Cholinergic function has long been associated with memory and learning. This association is aptly illustrated during aging where declines in cholinergic function are thought o underlie in part deficits in the ability to learn and remember. Cholinergic receptors are likely to be involved in the transduction of information during the processes of memory and learning and subtypes of both muscarinic and nicotinic cholinergic receptors have been described ar the molecular level. We have been described at the molecular level. We have produced or obtained antibodies specifically directed toward each of the subtypes of these receptors. Using these reagents, we can quantify each receptor in brain, which expresses multiple subtypes of both muscarinic and nicotinic receptors. We will utilize these antibodies in aged animals that have been behaviorally tested for their ability to learn and remember to try to determine specifically which receptors are associated with a decline in these functions. Additionally, we will attempt to answer the question of which receptor subtypes are located presynaptically on cholinergic terminals of septal-hippocampal neurons.
The specific aims are: 1. To examine the hypothesis that in aged rats the observed differences from rat to rat in the ability to learn is mirrored by a loss of a specific subtype(s) of muscarinic and/or nicotinic cholinergic receptor in the hippocampus or cerebral cortex. To do this, we will examine the density of each of the subtypes of receptor in young, middle aged, and aged rats which have been tested behaviorally to determine which receptor changes correlate with the loss of the ability to learn that occurs in a proportion of the aged population. 2. To examine the hypothesis that specific subtypes of muscarinic and nicotinic receptors are associated with cholinergic neurons originating in the medial septum and terminating in the hippocampus. Thus, we will determine the effects of fimbria-fornix transection on receptor subtypes in the septum and hippocampus. If a given subtype is mainly presynaptic we should see a decrease in its density. Additionally, we will examine in the septum the cellular localization of choline acetyltransferase and the MRNA encoding each of the subtypes of cholinergic receptors using immunocytochemistry and in situ hybridization, respectively. 3. To employ immunohistochemical methods to visualize and localize each of the subtypes of muscarinic and nicotinic receptors in rat brain. This methodology will be utilized to examine the affects of aging and fimbria-fornix lesions on cholinergic receptor subtypes.
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