Traumatic brain injury (TBI) continues to be a growing health concern in the United States. Motor deficits represent one of the major impairments experienced by TBI patients and most will live with enduring physical disabilities. One of the major challenges of neurorehabilitation is to identify adjuvant therapies that can amplify the impact of motor rehabilitation by harnessing key neural signaling systems known to drive compensatory and restorative neural plasticity. The TrkB receptor has emerged as one of the key signaling systems orchestrating such plasticity. Modulating this system, however, has proven difficult due to a lack of a selective TrkB agonist that can be easily delivered to the brain. A recently discovered compound, LM22A-4, has been shown to selectively activate the TrkB receptor and readily cross the blood brain barrier. The proposed experiments will take advantage of this novel compound to test the hypothesis that LM22A-4 enhances rehabilitation-dependent motor recovery and motor cortex plasticity after TBI. The effect of daily LM22A-4 treatment on forelimb motor function and the topography of forelimb movement representations will be studies using a well established rodent model of TBI. To further determine the role of TrkB receptor signaling in rehabilitation-dependent motor recovery and cortical plasticity, we will chronically disrupt TrkB signaling in both LM22A-4 and vehicle treated animals. Intracortical microstimulation will be used to derive motor maps of the forelimb contralateral to the lesion. Quantitative immunoblotting will be used to confirm changes in TrkB receptor phosphorylation and expression of downstream signaling proteins. We hypothesize that disrupting TrkB signaling will prevent enhanced motor recovery and motor map reorganization in LM22A-4 treated animals. The results have the potential to guide the development of novel therapies to enhance the quality of life in TBI patients.
|Effective start/end date||4/1/15 → 3/31/18|
- HHS: National Institutes of Health (NIH): $410,644.00