Enhancing Propriospinal Relays to Improve Functional Recovery after SCI
Abstract
Background and summary of the proposed research: Injury to the spinal cord can result in permanent loss of motor and sensory function below the level of injury. The loss of motor control is primarily due to severing of descending motor pathways from the cortex or brainstem. Regeneration of these long supraspinal pathways has proven to be very challenging, and little true regeneration has been observed. The spinal cord itself, however, contains numerous neurons that extend various lengths only within the spinal cord, termed propriospinal neurons. In several animal models, propriospinal neurons have been shown to promote recovery of hindlimb locomotion after cutting all axons from higher brain regions. In both cases, non-injured propriospinal axons can sprout to form circuit relays to bypass the lesion. In addition, it is well established that propriospinal axons regenerate much better than cortical or brainstem neurons, which typically control motor function in non-injured animals. However, the importance of these propriospinal neurons in mediating functional recovery is relatively understudied. The present study is designed to examine: (1) the functional contribution of propriospinal neurons in mediating hindlimb locomotor function after mid-thoracic spinal cord injury and (2) mechanisms to enhance propriospinal regeneration and plasticity to better promote functional recovery. For this study, we have developed a method to selectively silence the activity of propriospinal neurons to determine their role in functional recovery after a moderate contusion injury to the spinal cord. We have also developed methods to examine whether or not these neurons receive connection from higher brain motor regions. This information will allow us to map propriospinal neuron circuits and determine to what extent they bypass a lesion to contribute to functional recovery. These data also provide a platform on which we can adapt these circuits to enhance relay formation bypassing the lesion site. In the first aim of this study, we will selectively map and silence different neuronal population bypassing the lesion to determine which might contribute the most to functional recovery. In the second specific aim, we will examine a treatment previously shown to enhance the growth of multiple neuronal populations and functional recovery. However, which pathway contributes to functional recovery is still unclear. Again, by selectively silencing subpopulation of neurons, we can determine which pathway contributes to functional recovery. Since in this model we observe extensive spouting but little axon regeneration past the injury site, we think that functional recovery is mediated by enhanced connections between supraspinal neurons and propriospinal neurons bypassing the lesion. We will also examine if directly enhancing the spouting of propriospinal axons will promote functional recovery. Thus, this proposal will examine if propriospinal neurons, which bypass the lesion, can relay motor information past the lesion site, and if this "indirect" motor pathway can be enhanced to provide higher levels of functional recovery. The ultimate applicability of the research: This proposal will map adaptive spinal circuits and determine their role in functional recovery. We will also examine if plasticity along these pathways is beneficial to functional recovery. What types of patients will it help, and how will it help them? Our studies can be applied to either acute or chronic individuals with incomplete spinal cord injury. What are the potential clinical applications, benefit, and risks? If our hypothesis is correct, this study could open a new avenue to promote recovery in the absence of inducing long-distance regeneration. Treatment that inducing short distance regeneration or plasticity of endogenous spinal cord circuits could more easily be developed to enhance functional recovery. What is the projected time it may take to a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510595
Entities
People
- George Smith
Organizations
- Temple University
- United States Army