Behavioral Functions of Neuropeptides

神经肽的行为功能

• 批准号: 6979973
• 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/6979973
• 关键词: Alzheimer' s disease; attention; behavioral genetics; cerebral ventricles; fear; galanin; genetically modified animals; laboratory mouse; memory; molecular psychobiology; neuropeptide receptor; neuropsychology; neuroregulation; phenotype

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.

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。本实验室致力于研究甘丙肽抑制作用的行为伴随物。我们过去的实验表明，中枢微量注射甘丙肽对大鼠在几个学习和记忆任务中的表现有损害。我们发现，甘丙肽过表达的转基因小鼠显示类似的缺陷，学习和记忆任务，包括莫里斯水迷宫探针试验，嗅觉记忆的食物偏好的社会传播，和跟踪线索恐惧条件反射，与WT同窝对照组相比。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、五选择系列反应时间任务和相关挑战的测试。正常的能力，简单和复杂的组件，这个注意力的任务。这些结果支持这样一种解释，即GAL-tg的认知缺陷不是由潜在的注意力功能障碍引起的，而是实际上特定于学习和记忆。 去年，我们完成了新甘丙肽受体GAL-R1敲除小鼠的第一个完整的行为表型表征。今年，我们采用这些GAL-R1无效突变小鼠来解决以下问题：哪种甘丙肽受体亚型介导了口服甘丙肽的抑制作用。研究生Rose-Marie Karlsson在Craige Wrenn博士和Tim Sullivan的培训下，通过脑室内注射甘丙肽来计算小鼠的剂量反应曲线。Craige Wrenn博士、Tim Sullivan和霍华德休斯的学生实习生Dejaimenay斯蒂芬森将甘丙肽显微注射到GAL-R1无效突变和野生型同窝基因型的插管小鼠的侧脑室中。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肽诱导的缺陷。GAL-R1受体似乎是甘丙肽减少恐惧相关学习和记忆的至少一种亚型。这一发现将告知甘丙肽受体配体的选择，用于未来测试作为治疗阿尔茨海默病记忆缺陷的潜在疗法。 新的博士后研究员Nate Rustay开始研究甘丙肽受体拮抗剂M40改善甘丙肽过表达转基因小鼠记忆的能力。Rustay博士目前正在生成M40注入小鼠侧脑室的剂量反应曲线。这些实验的目的是为了验证这一假设，即阻断过量的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。