Cholinergic, N-methyl-D-aspartate (NMDA) and possibly other agonist-receptor interactions could mediate long-term behavioral deficits and/or transient unconsciousness following mild and moderate levels of traumatic brain injury (TBI). These interactions may mediate transient unconsciousness and long-term deficits by quite different but concurrently occurring processes. The purpose of this grant is to examine the mechanisms mediating such processes. Activation of a muscarinic, cholinergic neural system in the rostral pons may contribute to components of transient behavioral suppression (i.e., unconsciousness) following TBI. Research would study the descending anatomy of this system in the cat by examining effects of lesions of descending pathways on sensory and motor electrophysiological correlates of unconsciousness. In contrast, TBI may also produce widespread, excessive release of acetylcholine and excitatory amino acids which bind to their respective receptors, thereby increasing excitatory influences on neurons already subjected to mechanical stresses. Abnormal excitatory could disturb brain information flow pathways resulting in changes in cell function (possibly related to excessive intracellular levels of Ca2+) that have measurable behavioral effects. Experiments have shown that blockade of muscarinic cholinergic or NMDA receptors can reduce some long-term deficits and combined doses of both drugs can reduce cell death following secondary ischemic insult. Research would examine the effects of experimental TBI in the rat on long-term behavioral deficits including performance in a spatial memory task subserved by a restricted (hippocampal) neural substrate. The behavioral effects of concussion would be systematically compared to indices of long- term synaptic modification in specific regions of the hippocampus. Indices of synaptic modification include: 1) scintillation and autoradiographic studies of receptor binding; 2) quantitative ultrastructural analyses of synaptic elements and 3) electrophysiological assessments of long-term potentiation (LTP). We will also perform quantitative autoradiographic assessments of regional cerebral blood flow and examine the effects of administration of muscarinic and NMDA receptor antagonists on each of these measures. Proposed research would supplement data from ongoing clinical studies of anticholinergic treatment of human head injury.
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