Behavioral Functions of Neuropeptides

本实验室致力于研究甘丙肽抑制作用的行为伴随因素。神经肽甘丙肽定位于海马区，与乙酰胆碱共存于大鼠隔-海马通路，与去甲肾上腺素共存于蓝斑，抑制谷氨酸、乙酰胆碱、5-羟色胺和去甲肾上腺素的释放，并抑制诱发的阿德酸环化酶信号转导。在阿尔茨海默病患者的基底前脑中，甘丙素过度表达。我们过去的实验表明，中枢微量注射甘丙肽会损害大鼠在几个学习和记忆任务中的表现。我们发现，与对照组相比，过量表达甘丙素的转基因小鼠在学习和记忆任务上表现出类似的缺陷，包括Morris水迷宫空间学习探测试验，食物偏好社会传递中的嗅觉记忆，以及痕迹线索恐惧条件反射。 今年，博士后内森·鲁斯特尔测试了甘丙肽受体拮抗剂对甘丙素过度表达转基因小鼠记忆缺陷的修复能力。脑室内应用肽能甘丙肽拮抗剂M40逆转了甘丙肽过量表达转基因小鼠在痕迹提示恐惧条件反射方面的缺陷。这一发现支持了这样一种解释，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，翻译迹象表明，甘丙肽受体拮抗剂可以修复阿尔茨海默病患者的记忆缺陷。 今年，博士后凯瑟琳·贝利完成了一种新的Galanin亚型受体GAL-R2基因敲除小鼠的第一个完整的行为表型鉴定。突变品系是由我们的合作者、西雅图Nura公司的John Hohmann博士产生的。GAL-R2基因敲除小鼠在一般健康、家庭笼子行为、神经反射、感觉能力和运动功能方面表现正常。Gal-R2缺失突变体在追踪恐惧条件反射或Morris水迷宫空间导航方面没有表现出缺陷。贝利博士在高架的PLUS迷宫中发现了Gal-R2缺失突变体中类似焦虑症的表型。这一发现支持了新出现的证据，即甘丙肽是一种具有抗焦虑作用的抑制性神经调节剂。

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.