DOES TRAINING INFLUENCE CORTICAL REMODELING AFTER TBI?

Traumatic brain injury (TBI) is characterized by axonal damage in regions near to the injury and often results in differential expansion/disorganization of intracortical projections as well as axonal and dendritic changes. These structural changes evolve over time. It is accepted that cortical architecture changes after lesions or deprivation in adults, and that the modifications correlate with activity, although only a few reports of clear-cut expansions or reductions in cortical architecture are available. The relationship of these changes to functional activities has not been precisely demonstrated, but is essential to understand in order to maximize approaches to neurorehabilitation. In addition, the role of training in influencing the extent and distribution of cortical changes after a lesion, specifically TBI, is not known. Finally, it is also not known whether architectural changes after training are specific to the modality used.On another level, advanced imaging techniques are essential to diagnosing features of TBI, but current methods cannot distinguish between different features of structural changes. We developed a method of quantifying changes in architecture after TBI, which can be compared with advanced Magnetic Resonance Imaging (MRI) techniques to validate enhancements of MRI. This ability will provide an important tool that can be easily used to evaluate the structural changes realized with training and quickly translated for use in the clinic. In addition, observations that specific behaviors alter underlying structure will be highly useful to human rehabilitation.Hypothesis: After TBI, training induces intracortical structural changes that correlate with modality involved and with functionally related modalities.Specific Aim 1. Do lesions in different cortical locations result in region specific architectural changes?We know from our preliminary studies that changes in intracortical connections and architecture occur after mild TBI. Our preliminary results indicate that lesions in different regions of the brain (i.e. sensory vs motor) result in distinct patterns of structural reorganization. We will use lesions in sensory (barrel) and motor cortex according to coordinates established previously. At varying time points post TBI, injections of fluorescent tracers will be made into different layers of the cerebral cortex in order to evaluate intracortical changes in each lamina. We predict that each lesion will result in structural changes specific to the region targeted.Specific Aim 2. . How does training affect the pattern of longitudinal changes in intracortical connectivity after TBI? Can training in an unmatched modality affect the architecture in the injured brain region? How does the timing of training affect changes in architecture after TBI?Our early findings suggest that animals undergoing training show architectural changes that differ in comparison with those that receive no training. We pose the questions - will training using one modality specifically influence structural changes in the cortical representation specific to that modality? Does training initiated at different times influence structural changes? Does exercise alone alter intrinsic architecture? In this set of experiments, mice will undergo training that either does - or does not - correspond with the lesion site (e.g., somatosensory training after a motor cortex lesion and vice versa). We predict that training will produce structural alterations specific to the region trained and to the related cortical area.Specific Aim 3. Do observed changes in intracortical architecture correspond to modifications in MRI/DTI imaging?This aim will investigate TBI damage in the mouse combined with quantitative advanced MRI techniques and histopathology methods. We propose to identify reliable and specific imaging biomarkers of mTBI that can be translated into tools for clinical assessment. We will develop quantitative MRI measures to investigate the natural evolution of TBI injuries. Each brain will be subjected to injections of fluorescent tracers followed by MRI to allow comparison of known structure with MRI.This importance of this project to TBI research is two-fold. (i) We will expand our knowledge regarding the effects of training and exercise on precise cortical areas and their relation to functional changes. This result is highly translatable to the field of rehabilitation as the information we gain can be quickly and easily used in the clinic. (ii) Quantification of conventional MRI techniques is a necessary step to assure biological specificity of this method; validation in animal models is essential to fully understand the biological underpinnings of the MRI changes. These findings will also be very important to correlate with our structural analysis and easy to move into neurorehabilitation.