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 galanin administration 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 student intern Sophie Schlosser tested GAL-tg and WT mice on an attentional task, the five choice serial reaction time task. Normal abilities on simple and complex components of this attentional task support an interpretation that the cognitive deficits of GAL-tg are not caused by an attentional artifact. This year we completed the first full behavioral phenotyping characterization of a new galanin receptor GAL-R1 knockout mouse, generated by Tiina Iismaa and coworkers at the Garvan Medical Research Institute in Sydney, Australia. Postdoctoral fellows Andrew Holmes, Craige Wrenn, Jeff Kinney, and student interns Eric Gold and Sophie Schlosser completed a series of phenotyping studies on cognitive and emotional behaviors in the GAL-R1 null mutants, heterozygotes, and their wild type control littermates (WT). Controls experiments on measures of general health, neurological reflexes, vision, olfaction, nociception, feeding, and motor functions showed that GAL-R1 mutants were not significantly different from WT. Performance on the Morris water maze, social transmission of food preference, and cued and contextual fear conditioning was generally normal in the GAL-R1. These results support an interpretation that the GAL-R1 receptor is not critical for cognitive functions in mice. It remains possible that other neurotransmitters or receptors may compensate for the missing GAL-R1 receptor during development. Biochemical studies conducted by Dr. Craige Wrenn in the laboratory of our extramural collaborator Dr. Gary Wenk found normal levels of galanin peptide and choline acetyltransferase activity. The fact that GAL-R1 null mutants show normal performance on learning and memory tasks will enhance the use of this mutant line to uncover the role of other galanin receptor subtypes. Development of a therapeutic compound to treat the memory deficits in Alzheimer's disease may be advanced by knowledge of the galanin receptor subtype mediating the cogntive deficits seen in animal models of galanin overexpression. Dr. Holmes and student intern Eric Gold analyzed the GAL-R1 on anxiety-related tasks. Increased anxiety-like behaviors were detected in the elevated plus maze but not in the light/dark transitions or emergence test. Analysis of stress hormones revealed that the elevated plus maze was considerably more stressful than the other anxiety-related tests in these mice. Our data indicate that galanin exerts anxiolytic-like actions through the GAL-R1 receptor subtype, primarily under conditions of higher stress. Our collaborator Zsuzsanna Wiesenfeld-Hallin and her students completed the first characterization of GAL-tg and GAL-R1 mice on spinal cord reflexes associated with pain, along with our studies in simple tests of hot place and tail flick analgesia. Results show that only the more extreme models of neuropathic pain are influenced by overexpressed galanin or lack of the GAL-R1 receptor subtype. Central administration of galanin and peptidergic galanin receptor antagonists is ongoing. The first experiments were designed to determine whether intraventricular galanin impairs performance on learning and memory tasks in mice, similar to its actions in rats. Postbaccalaureate Jennifer Dreiling, technician Tim Sullivan, and Dr. Wrenn microinjected doses of galanin or vehicle into the lateral ventricle of stereotaxically cannulated male C57BL/6J mice, immediately before cognitive testing. Performance deficits were detected on components of both the Morris water maze spatial learning task and the fear conditioning emotional task, analogous to previous findings in rats administered intraventricular galanin, and in galanin overexpressing transgenic mice. This finding supports a more global interpretation of galanin as a neuropeptide that impairs cognitive abilities.
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