Acceleration forces induced by impact to the head are the cause of damage to axons throughout the brain. Long axons of white matter tracts are most vulnerable when the tissue is rapidly stretched upon impact. The injury results in significant damage to the myelin. Following mild traumatic brain injury (TBI), oligodendrocyte death is rarely observed. However, myelin abnormalities are nevertheless frequently observed. Ultra-structural analyses have shown myelin loss on intact axons (primary demyelination) as well as excess myelin sheath formation within the lesion, both of which underscore a disruption in myelin homeostasis. We hypothesize that mechanical impact on the brain disrupts myelin homeostasis in the mature oligodendrocyte. As myelin homeostasis is regulated by an array of transcription factors and gene expressions, we hypothesize that TBI initiates active signaling event(s) in oligodendrocytes and that this(these) intrinsic change(s) disrupt(s) myelin stability. In support to this hypothesis, data from our preliminary study show that stretch injury of oligodendrocyte activates the Erk1/2 pathway to induce myelin protein loss. Other injury-associated signals, including Ca2+ increase, glutamate and growth factor stimulation, also induced myelin loss in an Erk1/2-dependent manner. Furthermore, mild TBI on rodent brain induced Erk1/2 activation in white matter oligodendrocytes. Recent studies have shown that aberrant Erk1/2 activation in adult oligodendrocytes disrupts myelin homeostasis. We will test the hypothesis that TBI-induced Erk1/2 activation in oligodendrocytes contributes to myelin abnormalities (Aim 1). For the study, we will combine experimental TBI with the Erk1-/-,Erk2flox/flox:PLP-CreERT mouse line to determine whether inhibiting Erk1/2 activation in mature oligodendrocyte prevents TBI-induced myelin loss or improves myelin stability.
Aim 2 will test the hypothesis that myelin abnormalities in TBI results from an active signaling event that involves transcriptional changes in mature oligodendrocytes. We will use in vivo TRAP (translating ribosome affinity purification) to isolate TBI-responsive transcripts specific to mature oligodendrocyte in adult brain. Subsequent RNA-seq analysis will elucidate the TBI-induced oligodendrocyte transcriptome profile associated with myelin dysfunction.
Traumatic brain injury (TBI) accounts for approximately 75% of all brain-injured people in United States each year, and is particularly prevalent in contact sports. Chronic white matter atrophy or degeneration of myelinated axons is a common occurrence after TBI, which contributes to long- term functional deficits in the patients. While the neuronal pathology in TBI brain has been well characterized, the molecular basis of oligodendrocyte myelin loss has not been fully investigated. As a major component of white matter tracks, myelin enables fast nerve conduction and provides trophic and metabolic support to the neurons. Myelin loss leaves axons more vulnerable to second injury, and in long-term, leads to axonal degeneration and neuronal death. Therefore, preventing myelin loss or increasing myelin stability may be important in improving neuronal function after TBI. This proposal focuses on elucidating the molecular mechanisms underlying myelin loss in TBI and identifying molecular target(s) for development of interventions to improve myelin stability in adult brain following TBI.
