BEHAVIORAL FUNCTIONS OF NEUROPEPTIDES

神经肽甘丙肽与乙酰胆碱共存于大鼠隔海马通路，与学习和记忆有关，并在阿尔茨海默病的基底前脑中过表达。我们发现，甘丙肽管理大鼠损害性能的几个记忆任务。去年，博士后研究员Mike McDonald证明了甘丙肽受体拮抗剂M40增强了M-1毒蕈碱激动剂TZTP在患有192-IgG皂草素胆碱能损伤的大鼠中对延迟不匹配位置的有益作用。这些发现支持内源性甘丙肽在调节记忆过程所需的胆碱能通路中的抑制性调节作用，并表明甘丙肽拮抗剂可能是现有胆碱能疗法治疗阿尔茨海默氏痴呆症的有用辅助疗法。出版物：McDonald，Willard，Wenk，Crawley，甘丙肽拮抗剂M40与毒蕈碱M1激动剂的联合给药改善了具有胆碱能损伤的大鼠的延迟不匹配位置。神经科学杂志18：5-78-5085，1998年。博士后研究员特里·格里森去年设立了莫里斯水任务，以测试甘丙肽在这个广泛使用的记忆测试中的作用。脑室注射甘丙肽诱导的性能缺陷的潜伏期，以找到隐藏的平台在训练试验，并在选择性象限搜索在探测试验。检测到显着的遗传成分甘丙肽的反应。Wistar和Sprague-Dawley品系对甘丙肽的抑制作用敏感，而Long-Evans品系在这项任务中不受甘丙肽治疗的影响。在可见平台任务和Digiscan探索性运动中的表现在甘丙肽剂量下是正常的，这损害了Morris水任务的获得。出版物：Gleason，Dreiling和Crawley，Morris水任务中对甘丙肽反应的大鼠品系差异。神经肽，出版中，1999年。今年我们的甘丙肽研究计划获得了一个新的研究工具。甘丙肽过表达转基因小鼠由华盛顿大学西雅图的Robert Steiner和同事产生，并回交7代进入C57 BL/6 J背景用于我们的行为实验。博士后研究员Andrew Holmes和几名学生志愿者对甘丙肽转基因小鼠及其野生型对照同窝仔进行了首次行为表型分析。一般健康状况、笼舍行为、神经反射和运动功能正常。在第一批试点研究中，主要是在男性转基因动物中发现了几项记忆任务的表现受损。实验采用额外的记忆任务，行为测试解决领域的喂养，镇痛，焦虑，现在正在进行中。- 神经肽行为甘丙肽乙酰胆碱记忆阿尔茨海默病

The neuropeptide galanin coexists with acetylcholine in the rat septohippocampal pathway, relevant to learning and memory, and is overexpressed in the basal forebrain in Alzheimers disease. We discovered that galanin administration to rats impairs performance on several memory tasks. Last year, postdoctoral fellow Mike McDonald demonstrated that the galanin receptor antagonist, M40, potentiated the beneficial actions of an M-1 muscarinic agonist, TZTP, in rats with 192-IgG saporin cholinergic lesions, on delayed nonmatching to position. These findings support an inhibitory modulatory role for endogenous galanin in modulating cholinergic pathways necessary for memory processes, and indicate that galanin antagonists may be a useful adjunct therapy to existing cholinergic therapies for treating Alzheimers dementia. PUBLICATION: McDonald, Willard, Wenk, Crawley, Coadministration of a galanin antagonist M40 with a muscarinic M1 agonist improved delayed nonmatching to position in rats with choinergic lesions. Journal of Neuroscience 18: 5-78-5085, 1998.Postdoctoral fellow Terri Gleason set up the Morris water task last year, to test the actions of galanin in this widely used memory test. Intraventricularly administered galanin induced performance deficits on latency to find the hidden platform over training trials, and on selective quadrant search during the probe trial. Significant genetic components were detected in responsiveness to galanin. The Wistar and Sprague-Dawley strains were sensitive to the inhibitory actions of galanin, as compared to the Long-Evans strain which was unaffected by galanin treatment in this task. Performance on the visible platform task and in Digiscan exploratory locomotion was normal at doses of galanin which impaired acquisition of the Morris water task. PUBLICATION: Gleason, Dreiling and Crawley, Rat strain differences in response to galanin on the Morris water task. Neuropeptides, in press, 1999.This year our galanin research program received a new research tool. Galanin overexpressing transgenic mice were generated by Robert Steiner and coworkers at the University of Washington, Seattle, and backcrossed for 7 generations into a C57BL/6J background for our behavioral experiments. Postdoctoral fellow Andrew Holmes and several student volunteers conducting the first behavioral phenotyping on galanin transgenic mice and their wild type control littermates. General health, home cage behaviors, neurological reflexes, and motor functions were normal. Impaired performance on several memory tasks was detected in the first pilot studies, primarily in the male transgenics. Experiments employing additional memory tasks, behavioral tests addressing the domains of feeding, analgesia, and anxiety, are now ongoing. - neuropeptides behavior galanin acetylcholine memory Alzheimer's disease