Neural circuit disruption by diffuse brain injury: basis for morbidity & therapy

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DESCRIPTION (provided by applicant): Our long term goals are to develop effective pharmacological and rehabilitative treatment strategies that promote adaptive reorganization of brain-injured circuits to mitigate neurological dysfunction (morbidity) after diffuse traumatic brain injury (TBI). To achieve these goals, we will exploit a novel, reproducible, late-onset neurological deficit that we have observed in the diffuse brain-injured rat, analogous to agitation in brain injury survivors. In contrast to the soothing and pacifying nature of facial whisker stimulation in uninjured rats, brain- injured rats react to whisker stimulation by cowering, freezing and guarding the mystacial pads. This aberrant behavior is concomitant with axonal damage, neuronal atrophy, persistent inflammation and neuroplasticity, such that whisker stimulation activates brain regions outside the conventional somatosensory whisker circuit. The current proposal tests the hypothesis that diffuse brain injury-induced inflammation drives the maladaptive structural plasticity responsible for aberrant behavioral responses to whisker stimulation. The model system afforded by the brain-injured somatosensory whisker circuit provides a reductionistic approach to the complexity of diffuse TBI, to address pathological and reparative mechanisms associated with post-traumatic morbidity. This circuit in diffuse brain-injured adult male rats will be evaluated for (Aim 1) aberrant behaviors elicited by whisker stimulation, (Aim 2) chronic neuropathology, neuronal activation and circuit reorganization, and (Aim 3) neuroinflammation-driven neuroplastic responses that contribute to circuit reorganization and morbidity. An anti-inflammatory therapeutic regimen may provide a clinically relevant intervention to prevent circuit rewiring and the onset of morbidity. The innovative combination of behavioral, anatomical, functional and therapeutic approaches directed at the brain-injured somatosensory whisker circuit addresses the underlying mechanisms associated with unregulated structural plasticity in the injured brain. Uncovering these processes can direct treatments to mitigate the onset, reduce the duration and/or promote the resolution of neurological dysfunction. Results from this circuit can ultimately be expanded to other circuits in rodents and then man to improve quality of life for millions of TBI survivors and potentially others suffering from progressive neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: The present proposal focuses on the persistent morbidity experienced by diffuse brain injury survivors, for whom treatment options are limited. In diffuse brain-injured rats, aberrant responses to whisker stimulation will be employed as a tool to identify pathological and reparative mechanisms associated with somatosensory whisker circuit disruption. By developing, validating and implementing an animal model of one discrete post-traumatic morbidity, significant advancements can be made towards reshaping first one, then other, brain- injured circuits in rodents and man.