Animal Models Of Neuropsychiatric Disorders

我们的行为神经科学实验室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进行行为表型鉴定，这与我们在神经精神疾病动物模型中的研究兴趣相关。在过去的几年里，我们已经开发和完善了一种用于小鼠行为表型鉴定的多层次策略。此外，我们开发了新的小鼠行为任务，并将大鼠行为任务改编为小鼠行为任务。 在过去的一年里，博士后研究员安德鲁·霍姆斯博士扩大了5-羟色胺转运体(5-HTT)基因敲除小鼠的特征，该基因敲除小鼠是由NIMH IRP的Dennis Murphy博士和同事培育的。霍姆斯博士发现了一种惊人的焦虑样表型，这种表型在三种不同的焦虑任务中都得到了证实，这三种任务分别是高架加迷宫任务、明暗转换任务和开阔场地的涌现测试。与+/+野生型对照相比，5-HTT-/-组攻击性得分较低。与抑郁相关的任务显示，5-HTT-/-的基线行为正常，但对通过5-羟色胺转运体起作用的抗抑郁药缺乏反应。今年，霍姆斯博士和学生实习生埃里克·戈尔德比较了在C57BL/6J背景下培育的5-HTT突变体与在129/SvEvTac背景下培育的5-HTT突变体的行为表型。定性和定量的差异表明，129个背景中的保护性基因可以防止5-HTT突变的有害影响。今年，霍姆斯博士和戈尔德先生进行了进一步的研究，以评估5-HTT突变体在线索和语境恐惧条件作用下的情况，这是一种情绪记忆任务。对挑战剂量的抗抑郁药氟西汀和地昔帕明的敏感性表明，在这一情绪记忆任务中，突变小鼠和野生型小鼠的行为有所不同。由于5-羟色胺与几种人类神经精神疾病有关，而5-HTT拮抗剂如百忧解通常用于治疗抑郁症，5-HTT突变小鼠代表了一个有用的模型系统，可以进一步了解5-HTT能神经传递在精神疾病中的作用。 克劳利博士今年启动了一项新计划，旨在开发一种与自闭症相关的小鼠模型。这是一项与北卡罗来纳大学教堂山分校的研究人员合作的研究，特别是自闭症STAART项目主任约瑟夫·皮文博士。老鼠的行为遗传学实验是为了发现与代表自闭症基本症状的社会缺陷有关的新基因。克劳利博士设计了一种三室自动装置，用来测量小鼠的社交能力和社交新奇偏好。NIMH研究服务部的George Dold建造了这台设备的原型。北卡罗来纳大学神经发育障碍研究中心的Sheryl Moy博士和Jessica Nadler博士以及技术人员在近交系小鼠身上测试了该模型，包括C57BL/6J、DBA/2J、FVB/NJ和A/J。使用新仪器对所有品系的社会倾向进行了一致和定量的评分。

Our Laboratory of Behavioral Neuroscience 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 mouse behavioral phenotyping. Further, we develop new behavioral tasks for mice, and adapt rat behavioral tasks for mice. During the past year, postdoctoral fellow Dr. Andrew Holmes has expanded the characterization of the serotonin transporter (5-HTT) knockout mouse, generated by Dr. Dennis Murphy and coworkers here in the NIMH IRP. Dr. Holmes had found a striking anxiety-like phenotype that was confirmed in three different anxiety tasks, the elevated plus maze, the light/dark transitions task, and the emergence test in an open field. Aggression scores were lower in 5-HTT -/- as compared to +/+ wildtype littermate controls. Depression-related tasks revealed normal baseline behaviors in 5-HTT -/- but lack of response to antidepressants that act through the serotonin transporter. This year Dr. Holmes and student intern Eric Gold compared the behavioral phenotype of 5-HTT mutants bred onto a C57BL/6J background versus bred onto a 129/SvEvTac background. Qualitaive and quantitative differences indicate protective genes in the 129 background that prevent the deleterious effects of 5-HTT mutation. Further studies this year were conducted by Dr. Holmes and Mr. Gold to evaluate the 5-HTT mutants on cued and contextual fear conditioning, an emotional memory task. Sensitivity to challenge doses of the antidepressants fluoxetine and desipramine indicate differential actions on mutant versus wildtype littermate mice on this emotional memory task. Since serotonin is involved in several human neuropsychiatric disorders, and 5-HTT antagonists such as Prozac are commonly used to treat depression, the 5-HTT mutant mouse represents a useful model system to further understand the role of serotonergic neurotransmission in mental illnesses. Dr. Crawley began a new initiative this year to develop a mouse model relevant to autism. This is a collaborative study with investigators at the University of North Carolina Chapel Hill, particularly Dr. Joseph Piven, Director of the Autism STAART project. Mouse behavioral genetics experiments were conceived to discover new genes related to the social deficits that represent the fundamental symptoms of autism. Dr. Crawley designed a three chambered automated apparatus that measures sociability and social novelty preference in mice. George Dold, NIMH Research Services Branch, built the prototype apparatus. Drs. Sheryl Moy and Jessica Nadler and technicians in the UNC Neurodevelopmental Disorders Research Center tested the model in inbred strains of mice, including C57BL/6J, DBA/2J, FVB/NJ, and A/J. Social tendencies were scored consistently and quantitatively with the new apparatus for all strains.