Animal Models Of Neuropsychiatric Disorders

神经精神疾病的动物模型

• 批准号: 6501255
• 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/6501255
• 关键词: animal breeding; anxiety disorders; behavioral genetics; calmodulin; disease /disorder model; dopamine receptor; genetically modified animals; laboratory mouse; memory; model design /development; neurogenetics; psychomotor function; quantitative trait loci; schizophrenia; sensorimotor system

Our Section collaborates with several molecular geneticists laboratories on behavioral phenotyping of transgenic and knockout mice with mutations in genes expressed in the brain, relevant to our research interests in animal models of neuropsychiatric diseases. Over the past years, we have developed and refined a multitiered strategy for behavioral phenotyping. Rigorous methods for quantitate observations of general health, home cage behaviors, tests for sensory abilities, and motor functions, to ensure that the mutant line has no gross physical defects that would produce false positives on more complex behavioral tasks. Further, we have developed new behavioral tasks for mice, and adapted rat behavioral tasks for mice. The strategy for hypothesis testing reduces false negatives in the first characterization of a new mutant line. A constellation of ccomplementary tests is conducted for each behavioral domain, e.g. memory, feeding, anxiety, social behaviors, motor coordination. During the past year, these methods have been applied to the characterization of several mutant lines relevant to neuropsychiatric disorders. A dopamine D5 receptor knockout mouse generated by Dave Sibley, NINDS, was tested for behavioral phenotype by our postdoctoral fellow Andrew Holmes. Results indicate normal baseline behaviors but altered responses to a serotonergic agonist drug treatment on exploratory locomotion and on prepulse inhibition of acoustic startle. Knockout mice deficient in neurogranin, a substrate of calmodulin which regulates neuronal calcium flux, generated by Dr. Huang, NICHD, were tested by Tsuyoshi Miyakawa. Results indicate poor performance on spatial learning, associated with an anxiety-like phenotype. M3 and M5 muscarinic receptor knockout mice, generated by Jurgen Wess, NIDDK, were tested by Dr. Miyakawa. Severe deficits in feeding and body weight were detected in M3 null mutants, which appear to be related to a disturbance in insulin secretion. Serotonin transporter knockout mice, generated by Dennis Murphy, NIMH, were tested by postdoctoral fellow Andrew Holmes. A striking anxiety-like phenotype was confirmed in three different anxiety tasks, the elevated plus maze, the light/dark transitions task, and the emergence test in an open field. Galanin overexpressing transgenic mice, generated by Robert Steiner, University of Washington in Seattle, were tested by postdoctoral fellow Andrew Holmes. Anxiety-related and depression-related phenotypes were investigated, based on the coexistence of galanin with norepinephrine in the locus coeruleus and with serotonin in the dorsal raphe. Drug challenge experiments are in progress.

我们的部分与几个分子遗传学家实验室合作，就转基因和基因敲除小鼠的行为表型进行，其在大脑中表达的基因突变与我们在神经精神疾病的动物模型中的研究兴趣有关。在过去的几年中，我们制定并完善了行为表型的多层策略。量化一般健康，家庭笼行为，感官能力的测试和运动功能的严格方法，以确保突变线没有严重的身体缺陷，可以在更复杂的行为任务上产生误报。此外，我们为小鼠开发了新的行为任务，并针对小鼠进行了改编的大鼠行为任务。假设检验的策略可以减少新突变线的首次表征中的假阴性。为每个行为域进行了C综合测试的星座，例如记忆，喂养，焦虑，社交行为，运动协调。 在过去的一年中，这些方法已应用于与神经精神疾病相关的几种突变系的表征。我们的博士后同胞安德鲁·霍尔姆斯（Andrew Holmes）测试了由戴夫·西布利（Dave Sibley）产生的多巴胺D5受体基因敲除小鼠Ninds产生的行为表型。结果表明基线行为正常，但对探索性运动和对声学惊吓的预抑制作用的血清素能激动剂治疗的反应改变了。 敲除小鼠在神经素蛋白（钙调节蛋白的底物）中，由尼古拉（Tsuyoshi）宫川（Tsuyoshi Miyakawa）测试了由Huang，Nichd博士产生的调节神经元钙通量的底物。结果表明与焦虑样表型有关的空间学习表现不佳。 Miyakawa博士测试了由Jurgen Wess，Niddk产生的M3和M5毒蕈碱受体敲除小鼠。在M3无效突变体中检测到严重的喂养和体重缺陷，这似乎与胰岛素分泌的紊乱有关。 由NIMH丹尼斯·墨菲（Dennis Murphy）生成的5-羟色胺转运蛋白敲除小鼠由博士后同胞安德鲁·霍尔姆斯（Andrew Holmes）测试。在三个不同的焦虑任务，升高的迷宫，光/黑暗过渡任务以及在开放田里的出现测试中，确认了惊人的焦虑样表型。 由华盛顿大学的罗伯特·斯坦纳（Robert Steiner）在西雅图的罗伯特·斯坦纳（Robert Steiner）产生的过表达的Galanin过表达的转基因小鼠，由博士后研究员安德鲁·霍尔姆斯（Andrew Holmes）测试。基于Galanin与去核肾上腺素的共存以及背侧raphe中的5-羟色胺的共存，研究了与焦虑有关的表型和与抑郁相关的表型。毒品挑战实验正在进行中。