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，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，我们已经开发和完善了一个多层次的策略，小鼠行为表型。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。 在过去的一年里，博士后研究员Andrew Holmes博士扩大了5-羟色胺转运蛋白（5-HTT）敲除小鼠的特征，该小鼠由Dennis Murphy博士和NIMH IRP的同事产生。霍姆斯博士发现了一种惊人的焦虑样表型，在三种不同的焦虑任务中得到了证实，高架十字迷宫，明/暗转换任务和开放领域的出现测试。与+/+野生型同窝对照组相比，5-HTT -/-组的攻击性评分较低。抑郁症相关的任务显示正常的基线行为在5-HTT -/-，但缺乏反应的抗抑郁药，通过血清素转运体的作用。今年，Holmes博士和实习生Eric Gold比较了在C57 BL/6 J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。定性和定量差异表明129背景中的保护性基因防止5-HTT突变的有害作用。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突变体对线索和情境恐惧条件反射的影响，这是一项情绪记忆任务。对抗抑郁药氟西汀和地昔帕明的激发剂量的敏感性表明突变型与野生型同窝小鼠在这种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，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，以进一步了解神经递质神经传递在精神疾病中的作用。 博士克劳利今年开始了一项新的计划，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州查佩尔山大学的研究人员合作的研究，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为了发现与代表自闭症基本症状的社会缺陷相关的新基因。克劳利博士设计了一种三腔自动化装置，用于测量小鼠的社交能力和社交新奇偏好。乔治多尔德，NIMH研究服务分支，建立了原型装置。Sheryl Moy和Jessica Nadler博士以及美国神经发育障碍研究中心的技术人员在近交系小鼠中测试了该模型，包括C57 BL/6 J，DBA/2 J，FVB/NJ和A/J。