Although cognitive dysfunction is one of the most debilitating sequela of traumatic brain injury, current treatments are limited in scope due to the lack of clearly understood mechanisms involved in the pathophysiology of traumatic brain injury. Such injury in young adults has been shown to induce delayed neurobehavioral sequelae, which may not become fully manifest until senescence. Clinically, age related cognitive deficits have been shown to be exacerbated following brain injury. In addition, development of neurodegenerative disorders appears to be more prevalent following brain trauma. Recent evidence suggests that much of the pathophysiological sequelae of traumatic brain injury may be due to alterations in endogenous neurochemical processes, including a marked release of excitatory amino acid transmitters which become toxic at high concentrations. The hippocampus, thought to be integrally involved in spatial learning and memory, and which is rich in excitatory amino acid receptors, has been shown to be selectively vulnerable to damage following experimental brain injury. Using a model of fluid percussion brain injury in the rat, the applicants found a correlation between the severity of post traumatic cognitive dysfunction and the extent of selective loss of neurons in the hippocampus. In addition, they have demonstrated that excitatory amino acid receptor antagonists may attenuate post traumatic memory dysfunction and spare hippocampal and neuronal loss. However, little is known about the long-term histopathology of brain injury or of the efficacy of excitatory amino acid antagonists to improve long-term functional outcome. Also, little is known about the role that brain injury may play in the development of age related cognitive dysfunction and/or neurodegenerative disorders, and no current therapies are available that may augment post traumatic cognitive ability.
The specific aims of the present proposal are, 1) to characterize the effects of experimental brain injury in young adult rats on the development of cognitive dysfunction and histopathology through senescence. The applicants will accomplish this using Morris water maze testing to determine cognitive status of brain injured animals, and by examining the brains of these animals for neuronal cell loss, neuronal degeneration, blood brain barrier breakdown, microtubule associated protein (MAP2) loss and beta-amyloid 4 disposition, which is observed in Alzheimer's disease. 2) To evaluate the differences in cognitive and histopathologic outcome between young and old animals shortly following brain injury. Positive results from these studies may lead to novel approaches for acute and chronic management of post traumatic cognitive dysfunction. 3) To evaluate the long-term efficacy of selective excitatory amino acid antagonists and excitatory amino acid antagonist release inhibitors to attenuate post traumatic neuronal damage and cognitive dysfunction. 4) To evaluate the therapeutic efficacy of cognition enhancers on persisting post traumatic cognitive dysfunction in young and aging rats.
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