Our laboratory is engaged in investigating the behavioral concomitants of the inhibitory effects of galanin. 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 adenylate cyclase signal transduction. Galanin is overexpressed in the basal forebrain in Alzheimers disease. Our past experiments revealed that central microinjection of galanin in rats impairs performance on several learning and memory tasks. We discovered that galanin overexpressing transgenic mice (GAL-tg) display analogous deficits on learning and memory tasks including the Morris water maze spatial learning probe trial, olfactory memory in social transmission of food preference, and trace cued fear conditioning, when compared to WT littermate controls. GAL-tg mice represent a mouse model of galanin overexpression in Alzheimers disease, which can be used as a translational tool to test hypotheses and generate novel therapeutics for treating the memory loss that characterizes Alzheimers disease.? ? Postdoctoral fellow Kathleen Bailey has now completed the first full behavioral phenotyping characterization of a new galanin subtype receptor GAL-R2 knockout mouse. GAL-R2 null mutants were normal on control measures of general health, home cage behaviors, neurological reflexes, sensory abilities, motor functions, social approach, trace fear conditioning, and spatial navigation in the Morris water maze. Dr. Bailey confirmed and extended an initial finding that GAL-R2 displays an anxiogenic-like phenotype specific to the elevated plus maze. Phenotypes on other measures of stress and anxiety-like traits, including stress-induced hyperthermia and light/dark exploration, were similar across gentoypes, indicating a highly selective anxiety-like effect of the GAL-R2 mutation in the elevated plus maze. Dr. Baileys findings support the emerging evidence that galanin is an inhibitory neuromodulator with anxiolytic actions in specific conflict situations.? ? This year Dr. Bailey generated a double knockout line with mutations in both the GAL-R1 and GAL-R2 receptor subtypes. Because the GAL-R1 and GAL-R2 subtypes have similar neuroantaomical distributions, it is possible that one can compensate for the loss of the other. Eliminating both subtypes may unmask stronger behavioral phenotypes than single subtype mutations. Breeding is ongoing to generate the large number of -/-/-/- and +/+/+/+ control mice needed for behavioral analyses. Initial findings indicate normal scores on control measures of general health, home cage behaviors, neurological reflexes, sensory abilities, and motor functions in the double knockouts. Full characterization of cognitive and anxiety-related traits is in progress.? ? Oxytocin knockout mice were characterized on social behaviors and control measures of general health, home cage behaviors, neurological reflexes, sensory abilities, and motor functions. Normal phenotypes were detected for all genotypes on these control measures. Social approach behaviors are described in Project Z01 MH002179-21 SBG, Animal Models of Neuropsychiatric Disorders.? ? Vasopressin receptor 1b knockout mice were characterized on social behaviors and control measures of general health, home cage behaviors, neurological reflexes, sensory abilities, and motor functions. Normal phenotypes were detected for all genotypes on these control measures. Social approach behaviors are described in Project Z01 MH002179-21 SBG, Animal Models of Neuropsychiatric Disorders.
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