ANIMAL MODELS OF NEUROPSYCHIATRIC DISORDERS

神经精神疾病的动物模型

• 批准号: 6432798
• 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/6432798
• 关键词: animal breeding; behavioral genetics; disease /disorder model; genetically modified animals; laboratory mouse; memory; model design /development; neurogenetics; psychomotor function; quantitative trait loci; schizophrenia; sensorimotor system

Quantitative trait loci analysis for genes linked to deficits in prepulse inhibition is ongoing. Prepulse inhibiton is a measure of sensorimotor gating which is abnormal in several neuropsychiatric disorders, including schizophrenia. Normal prepulse inhibition in AKR mice and impaired prepulse inhibition in C57BL/6J mice provides a basis for discovering genes linked to this trait in mice, that may indicate candidate genes to investigate in schizophrenia. AKR x C57BL/6J F2 mice were behaviorally characterized by Richard Paylor and genotyped by collaborators Alan Sanders and Pablo Gejman. Several suggestive chromosomal loci were identified in the 10% extremes of the behavioral distribution. The entire test population of 500 mice was then genotyped with a denser set of microsatellite markers around the suggestive loci. The full data set is now being analyzed statistially for significant linkages. Suggestive loci are being further explored in the F5 generation, selectively bred from individual mice at the extremes of the distribution for the prepulse inhibition behavioral phenotype. 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. PUBLICATION: Crawley JN (1999) Behavioral phenotyping of transgenic and knockout mice. Brain Research Special Issue on Knockouts and Mutants 835:18-26.These methods are currently being applied to the characterization of a) a dopamine D5 receptor knockout mouse generated by Dave Sibley, NINDS, being tested for behavioral phenotype by our postdoctoral fellow Andrew Holmes; (PUBLICATION submitted)b) a knockout mouse deficient in neurogranin, a substrate of calmodulin which regulates neuronal calcium flux, generated by Dr. Huang, NICHD, behavioral testing being conducted by Tsuyoshi Miyakawac) M3 and M5 muscarinic receptor knockout mice, generated by Jurgen Wess, NIDDK, behavioral testing being conducted by Tsuyoshi Miyakawa. (PUBLICATION submitted)d) Serotonin transporter knockout mouse, generated by Dennis Murphy, NIMH, behavioral testing being conducted by Andrew Holmes.

与前脉冲抑制缺陷相关的基因的数量性状位点分析正在进行中。 前脉冲门控是感觉运动门控的一种测量方法，在包括精神分裂症在内的几种神经精神疾病中是异常的。 AKR小鼠中正常的前脉冲抑制和C57 BL/6 J小鼠中受损的前脉冲抑制为发现小鼠中与该性状相关的基因提供了基础，这可能表明在精神分裂症中研究的候选基因。 AKR x C57 BL/6 J F2小鼠的行为特征由Richard Paylor进行，基因分型由合作者Alan Sanders和巴勃罗Gejman进行。 在行为分布的10%极端中确定了几个提示性的染色体位点。 然后用一组密集的微卫星标记围绕暗示性位点对500只小鼠的整个测试群体进行基因分型。 目前正在对全部数据集进行统计分析，以找出重要的联系。 在F5代中正在进一步探索暗示性基因座，F5代选择性地从前脉冲抑制行为表型分布极端的个体小鼠中繁殖。本科与几个分子遗传学家实验室合作，对大脑中表达基因突变的转基因和敲除小鼠进行行为表型分析，这与我们在神经精神疾病动物模型中的研究兴趣有关。 在过去的几年里，我们已经开发和完善了行为表型的多层次策略。 对一般健康状况、笼舍行为、感觉能力和运动功能进行定量观察的严格方法，以确保突变品系没有在更复杂的行为任务中产生假阳性的严重身体缺陷。 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。 假设检验的策略减少了新突变株系首次表征中的假阴性。 针对每个行为领域，例如记忆、进食、焦虑、社会行为、运动协调，进行一系列补充测试。出版物：Crawley JN（1999）转基因和基因敲除小鼠的行为表型。 这些方法目前正被应用于a）由NINDS的Dave Sibley产生的多巴胺D5受体敲除小鼠的表征，我们的博士后研究员Andrew Holmes正在测试其行为表型;（提交的出版物）B）由Huang博士，NICHD，产生的神经颗粒蛋白缺陷的敲除小鼠，神经颗粒蛋白是调节神经元钙流动的钙调蛋白的底物，行为测试由TsuyoshiMiyakawac进行）M3和M5毒蕈碱受体敲除小鼠，由JurgenWess，NIDDK产生，行为测试由TsuyoshiMiyakawa进行。d）5-羟色胺转运蛋白敲除小鼠，由NIMH的Dennis Murphy产生，行为测试由Andrew Holmes进行。