Somatosensory Circut Disruption and Rehabilitation after Diffuse Brain Injury

An overwhelming majority of traumatic brain injuries (TBI) are mild and diffuse in nature. These nonfatal injuries preclude immediate post-mortem analysis and conventional imaging routinely fails to detect abnormalities despite neurological dysfunction. Experimental models have identified acute molecular pathways involved in post-traumatic degeneration, but over time the multi-focal sites of pathology become obscured amongst healthy tissue. Recent observations have identified injury-induced chronic neuronal atrophy in the thalamic relay for whisker somatosensation, which likely contributes to the robust, aberrant behavioral responses to whisker stimulation. For the first time, these functional deficits and structural alterations provide an anatomical focus for the analysis of post-traumatic synaptic deafferentation and reinnervation. Clusters of high density glutamatergic synapses make the somatosensory whisker-barrel circuit vulnerable to excitotoxic processes, and optimal for recording extracellular glutamate dynamics (1 ms time resolution). Within the injured circuit, enzyme-based multisite microelectrodes can measure extracellular glutamate on a second-bysecond basis to provide a neurochemical profile for the cyto-architecture of the microenvironment at the electrode. Therefore, the hypothesis emerges that injury-induced changes in the neurochemical profile of the somatosensory whisker-barrel circuit reflect synaptic deafferentation and circuit restructuring responsible for post-traumatic morbidity. In diffuse brain-injured rats, Aim 1 is to chart the basal, evoked and modulated neurochemical profile in the brain-injured somatosensory thalamus and cortex using in vivo electrochemistry. Aim 2 is to monitor extracellular glutamate during active and passive whisker stimulation after diffuse brain injury. These studies will circumvent a major impediment to understanding diffuse pathology postinjury: the identification of circuits undergoing cyto-architectural rearrangement after the acute pathology subsides. Experiments will quantify functional impairments and structural alterations in discrete regions along the circuit. By uncovering some of the degenerative and reparative mechanisms responsible for circuit disruption, rational therapeutic interventions may be possible to mitigate post-traumatic neurological dysfunction, improving quality of life for millions of TBI survivors.