Behavioral Functions of Neuropeptides

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。本实验室致力于研究甘丙肽抑制作用的行为伴随因素。我们过去的实验表明，中枢微量注射甘丙素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，Craige Wrenn博士和合作者Janita Turchi博士完成了对GAL-TG和WT小鼠的注意力任务、五项选择系列反应时间任务和相关挑战的测试。这项注意任务的简单和复杂成分的正常能力被揭示出来。这些结果支持一种解释，即GAL-TG的认知缺陷不是由潜在的注意障碍引起的，而实际上是学习和记忆所特有的。 去年，我们完成了一种新的甘丙素受体GAL-R1基因敲除小鼠的第一个完整的行为表型鉴定。今年，我们利用这些Gal-R1缺失突变小鼠来解决以下问题：哪种甘丙素受体亚型介导了药物给药甘丙素的抑制作用。研究生Rose-Marie Karlsson在Craige Wrenn博士和Tim Sullivan博士的培训下，脑室注射剂量的甘丙素，以绘制小鼠的剂量-反应曲线。Craige Wrenn博士、Tim Sullivan博士和Howard Hughes学生实习生Dejaimenay Stephenson博士将Galanin显微注射到Gal-R1零突变和野生型斜位基因空腹小鼠的侧脑室。甘丙肽在恐惧条件反射中产生了预期的损伤。GAL-R1基因敲除小鼠在这项情绪记忆任务中没有表现出甘丙素诱导的缺陷。Gal-R1受体似乎至少是一个亚型，甘丙素通过它来减少与恐惧相关的学习和记忆。这一发现将为选择甘丙肽受体配体进行未来的测试提供信息，作为治疗阿尔茨海默病记忆缺陷的潜在疗法。 新的博士后Nate Rustay开始研究Galanin受体拮抗剂M40在过量表达Galanin转基因小鼠中改善记忆的能力。鲁斯泰尔博士目前正在制作M40进入小鼠侧脑室的剂量反应曲线。这些实验旨在验证这样一种假设，即阻断过量内源性甘丙肽的抑制作用将改善小鼠在记忆任务中的表现，从而损害认知能力。

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 laboratory is engaged in investigating the behavioral concomittants of the inhibitory effects of galanin. Our past experiments revealed that central microinjection of galanin to 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 probe trial, on olfactory memory in social transmission of food preference, and on trace cued fear conditioning, when compared to WT littermate controls. This year, Dr. Craige Wrenn and collaborator Dr. Janita Turchi completed testing GAL-tg and WT mice on an attentional task, the five choice serial reaction time task, and associated challenges. Normal abilities on simple and complex components of this attentional task were revealed. These results support an interpretation that the cognitive deficits of GAL-tg are not caused by an underlying attentional dysfunction, but in fact are specific to learning and memory. Last year we completed the first full behavioral phenotyping characterization of a new galanin receptor GAL-R1 knockout mouse. This year we employed these GAL-R1 null mutant mice to address the question of which galanin receptor subtype mediates the inhibitory actions of pharmacologically administered galanin. Graduate student Rose-Marie Karlsson, with training by Dr. Craige Wrenn and Tim Sullivan, administered doses of galanin intraventricularly to work out dose-response curves in mice. Dr. Craige Wrenn, Tim Sullivan, and Howard Hughes student intern Dejaimenay Stephenson microinjected galanin into the lateral ventricles of cannulated mice of the GAL-R1 null mutant and wildtype littermate genotypes. Galanin produced the expected impairments in fear conditioning. GAL-R1 knockout mice did not display galanin-induced deficits on this emotional memory task. The GAL-R1 receptor appears to be at least one subtype through which galanin acts to reduce fear-associated learning and memory. This finding will inform the choice of galanin receptor ligands for future testing as potential therapeutics for treating memory deficits in Alzheimer's disesae. New postdoctoral fellow Nate Rustay began an investigation into the ability of a galanin receptor antagonist, M40, to improve memory in galanin overexpressing transgenic mice. Dr. Rustay is presently generating dose response curves for M40 administered into the lateral ventricles of mice. These experiments are designed to test the hypothesis that blocking the inhibitory actions of excess endogenous galanin will improve performance on memory tasks in mice.uropeptide that impairs cognitive abilities.