reorganization after spinal cord injury

Craig H Neilsen Foundation to Andrea Tedeschi

USD 299,064
2017 - 2019
Project list item
Enhancing Corticospinal Excitability to Improve Functional Recovery

Craig H Neilsen Foundation to Jennifer Ann Iddings, Edelle Carmen Field-Fote

USD 143,894
2017 - 2019
Project list item
MicroRNA-155 is a novel target for ameliorating SCI-induced neuropathic pain and locomotor deficits

Craig H Neilsen Foundation to Steven Maier, Andrew Gaudet

USD 300,000
2016 - 2019
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