BEHAVIORAL FUNCTIONS OF NEUROPEPTIDES

神经肽甘丙肽位于海马中，与大鼠隔海马通路中的乙酰胆碱共存，与蓝斑中的去甲肾上腺素共存，并抑制谷氨酸、乙酰胆碱和去甲肾上腺素的释放。 甘丙肽在阿尔茨海默病的基底前脑中过度表达。本实验室致力于研究甘丙肽对认知过程所必需的神经递质的抑制作用的行为伴随物。 我们的实验表明，甘丙肽管理大鼠损害性能的几个记忆任务。 去年，博士后Terri Gleason设立了Morris水任务，以测试甘丙肽在这个广泛使用的空间学习测试中的作用。 脑室注射甘丙肽主要在探测试验期间选择性象限搜索引起性能缺陷。 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。 在可见的平台任务和Digiscan探索性运动的性能是正常的甘丙肽的剂量，损害收购的莫里斯水任务使用空间环境线索。出版物：Gleason TC，Dreiling JL，Crawley JN（1999）Morris水任务中对甘丙肽反应的大鼠品系差异。神经肽33：265- 270.博士后研究员杰夫·金尼（Jeff Kinney）发起了一项关于甘丙肽诱导的莫里斯任务缺陷的性质的调查。 比较甘丙肽的获得与保留效果。 脑室微量注射甘丙肽时，无论是之前或之后的培训课程管理在Sprague-Dawley大鼠的探测试验性能产生赤字。 时程分析显示，甘丙肽在每天训练结束后5分钟、30分钟和3小时的时间点给药完全消除了选择性象限搜索。 在训练试验后18小时给予甘丙肽时，探测试验的表现正常。 这一令人兴奋的发现表明甘丙肽对记忆巩固所必需的生化过程具有直接的抑制作用。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是由华盛顿大学西雅图的Robert Steiner及其同事在多巴胺β羟化酶启动子上产生的。 将嵌合体系回交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。 在年龄为8、16和24个月的甘丙肽转基因小鼠中发现Morris水任务的表现受损。 行为缺陷的概况与给予外源性甘丙肽的大鼠中观察到的相似。 在可见和隐藏平台组件上的正常性能之后，在探测试验中缺乏选择性搜索。博士后Craige Wrenn测试了甘丙肽转基因小鼠的第二项记忆任务，即食物偏好的社会传播。 野生型同窝对照小鼠显示出对具有先前被笼仔24小时前食用的风味的食物的预期偏好。 甘丙肽转基因小鼠没有表现出偏好消费的食物含有社会传递气味线索，相比，消费的食物含有一种新的气味。 甘丙肽转基因小鼠在这个嗅觉记忆任务上的表现不佳支持了莫里斯空间导航任务的结果，证实了甘丙肽过表达小鼠的认知缺陷。对甘丙肽过表达转基因品系的学习和记忆的评价正在进行中。 产生初步发现的实验正在用新一批小鼠重复进行，并使用额外的行为任务。

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 on neurotransmitters necessary for cognitive processes. Our experiments have revealed that galanin administration to rats impairs performance on several memory tasks. Last year, postdoctoral fellow Terri Gleason set up the Morris water task, to test the actions of galanin in this widely used spatial learning test. Intraventricularly administered galanin induced performance deficits primarily 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 using spatial environmental cues. PUBLICATION: Gleason TC, Dreiling JL, Crawley JN (1999) Rat strain differences in response to galanin on the Morris water task. Neuropeptides 33:265-270.Postdoctoral fellow Jeff Kinney initiated an investigation into the nature of the galanin-induced deficit on the Morris task. Aquisition versus retention effects of galanin were compared. Intraventricularly microinjected galanin produced deficits on probe trial performance in Sprague-Dawley rats when galanin was administered either before or after the training sessions. Time-course analysis revealed that galanin administration at time points of 5 minutes, 30 minutes, and 3 hours after the end of the daily training sessions completely abolished selective quadrant search. Performance on the probe trial was normal when galanin was administered 18 hours after the training trials. This exciting finding indicates that galanin has a direct inhibitory action on biochemical processes necessary for memory consolidation. This year our galanin research program received a new research tool. Galanin overexpressing transgenic mice were generated on a dopamine beta hydroxylase promoter by Robert Steiner and coworkers at the University of Washington, Seattle. The chimera line was backcrossed for 7 generations into a C57BL/6J background for our behavioral experiments. Postdoctoral fellow Andrew Holmes and several student volunteers conducted 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 the Morris water task was found in the galanin transgenic mice at ages 8, 16, and 24 months. The profile of the behavioral deficits was similar to that seen in rats given exogenous galanin. Normal performance on the visible and hidden platform components were followed by lack of selective search on the probe trial. Postdoctoral fellow Craige Wrenn tested the galanin transgenic mice on a second memory task, social transmission of food preference. Wild type littermate control mice showed the expected preference for a food scented with a flavor previously consumed by a cagemate 24 hours earlier. The galanin transgenic mice did not show a preference for consuming the food containing the socially transmitter odor cue, as compared to consumption of food containing a novel odor. Poor performance by the galanin transgenics on this olfactory memory task supports the results of the Morris spatial navigation task, confirming a cognitive deficit in the galanin overexpressing mice. Evaluation of learning and memory in the galanin overexpressing transgenic line is proceeding. Experiments generating the initial findings are being repeated with a new batch of mice, and using additional behavioral tasks.