Animal Models Of Neuropsychiatric Disorders

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。 在过去的一年中，这些方法已被应用于表征几个突变株相关的神经精神疾病。由NINDS的Dave Sibley产生的多巴胺D5受体敲除小鼠由我们的博士后研究员Andrew Holmes测试行为表型。结果表明，正常的基线行为，但改变的反应，探索性运动和声惊吓的前脉冲抑制的多巴胺能激动剂药物治疗。 由Huang博士，NICHD产生的神经颗粒蛋白（一种调节神经元钙流的钙调蛋白底物）缺陷的敲除小鼠由Tsuyoshi Miyakawa进行测试。结果表明，空间学习的表现不佳，与焦虑样表型。 由Jurgen Wess，NIDDK产生的M3和M5毒蕈碱受体敲除小鼠由Miyakawa博士进行检测。在M3无效突变体中检测到摄食和体重严重不足，这似乎与胰岛素分泌紊乱有关。 由NIMH的Dennis Murphy产生的5-羟色胺转运体敲除小鼠由博士后研究员Andrew Holmes进行测试。一个惊人的焦虑样表型被证实在三个不同的焦虑任务，高架十字迷宫，光/暗转换任务，并出现在一个开放的领域测试。 由西雅图的华盛顿大学的罗伯特·施泰纳培育的甘丙肽过表达转基因小鼠由博士后研究员安德鲁·霍姆斯进行了测试。基于甘丙肽与去甲肾上腺素在蓝斑和5-羟色胺在中缝背核的共存，研究了抑郁症相关和抑郁症相关的表型。药物挑战实验正在进行中。

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.