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.

神经肽葡萄蛋白位于海马，与乙酰胆碱在大鼠septohappocampal途径中共存，与不能脱甲肾上腺素共存，并抑制谷氨酸，乙酰胆碱和非甲肾上腺素的释放。加拉宁在阿尔茨海默氏病的基础前脑中过表达。我们的实验室正在研究Galanin抑制作用的行为同伴。我们过去的实验表明，加拉宁对大鼠的管理会损害几项学习和记忆任务的表现。去年，我们的Galanin研究计划集中于Galanin过表达转基因小鼠的行为表型，由Robert Steiner和西雅图华盛顿大学的同事生产，以及由Tiina IISMAA和同事在澳大利亚Sydney的Garvan Medical Research Institute的Tiina IISMAA和同事产生的新的Galanin受体Gal-R1敲除鼠标。 博士后研究员安德鲁·霍尔姆斯（Andrew Holmes），克雷格·沃恩（Craige Wrenn），杰夫·金尼（Jeff Kinney）和几位学生志愿者完成了一系列关于GAL-TG中认知和情感行为的表型研究，以及对Gal-R1 Null突变体，Heterozygotes，Heteryzygotes和他们的野生型控制型littermate（WT）的第一种行为表型。 GAL-TG在莫里斯水迷宫探针试验中表现出性能缺陷，与WT同窝型对照组相比，在食物偏好的社交传播中，嗅觉记忆和痕量恐惧条件。博士。福尔摩斯（Holmes），Wrenn和Kinney在两只小鼠中复制了这些发现。控制视力，嗅觉，伤害感受，喂养和运动功能的测量的实验表明，GAL-TG与WT没有显着差异，从而避免了对认知缺陷的潜在人为解释。开始了初步研究，以测试中央施用的Galanin拮抗剂挽救GAL-TG中记忆缺陷的能力。 我们的发现表明，更具挑战性的记忆任务对小鼠的Galanin过表达更为敏感。这些结果与当前的理论一致，即神经肽是在高神经元放电条件下释放的神经调节剂，这些神经调节剂将高度选择性的信息传达给突触后神经元。加拉宁过表达小鼠的认知缺陷可能与galanin过表达的患者患有阿尔茨海默氏病的患者的认知缺陷有关。这个翻译项目将继续评估啮齿动物中的Galanin受体拮抗剂，因为它们能够减轻阿尔茨海默氏症患者Galanin过表达可能引起的记忆丧失的能力。 福尔摩斯博士进一步分析了与人类焦虑有关的任务中GAL-TG系的行为表型。在高架的迷宫，浅色/黑暗探索，开放场中心时间或开放场运动的基线得分中未检测到基因型差异。 GAL-TG在光/黑暗探索中显示出对苯二氮卓的预期抗焦虑反应。然而，Gal-TG未能显示出对Yohimbine的焦虑反应，表明仅在高应激条件下，多余的甘氨酸的抗焦虑作用。 GAL-R1无效突变体和杂合子表现出正常的一般健康，家居笼子行为，神经反射和运动功能。在两只独立的小鼠中，已经检测到了几种学习和记忆任务的不可预测的障碍。一种假设是，当GAL-R1受体突变时，甘氨酸肽水平升高。 Wrenn博士与亚利桑那大学的Gary Wenk教授合作进行了放射免疫测定法，以检验这一假设。初始数据不支持此解释。 Gal-R1受体在认知过程中的作用正在进一步探索药理学挑战。霍姆斯博士还在分析与焦虑有关的任务的GAL-R1。 加拉宁在静脉内对大鼠进行静脉内治疗会损害获取和工作记忆。 Kinney博士完成了一系列实验，以测试Galanin是否还会损害记忆巩固。 5分钟前，1分钟，30分钟，3小时后，在莫里斯水上的每日培训课程后，对加拉宁进行了微注射。探针试验的性能缺陷在训练前后的时间点相同，直至构成整合期的3小时时间点。在整合完成后，在18小时的时间点未检测到性能缺陷。用腺苷酸环化酶激活剂福斯科蛋白预处理可阻止加拉蛋白诱导的抑制作用，这表明通过cAMP突触后的细胞内信号传导级联反应机制。