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.

我们部门与多个分子遗传学家实验室合作，对大脑中表达的基因发生突变的转基因和基因敲除小鼠的行为表型进行分析，这与我们对神经精神疾病动物模型的研究兴趣相关。在过去的几年里，我们开发并完善了行为表型分析的多层策略。对一般健康状况、笼内行为、感觉能力测试和运动功能进行定量观察的严格方法，以确保突变系不存在会在更复杂的行为任务中产生误报的严重物理缺陷。此外，我们还为小鼠开发了新的行为任务，并为小鼠调整了大鼠行为任务。假设检验策略减少了新突变系首次表征时的假阴性。针对每个行为领域进行一系列补充测试，例如记忆、进食、焦虑、社交行为、运动协调。 在过去的一年中，这些方法已应用于表征与神经精神疾病相关的几种突变系。我们的博士后研究员 Andrew Holmes 对 NINDS 的 Dave Sibley 培育的多巴胺 D5 受体敲除小鼠进行了行为表型测试。结果表明基线行为正常，但对探索性运动和声惊吓的前脉冲抑制的血清素激动剂药物治疗的反应改变。 宫川刚 (Tsuyoshi Miyakawa) 测试了由 NICHD 的 Huang 博士培育的缺乏神经粒蛋白（一种调节神经元钙通量的钙调蛋白底物）的基因敲除小鼠。结果表明，空间学习表现不佳，与焦虑样表型相关。 NIDDK 的 Jurgen Wess 培育的 M3 和 M5 毒蕈碱受体敲除小鼠由 Miyakawa 博士进行了测试。在 M3 无效突变体中检测到严重的摄食和体重缺陷，这似乎与胰岛素分泌紊乱有关。 5-羟色胺转运蛋白敲除小鼠由 NIMH 的 Dennis Murphy 培育，并由博士后研究员 Andrew Holmes 进行了测试。在三种不同的焦虑任务中证实了显着的焦虑样表型，即高架十字迷宫、明/暗转换任务和开放场地的涌现测试。 甘丙肽过度表达的转基因小鼠由西雅图华盛顿大学的罗伯特·斯坦纳培育，并由博士后研究员安德鲁·霍姆斯进行了测试。基于甘丙肽与蓝斑中的去甲肾上腺素以及中缝背侧中的血清素的共存，研究了与焦虑相关和抑郁相关的表型。药物挑战实验正在进行中。