Neurological deficits, especially memory dysfunctions, are one of the most prominent and persistent consequences of traumatic brain injury (TBI) in humans. While considerable effort has been made to define the acute pathobiologic mechanisms that induce neurological deficits such as memory, little effort has been made to examine mechanisms mediating the maintenance of enduring neurological disturbances and recovery from these disturbances following TBI. The overall objective of this project is to investigate long-term changes in cholinergic neurotransmission within the hippocampus and to relate these changes to the recovery of spatial memory deficits following TBI. We will initially determine the time course of recovery from spatial memory deficits that are (1) """"""""overt"""""""": detectable by routine behavioral assessments, or (2) """"""""covert"""""""": undetectable in the absence of secondary pharmacological challenges such as anticholinergics in order to define the time points employed in the subsequent neuropharmacological studies. At each phase of recovery we will determine the nature of the damage to the cholinergic system in the hippocampus. Using biochemical, pharmacological and immunohistochemical techniques, we will determine if the deficiency in cholinergic function results from loss of cholinergic terminals innervating the hippocampus or from a more restricted impairment of cholinergic neurotransmission. Changes in cholinergic properties will be assessed by measuring levels of choline acetyltransferase, the capacity to synthesize and release acetylcholine, and the levels and binding characteristics of muscarinic receptors. By monitoring these features at various times following TBI, we will correlate cholinergic deficiencies with behaviorally assessed memory disability. Substantial evidence suggests that TBI produces a relatively brief period of excessive excitation of specific receptor subtypes that exceeds normal physiological limits during which moderate hypothermia can reduce injury and improve outcome. Following the acute stage of neural injury, a chronic state of hypoexcitability and neurotransmission deficiency may persist during which specific neurotransmitter agonists may be useful in improving outcome. We will determine whether acute therapy with moderate hypothermia (30oC) or chronic increases in cholinergic tone produced by administration of a cholinesterase inhibitor tetrahydroamnoacridine (THA) will attenuate behavioral and neurochemical deficits in cholinergic neurotransmission in the hippocampus.
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