BEHAVIORAL FUNCTIONS OF NEUROPEPTIDES

神经肽甘丙肽与乙酰胆碱共存于大鼠中隔海马通路，与学习和记忆有关，并在阿尔茨海默病的基底前脑中过度表达。我们发现，给大鼠服用甘丙肽会损害其在多项记忆任务中的表现。去年，博士后Mike McDonald证明，在192-IgG皂素胆碱能损伤的大鼠中，甘丙肽受体拮抗剂M40增强了M-1毒蕈碱受体激动剂TZTP的有益作用，从而延缓了与位置的不匹配。这些发现支持内源性甘丙氨酸在调节记忆过程所需的胆碱能通路中的抑制调节作用，并表明甘丙氨酸拮抗剂可能是治疗阿尔茨海默氏痴呆症的现有胆碱能疗法的有用辅助疗法。发表：McDonald， Willard, Wenk, Crawley，甘丙肽拮抗剂M40与毒蕈碱M1激动剂联合使用可改善胆碱能病变大鼠的延迟不匹配位置。中国生物医学工程学报（英文版），1998。博士后特里·格里森（Terri Gleason）去年设立了莫里斯水任务，以测试甘丙氨酸在这种广泛使用的记忆测试中的作用。在训练试验中，脑室内给予甘丙肽会导致潜伏时间寻找隐藏平台的性能下降，以及在探针试验中选择性象限搜索的性能下降。在对丙氨酸的反应中检测到显著的遗传成分。Wistar和Sprague-Dawley菌株对丙氨酸的抑制作用敏感，而Long-Evans菌株对丙氨酸的抑制作用不受影响。在可见平台任务和Digiscan探索性运动中，丙氨酸剂量的表现正常，但损害了莫里斯水任务的获得。发表：Gleason， Dreiling和Crawley， Morris水任务中对甘丙氨酸反应的大鼠品系差异。神经肽，出版，1999。今年我们的甘丙肽研究项目获得了一个新的研究工具。在西雅图华盛顿大学的Robert Steiner和他的同事们培育出了过表达Galanin的转基因小鼠，并将其回交7代为C57BL/6J背景，用于我们的行为实验。博士后研究员安德鲁·霍姆斯和几名学生志愿者对甘丙肽转基因小鼠及其野生型对照幼崽进行了首次行为表型分析。一般健康状况、居家笼内行为、神经反射和运动功能正常。在最初的试点研究中，主要是在雄性转基因动物中发现了一些记忆任务的受损表现。实验采用额外的记忆任务，解决喂养，镇痛和焦虑领域的行为测试，现在正在进行中。-神经肽行为丙氨酸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