Improving Traumatic Brain Injury Outcomes Through Gene Therapy and Exercise

Abstract

Effective interventions that improve traumatic brain injury (TBI) outcomes are lacking, and concerns remain with current surgical and pharmacological treatments. Consequently, there is a significant need for identifying novel non-surgical and non-pharmacological interventions that improve TBI outcomes. Increasing production of neuroprotective molecules such as neuroglobin, vascular endothelial growth factor-A (VEGF-A), erythropoietin (EPO), and heme oxygenase-1 (HO-1) in the brain prior to TBI, or early after injury, may improve outcomes. The purpose of this dissertation was to determine whether gene therapy (i.e., overexpression of the neuroglobin gene) and/or pre-TBI exercise could improve post-TBI sensorimotor and cognitive function in adult mice by increasing brain expression of neuroglobin, VEGF-A, EPO, and HO-1. Additional objectives included determining what cell types and brain regions demonstrated endogenous production of neuroglobin, VEGF-A, EPO, and HO-1 after gene therapy, exercise, and TBI. The central hypothesis of this dissertation is that improved post-TBI sensorimotor and cognitive function are linked to gene therapy and/or pre-TBI exercise increasing the production of these neuroprotective proteins in brain regions responsible for movement (i.e., sensorimotor cortex) and memory (i.e., hippocampus). Study results indicated significantly improved post-TBI sensorimotor function in transgenic mice that overexpressed neuroglobin, and mice that engaged in 6 weeks of voluntary pre-TBI exercise. Improved post-TBI sensorimotor function (i.e., reduction in sensorimotor deficits while walking) was associated with increased neuroglobin production in neurons and glial cells throughout the brain of transgenic neuroglobin overexpressing mice, and increased VEGF-A and EPO in sensorimotor cortex neurons of pre-TBI exercise mice. Pre-TBI exercise mice also showed improved post-TBI cognitive function (i.e., reduction in spatial learning memory errors), and increased VEGF-A production within hippocampal neurons. These findings suggest that improved post-TBI sensorimotor and cognitive function are linked to gene therapy and/or exercise increasing the expression of neuroglobin, VEGF-A, and EPO in brain regions responsible for movement and memory. An increased production of these neuroprotective proteins was observed within brain neurons before TBI, or early after injury during the acute recovery phase. Interventions that increase neuroglobin, VEGF-A, and EPO production in brain neurons prior to TBI, or early after injury, may improve outcomes by optimizing neuroprotection.