Animal Models Of Neuropsychiatric Disorders

神经精神疾病的动物模型

• 批准号: 6823807
• 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/6823807
• 关键词: anxiety disorders; autism; behavioral genetics; depression; disease /disorder model; dopamine receptor; gene expression; genetically modified animals; laboratory mouse; memory; model design /development; neurogenetics; neuropsychology; psychomotor function; quantitative trait loci; sensorimotor system; serotonin; serotonin transporter

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.

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，在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，与我们在神经精神疾病的动物模型中的研究兴趣有关。在过去的几年中，我们制定并完善了一种多层策略，用于小鼠行为表型。此外，我们为小鼠开发新的行为任务，并适应小鼠的大鼠行为任务。 在过去的一年中，博士后安德鲁·霍尔姆斯（Andrew Holmes）博士扩大了丹尼斯·墨菲（Dennis Murphy）博士和同事在NIMH IRP中生成的5-羟色胺转运蛋白（5-HTT）敲除老鼠的表征。福尔摩斯博士发现了一个引人注目的焦虑样表型，该表型在三个不同的焦虑任务中得到了证实，即高架迷宫，光/黑暗的过渡任务以及在空旷的地方进行的出现测试。与 +/ +野生型同窝对照组相比，5-HTT - / - 的攻击得分较低。与抑郁症相关的任务显示5-HTT - / - 的基线行为正常，但缺乏对通过5-羟色胺转运蛋白起作用的抗抑郁药的反应。今年，Holmes博士和学生Inters Eric Gold将繁殖到C57BL/6J背景上的5-HTT突变体的行为表型与繁殖到129/SVEVTAC背景的行为表型。质量和定量差异表明在129个背景下进行保护基因，以防止5-HTT突变的有害作用。霍姆斯博士和戈德先生今年进行了进一步的研究，以评估5-HTT突变体在提示和上下文恐惧条件上，这是一项情感记忆任务。对挑战抗抑郁剂氟西汀和去丙胺剂量的敏感性表明对突变体与wildtype窝窝小鼠在这项情绪记忆任务上的差异作用。由于5-羟色胺参与了几种人类神经精神疾病，而5-HTT拮抗剂（例如百忧解）通常用于治疗抑郁症，因此5-HTT突变小鼠代表了一种有用的模型系统，可以进一步了解血清素能神经传递在精神疾病中的作用。 Crawley博士今年开始了一项新计划，以开发与自闭症相关的鼠标模型。这是与北卡罗来纳大学教堂山的研究人员的合作研究，特别是自闭症Staart项目主任Joseph Piven博士。小鼠行为遗传学实验被认为是发现与代表自闭症基本症状的社会缺陷有关的新基因。 Crawley博士设计了一个三个腔室的自动化设备，该设备衡量了小鼠的社交性和社会新颖性偏好。 NIMH研究服务部门乔治·多尔德（George Dold）建造了原型设备。博士。 Sheryl Moy和Jessica Nadler以及UNC神经发育障碍研究中心的技术人员在包括C57BL/6J，DBA/2J，FVB/NJ和A/J的小鼠中测试了该模型。社会倾向是通过各种菌株的新设备一致和定量评分的。