Traumatic brain injury (TBI) occurs to US citizens at the rate of 500,000 cases/yr., with 50,000 deaths and 50,000 survivors with severe residual deficits. Learning and memory are commonly impaired after TBI in humans. These higher cognitive functions play a key role i the successful recovery and rehabilitation from TBI. In humans, the ventral forebrain cholinergic neurons appear to play a significant role in memory, as suggested by the pathophysiology of Alzheimer's Disease. In a similar wy, the pathophysiology of the memory and learning deficits following TBI may be caused by damage to these neurons. There are three specific aims; 1. Characterization of noncholinergic ventrobasal forebrain neuron response to TBI; 2. Further characterization of cholinergic ventrobasal forebrain neuron response to TBI; and 3. Mechanisms of repair and recovery after TBI.
These specific aims are focused towards addressing the central hypothesis: TBI causes quantifiable neuronal damage in populations known to be involved in learning and memory. The first specific aim is formulated to answer the hypothesis that noncholinergic neurons in the ventral forebrain region may respond differently than cholinergic neurons to experimental TBI. The second specific aim is targeted towards answering two hypotheses; 1) Experimental TBI causes a loss of acetyl choline in the terminal projection fields of the septal neurons; and 2) Experimental TBI causes a permanent loss of septal neurons. The third specific aim addresses two hypotheses: 1) The extent of cholinergic neuron damage and subsequent degree of recovery in dependent on age of the experimental subject; and 2) neuron protection drugs (21 amino steroids) are capable of modifying the response to experimental TBI and may give some indirect insight into the molecular mechanisms underlying this particular group of neurons susceptibility to injury. TBI is modelled by using the well described rodent fluid percussion injury system. Techniques include use of quantitative immunocytochemistry of specific neuron populations and histochemistry and neurochemistry of cholinergic neurotransmitters. Memory capability is determined using the water maze. Overall, the methodology has a long and accepted record in the study of cholinergic neuron populations. These techniques have created a better pathophysiologic description of neurodegenerative disorders and can be directly applied to the study of the pathophysiology of head injury. The result of the proposed experiments should be a better description of the pathophysiologic mechanisms in head injury, as well s suggesting a rational basis for treatment.
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| Carbonell, W S; Maris, D O; McCall, T et al. (1998) Adaptation of the fluid percussion injury model to the mouse. J Neurotrauma 15:217-29 |
