Animal Models Of Neuropsychiatric Disorders

我们科与几个分子遗传学家实验室合作，研究大脑中表达基因突变的转基因和敲除小鼠的行为表型，这与我们在神经精神疾病动物模型方面的研究兴趣相关。在过去的几年中，我们已经开发并完善了行为表型的多层策略。采用严格的方法对一般健康状况、家庭笼内行为、感觉能力和运动功能进行定量观察，以确保突变品系没有严重的身体缺陷，不会在更复杂的行为任务中产生假阳性。此外，我们还开发了新的小鼠行为任务，并为小鼠调整了大鼠行为任务。假设检验的策略减少了在新突变系的第一次表征中的假阴性。对每个行为领域进行一系列补充测试，例如记忆、进食、焦虑、社会行为、运动协调。在过去的一年中，这些方法已被应用于与神经精神疾病相关的几种突变系的表征。由Dave Sibley， NINDS培养的多巴胺D5受体敲除小鼠，由我们的博士后研究员Andrew Holmes进行了行为表型测试。结果表明，基线行为正常，但血清素能激动剂药物治疗对探索性运动和脉冲前抑制声惊的反应发生了改变。

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.