Behavioral Functions Of Neuropeptides

神经肽的行为功能

• 批准号: 6501254
• 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/6501254
• 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 on a new research tool. Galanin overexpressing transgenic mice generated on a dopamine beta hydroxylase promoter by Robert Steiner and coworkers at the University of Washington, Seattle were evaluated for behavioral phenotype. The chimera line was backcrossed for 7 generations into a C57BL/6J background and bred at The Jackson Laboratory for our behavioral experiments. Postdoctoral fellow Andrew Holmes and several student volunteers completed the first behavioral phenotyping on galanin transgenic mice (GAL-tg) and their wild type control littermates (WT). General health, home cage behaviors, neurological reflexes, and motor functions were normal. Dr. Holmes discovered impaired performance on the Morris water task in the GAL-tg 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 was followed by lack of selective search on the probe trial. Postdoctoral fellow Jeff Kinney replicated these findings in a separate group of GAL-tg and WT mice. Dr. Holmes analyzed the probe trial deficit further. No genotype differences were detected on swim speed, thigmotaxis, or sequence of swim pattern across ten second time bins in the probe trial. These findings indicate that the GAL-tg mutation produces a selective deficit in the ability of mice to generate a cognitive map based on distal spatial cues. 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. GAL-tg 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. Dr. Wrenn replicated this finding in a separate group of GAL-tg and WT mice. Dr. Wrenn completed several critical control experiments, demonstrating that GAL-tg engaged in normal levels of social interaction with the demonstrator cagemate, and displayed normal olfactory abilities. Dr. Kinney tested the galanin transgenic mice on a third memory task, cued and contextual fear conditioning. GAL-tg were not significantly different than WT on freezing to the identical context in which an aversive stimulus had been presented, nor on freezing to an auditory cue previously paired with the aversive stimulus but presented in a new context. Dr. Kinney then employed the trace fear conditioning modification. The emotional learning task was made more difficult by the insertion of a delay between the aversive unconditioned stimulus and the auditory cue during training. GAL-tg showed poor performance on auditory cued freezing in the trace fear conditioning task. Dr. Kinney conducted critical control experiments that indicated normal analgesic responses and normal hearing in the GAL-tg. Poor performance by the galanin transgenics on the probe trial of the Morris spatial navigation task, on the social transmision of food preference olfactory task, and on the trace fear conditioning emtional memory task, confirm a cognitive deficit in the galanin overexpressing mice. Corroboration across three diverse learning and memory tasks, representing highly divergent sensory and motor demands, supports the interpretation of a generalized cognitive disorder in GAL-tg mice. 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.

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研究计划着重于一种新的研究工具。 Galanin过表达的转基因小鼠由Robert Steiner在多巴胺β羟化酶启动子上产生的转基因小鼠和华盛顿大学的同事进行了行为表型的评估。将嵌合线线串入7代，回到C57BL/6J背景中，并在杰克逊实验室繁殖我们的行为实验。博士后安德鲁·霍尔姆斯（Andrew Holmes）和几位学生志愿者完成了对加拉蛋白转基因小鼠（GAL-TG）及其野生型控制同窝仔（WT）的第一个行为表型。一般健康，家庭笼行为，神经反射和运动功能正常。 福尔摩斯博士发现，在8、16和24个月的GAL-TG中，莫里斯水务任务的表现受损。行为缺陷的特征与给定外源性甘丙蛋白的大鼠相似。在可见和隐藏的平台组件上的正常性能之后，在探针试验中缺乏选择性搜索。博士后研究员杰夫·金尼（Jeff Kinney）在另一组Gal-TG和WT小鼠中复制了这些发现。福尔摩斯博士进一步分析了探针试验赤字。在探针试验中，在十个第二次垃圾箱中，在游泳速度，thigmotaxis或游泳模式的序列上未检测到基因型差异。这些发现表明，GAL-TG突变会在小鼠基于远端空间提示产生认知图的能力中产生选择性缺陷。 博士后Craige Wrenn对Galanin转基因小鼠进行了第二次记忆任务，即食物偏好的社交传播。野生型窝窝对照小鼠表现出对食物的预期偏好，该食物闻到了24小时前由卡盖氏症的风味散发出的味道。与食用含有新型气味的食物相比，Gal-TG并未显示出食用含有社会发射器气味提示的食物的偏爱。 Wrenn博士在另一组Gal-TG和WT小鼠中复制了这一发现。 Wrenn博士完成了一些关键的控制实验，表明GAL-TG与示威者Cagemate的社交互动水平正常，并表现出正常的嗅觉能力。 金尼博士在第三项记忆任务和上下文恐惧条件下测试了加拉宁转基因小鼠。 GAL-TG与冻结的wt无显着差异，以呈现出厌恶刺激的相同环境，也没有与以前与厌恶刺激配对但在新背景下呈现的听觉提示冻结。金尼博士随后采用了痕量恐惧条件修改。通过在训练过程中厌恶无条件的刺激与听觉提示之间的延迟，使情感学习任务变得更加困难。 GAL-TG表现出在痕量恐惧调节任务中冻结的听觉表现较差的表现。 Kinney博士进行了关键的控制实验，表明GAL-TG中表明正常的镇痛反应和正常听力。 Galanin转基因在莫里斯空间导航任务，食品偏爱嗅觉任务的社会传播以及在痕量恐惧条件调节性记忆任务上的探测试验中的表现不佳，确认了Galanin过表达小鼠的认知缺陷。代表高度不同的感觉和运动需求的三种不同学习和记忆任务的佐证，支持对GAL-TG小鼠的普遍认知障碍的解释。 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。