Behavioral Functions of Neuropeptides

神经肽的行为功能

• 批准号: 7136223
• 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/7136223
• 关键词: Alzheimer' s disease; attention; behavior test; behavioral genetics; fear; galanin; genetically modified animals; laboratory mouse; laboratory rat; learning; memory; neuropeptide receptor; neuropsychology; neuroregulation; tranquilizer

Our laboratory is engaged in investigating the behavioral concomittants of the inhibitory effects of galanin. The neuropeptide galanin is localized in the hippocampus, coexists with acetylcholine in the rat septohippocampal pathway, coexists with norepinephrine in the locus coeruleus, inhibits the release of glutamate, acetylcholine, serotonin, and norepinephrine, and inhibits evoked adeylate cyclase signal transduction. Galanin is overexpressed in the basal forebrain in Alzheimer's disease. Our past experiments revealed that central microinjection of galanin in rats impairs performance on several learning and memory tasks. We discovered that galanin overexpressing transgenic mice display analogous deficits on learning and memory tasks including the Morris water maze spatial learning probe trial, olfactory memory in social transmission of food preference, and trace cued fear conditioning, when compared to WT littermate controls. This year postdoctoral fellow Nathan Rustay tested the ability of a galanin receptor antagonist to rescue the memory deficits in galanin overexpressing transgenic mice. Intraventricular treatment with the peptidergic galanin antagonist M40 reversed the deficit on trace cued fear conditioning in galanin overexpressing transgenic mice. This finding supports the interpretation that the cognitive deficits in galanin transgenic mice are caused by the excess galanin peptide in the brain, not by some unknown compensatory mechanism. Further, translational indications are that a galanin receptor antagonist could rescue memory deficits in Alzheimer's patients. This year postdoctoral fellow Kathleen Bailey completed the first full behavioral phenotyping characterization of a new galanin subtype receptor GAL-R2 knockout mouse. The mutant line was generated by our collaborator Dr. John Hohmann at Nura, Inc. in Seattle. GAL-R2 knockout mice appeared normal on measures of general health, home cage behaviors, neurological reflexes, sensory abilities, and motor functions. GAL-R2 null mutants did not display deficits on trace fear conditioning or on spatial navigation in the Morris water maze. Dr. Bailey discovered an anxiogenic-like phenotype in GAL-R2 null mutants on the elevated plus maze. This finding supports the emerging evidence that galanin is an inhibitory neuromodulator with anxiolytic actions.

本实验室致力于研究甘丙肽抑制作用的行为伴随物。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，抑制谷氨酸、乙酰胆碱、5-羟色胺和去甲肾上腺素的释放，并抑制诱发的腺苷酸环化酶信号转导。甘丙肽在阿尔茨海默病的基底前脑中过度表达。我们过去的实验表明，在大鼠的中枢微量注射甘丙肽损害的表现在几个学习和记忆任务。我们发现，甘丙肽过表达的转基因小鼠显示类似的缺陷的学习和记忆任务，包括莫里斯水迷宫空间学习探测试验，嗅觉记忆的食物偏好的社会传播，和跟踪线索的恐惧条件反射，与WT同窝对照组相比。 今年，博士后研究员Nathan Rustay测试了甘丙肽受体拮抗剂拯救甘丙肽过度表达转基因小鼠记忆缺陷的能力。脑室内治疗的肽能甘丙肽拮抗剂M40逆转了赤字的痕迹线索恐惧条件在甘丙肽过表达转基因小鼠。这一发现支持了这样的解释，即甘丙肽转基因小鼠的认知缺陷是由大脑中过量的甘丙肽引起的，而不是由某种未知的补偿机制引起的。此外，转译迹象表明甘丙肽受体拮抗剂可以挽救阿尔茨海默病患者的记忆缺陷。 今年博士后研究员Kathleen Bailey完成了新甘丙肽亚型受体GAL-R2敲除小鼠的首次完整行为表型表征。突变株系由我们的合作者Nura，Inc.的John Hohmann博士产生。在西雅图。GAL-R2基因敲除小鼠在一般健康状况、笼内行为、神经反射、感觉能力和运动功能方面表现正常。GAL-R2无效突变体在Morris水迷宫中没有显示出对痕量恐惧条件反射或空间导航的缺陷。Bailey博士在高架十字迷宫中发现了GAL-R2无效突变体中的致焦虑样表型。这一发现支持了甘丙肽是一种具有抗焦虑作用的抑制性神经调质的新证据。