Behavioral Functions Of Neuropeptides

神经肽的行为功能

• 批准号: 6671539
• 负责人: Jacqueline N Crawley
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6671539
• 关键词: acetylcholine; behavioral genetics; central neural pathway /tract; dementia; disease /disorder model; dopamine; experimental brain lesion; galanin; genetically modified animals; immunoconjugates; laboratory mouse; laboratory rat; neurochemistry; neuropeptides; neuropharmacology; phenotype; psychomotor function

The neuropeptide galanin is localized in the hippocampus, coexists with acetylcholine in the rat septohippocampal pathway, coexists with norepinephrine in the locus coeruleus, and inhibits the release of glutamate, acetylcholine, and norepinephrine. 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. Last year, our galanin research program focused behavioral phenotyping of galanin overexpressing transgenic mice, generated by Robert Steiner and coworkers at the University of Washington in Seattle, and 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 several student volunteers completed a series of phenotyping studies on cognitive and emotional behaviors in the GAL-tg, and the first behavioral phenotyping on GAL-R1 null mutants, heterozygotes, and their wild type control littermates (WT). GAL-tg showed performance deficits on the Morris water maze probe trial, on olfactory memory in social transmission of food preference, and on trace fear conditioning, as compared to WT littermate controls. Drs. Holmes, Wrenn, and Kinney replicated these findings in two cohorts of mice. Controls experiments on measures of vision, olfaction, nociception, feeding, and motor functions showed that GAL-tg were not significantly different from WT, thus avoiding a potential artifactual interpretation of the cognitive deficits. Preliminary studies were initiated to test the ability of a centrally administered galanin antagonist to rescue the memory deficits in GAL-tg. Our findings indicate that more challenging memory tasks are more sensitive to galanin overexpression in mice. These results are consistent with the current theory that neuropeptides are neuromodulators released under conditions of high neuronal firing, that convey highly selective information to postsynaptic neurons. Cognitive deficits in galanin overexpressing mice may be relevant to cognitive deficits in galanin overexpressing patients suffering from Alzheimer's disease. This translational project will proceed to evaluate galanin receptor antagonists in rodents, for their ability to ameliorate memory loss that may be caused by galanin overexpression in Alzheimer's patients. Dr. Holmes further analyzed behavioral phenotypes of the GAL-tg line in tasks relevant to human anxiety. No genotype differences were detected in baseline scores on the elevated plus maze, light/dark exploration, open field center time, or open field locomotion. GAL-tg showed the expected anxiolytic response to a benzodiazepine on light/dark exploration. However, GAL-tg failed to show an anxiogenic response to yohimbine, indicating an anxiolytic action of excess galanin only under conditions of high stress. GAL-R1 null mutants and heterozygotes displayed normal general health, home cage behaviors, neurological reflexes, and motor functions. Unpredicted impairments on several learning and memory tasks have been detected in two independent groups of mice. One hypothesis is that galanin peptide levels increase when the GAL-R1 receptor is mutated. Radioimmunoassays were conducted by Dr. Wrenn, in collaboration with Professor Gary Wenk at the University of Arizona, to test this hypothesis. Initial data do not support this explanation. The role of the GAL-R1 receptor in cognitive processes is being further explored with pharmacological challenges. Dr. Holmes is also analyzing the GAL-R1 on anxiety-related tasks. Galanin administered intraventricularly to rats impairs acquisition and working memory. Dr. Kinney completed a series of experiments to test whether galanin also impairs memory consolidation. Galanin was microinjected 5 minutes before, 1 minute after, 30 minutes after, 3 hours after, and 18 hours after daily training sessions in the Morris water task. Performance deficits on the probe trial were identical at time time points before and after training, up to the 3 hour time point, which constitutes the consolidation period. No performance deficits were detected at the 18 hour time point, after consolidation is complete. Pretreatment with the adenylate cyclase activator forskolin prevented the galanin-induced inhibition, suggesting a mechanism through the cAMP postsynaptic intracellular signalling cascade.

甘丙肽定位于海马，与大鼠海马中隔通路的乙酰胆碱共存，与蓝斑处的去甲肾上腺素共存，抑制谷氨酸、乙酰胆碱和去甲肾上腺素的释放。丙氨酸在阿尔茨海默病的基底前脑过度表达。我们的实验室致力于研究丙氨酸抑制作用的行为伴随物。我们过去的实验表明，给大鼠服用甘丙肽会损害其在一些学习和记忆任务中的表现。去年，我们的甘丙肽研究项目聚焦于甘丙肽过表达转基因小鼠的行为表型，由西雅图华盛顿大学的Robert Steiner和他的同事培育，以及由澳大利亚悉尼Garvan医学研究所的Tiina Iismaa和他的同事培育的一种新的甘丙肽受体GAL-R1敲除小鼠。