Behavioral Functions of Neuropeptides

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The neuropeptide galanin is localized in the hippocampus, coexists with acetylcholine in the rat septohippocampal pathway, coexists with norepinephrine in the locus coeruleus, inhibits the release of glutamate, acetylcholine, serotonin, and norepinephrine, and inhibits evoked adeylate cyclase signal transduction. Galanin is overexpressed in the basal forebrain in Alzheimer's disease. Our laboratory is engaged in investigating the behavioral concomittants of the inhibitory effects of galanin. Our past experiments revealed that central microinjection of galanin to rats impairs performance on several learning and memory tasks. We discovered that galanin overexpressing transgenic mice display analogous deficits on learning and memory tasks including the Morris water maze probe trial, on olfactory memory in social transmission of food preference, and on trace cued fear conditioning, when compared to WT littermate controls. This year, Dr. Craige Wrenn and collaborator Dr. Janita Turchi completed testing GAL-tg and WT mice on an attentional task, the five choice serial reaction time task, and associated challenges. Normal abilities on simple and complex components of this attentional task were revealed. These results support an interpretation that the cognitive deficits of GAL-tg are not caused by an underlying attentional dysfunction, but in fact are specific to learning and memory. Last year we completed the first full behavioral phenotyping characterization of a new galanin receptor GAL-R1 knockout mouse. This year we employed these GAL-R1 null mutant mice to address the question of which galanin receptor subtype mediates the inhibitory actions of pharmacologically administered galanin. Graduate student Rose-Marie Karlsson, with training by Dr. Craige Wrenn and Tim Sullivan, administered doses of galanin intraventricularly to work out dose-response curves in mice. Dr. Craige Wrenn, Tim Sullivan, and Howard Hughes student intern Dejaimenay Stephenson microinjected galanin into the lateral ventricles of cannulated mice of the GAL-R1 null mutant and wildtype littermate genotypes. Galanin produced the expected impairments in fear conditioning. GAL-R1 knockout mice did not display galanin-induced deficits on this emotional memory task. The GAL-R1 receptor appears to be at least one subtype through which galanin acts to reduce fear-associated learning and memory. This finding will inform the choice of galanin receptor ligands for future testing as potential therapeutics for treating memory deficits in Alzheimer's disesae. New postdoctoral fellow Nate Rustay began an investigation into the ability of a galanin receptor antagonist, M40, to improve memory in galanin overexpressing transgenic mice. Dr. Rustay is presently generating dose response curves for M40 administered into the lateral ventricles of mice. These experiments are designed to test the hypothesis that blocking the inhibitory actions of excess endogenous galanin will improve performance on memory tasks in mice.uropeptide that impairs cognitive abilities.