USING NEURAL STEM/PROGENITOR CELLS TO REPAIR SIMPLE NEURAL CIRCUITS AFTER TBI

One of the clear pathologies that occur after mild to moderate TBI during warfare is a diffuse form of damage to axons entering and leaving the cerebral cortex. Although this is a clear pathology, relatively little is known about the underlying structural and functional effects. The proposed studies will allow us to understand the precise type of axonal injuries that occur after TBI, to follow the course of the injuries over time, to understand potential underlying mechanisms, and to assess the possibility of mechanistic treatments to repair the damage. We will also relate the damage induced after injury to functional and behavioral responses. Although a few studies have addressed the effect of TBI on barrel cortex, no study has defined the axonal damage or attempted to assess the underlying fundamental changes that occur in response to the injury. We propose barrel cortex as an excellent model to study neocortical plasticity in that both the function and architecture is well characterized, including the axonal projections to and within a given barrel and the activity evoked in response to whisker stimulation. We also know that substantial plasticity occurs in adult barrel cortex, primarily evaluated in response to altered input from the whiskers. This adult plasticity primarily occurs in the upper layers of the neocortex, in contrast to the changes that occur during the critical period of development, which predominantly affects layer 4.We will therefore use a model of plasticity in conjunction with TBI, which is often used to assess changes in barrel cortex: alteration of sensory input from a set of whiskers. This will allow us to assess the ability of barrel cortex to display plastic changes with and without accompanying TBI. In order to increase the possibility of obtaining an increase in response and plastic changes, we will also use a reward in conjunction with stimulation. Many of the changes associated with adult plasticity indicate alterations in the balance of excitation and inhibition; several studies of underlying mechanism suggest that increased ability for plastic changes occurs with increased excitability and reduced GABAergic inhibition, although mixed effects are also possible. We will assess functional changes and use transgenic animals that display fluorescence in response to excitation (the Arc transgenic mice) or inhibition (GAD transgenic mice). We will also work in close conjunction with Dr. Galdzicki, whose project proposed in the Neuroplasticity Group will specifically assess underlying alterations in excitation and inhibition after TBI.