ANIMAL MODELS OF NEUROPSYCHIATRIC DISORDERS

与脉冲前抑制缺陷相关的基因的定量性状基因分析正在进行中。脉冲前抑制是感觉运动门控的一种测量方法，这在包括精神分裂症在内的几种神经精神障碍中是不正常的。AKR小鼠正常的前脉冲抑制和C57BL/6J小鼠受损的前脉冲抑制为在小鼠中发现与这一特性相关的基因提供了基础，这些基因可能为精神分裂症的研究提供候选基因。AKR x C57BL/6J F2小鼠由理查德·佩勒描述行为特征，由合作者艾伦·桑德斯和巴勃罗·盖曼进行基因分型。在行为分布的10%的极端范围内，发现了几个可能的染色体位点。然后，对整个测试种群的500只小鼠进行了基因分型，并在暗示的基因座周围使用了一组密度更高的微卫星标记。目前正在对整个数据集进行统计分析，以寻找重要的联系。提示基因座在F5代中被进一步探索，从脉冲前抑制行为表型的分布极端的个体小鼠中选择性地繁殖。我们的部门与几个分子遗传学家实验室合作，对大脑中表达的基因突变的转基因和基因敲除小鼠的行为表型进行研究，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，我们已经开发和完善了一种多层次的行为表型分析策略。对一般健康、笼子行为、感觉能力和运动功能进行量化观察的严格方法，以确保突变品系没有可能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，并使大鼠的行为任务适用于小鼠。假设检验的策略减少了在新突变系的第一次表征中的假阴性。针对每个行为领域，例如记忆、进食、焦虑、社交行为、运动协调，进行了一系列互补测试。出版：Crawley JN(1999)转基因和基因敲除小鼠的行为表型。脑研究特刊关于基因敲除和突变体835：18-26.这些方法目前正在用于表征a)多巴胺D5受体基因敲除小鼠，由NINDS的Dave Sibley产生，正在由我们的博士后研究员Andrew Holmes进行行为表型测试；(B)缺乏神经颗粒素的基因敲除小鼠，由NICHD黄博士产生，这种钙调蛋白底物调节神经元钙通量；由宫川刚博士产生的M3和M5 M受体基因敲除小鼠，由Jurgen Wess，NIDDK产生，行为测试由宫川刚博士进行。(提交的出版物)d)5-羟色胺转运体基因敲除小鼠，由Dennis Murphy，NIMH产生，行为测试由Andrew Holmes进行。

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.