Transgenic animal models for neuroscience research

用于神经科学研究的转基因动物模型

• 批准号: 8158400
• 负责人: James Pickel
• 金额: $ 158.88万
• 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/8158400
• 关键词: Animal Model; Neurosciences Research; Transgenic Animals

SUMMARY The potential associations between human genes and mental disorders are being increasingly identified, but with these associations comes a conspicuous lack of understanding of how these genes function in an afflicted, or even a persumably normal brain. By creating animals with the same genetic changes and even some carrying entire human disease genes these associations can be tested. By producing mice with human disease alleles neuroscientists can study the behavioral, developmental, anatomical, cellular and biochemical levels of the disease. This approach allows the investigator to define the normal function of these genes. This method has been used to provide animal models for many research projects at the NIH IRP as well as with collaborators in the extramural program. The details of these experiments are described in investigators own reports. Below is a partial list of research projects the Transgenic core has pursued in the last year. A wide range of areas of investigation have benefited from animal models produced by the core facility. These projects can elucidate function at the level of specific molecules, gene expression, cell biology, neural circuits, learning, or complex behavior, and include studies of specific diseases. Schizophrenia: Mice with behavioral characteristics that resemble schizophrenia were produced by mating effecter mice from the core facility with responder mice. The latter carried a conditional ablation of the NMDA receptor. The offspring of these matings were engineered to lack NMDA receptors in a subset of corticolimbic interneurons. They displayed behavioral deficits in normal mating, nest-building and anxiety-like behavior. Memory dysfunction was also revealed in these animals. Stress: The role of a specific gene (catachol-O-methyltransferase) in the susceptibility to stress was demonstrated in mice that were engineered to have reduced levels of this gene. Learning and memory: The effect of specific and tightly controlled protein synthesis on learning and memory was studied. In addition, transgenic mouse models have been used to show the role of specific peptide-expressing cells to influence the link between fear and behavior and learning. Manipulating circuitry: Mice have been produced for two separate laboratories which have specific neurons that could be rendered transiently inactive by light activated ion channels. Those laboratories are investigating different neural circuits that are active in learning and addiction. Drug addiction: Lines of transgenic rats that express GFP in response to afferent input activation of the fos gene were generated in the core facility. These rats are being used by Bruce Hopes laboratory in NIDA to study patterns of neural activity in response to addictive drugs. Neurogenesis: Transgenic mice and, more recently, transgenic rats have been generated to study the role of neurogenesis in adults. From mid-gestation and continuing into old age, new neurons are produced in the brain. The role of new cells appearing in adults is especially interesting, and suggests a function in learning and memory and potential treatments for neurodegenerative disorders. Autism and Phelan-McDermid syndrome: Mice are being produced in the core facility in which expression of the SHANK3 gene can be manipulated. SHANK3 is the only gene to be conclusively linked to an autism spectrum disorder. Mucolipidosis IV: The mouse model of this disease resulted from a long-standing collaboration with the Slaugenhaupt laboratory and has continued to yield results, including a description of the neuropathy that may be associated with this disease. The core facility continues to distribute these animals. Familial dysautonomia: Another collaboration with the Slaugenhaupt lab resulted in a model for this disease. Lines carrying either a human normal or disease gene are being created in the core. These lines are crossed into a null line to replace the endogenous IKBKAP gene with its human disease equivalent. Glial activity reporters: The core produced a mouse line with a transgene that indicated the concentration of calcium in glial cells. By changes in its fluorescent properties, the calcium concentration and associated activity has been demonstrated in these cells. Reporter and effector mice and rats: Several lines that express effector molecules such as CRE recombinase at specific temporal and spatial compartments were produced. The core also created other lines that were used to report the activity of these and other recombinases. Mice, such as those from the Gensat project, were rederived and exported.

摘要 人们越来越多地认识到人类基因和精神障碍之间的潜在联系，但随之而来的是对这些基因在患病甚至完全正常的大脑中如何发挥作用的明显缺乏了解。通过创造具有相同基因变化的动物，甚至有些动物携带完整的人类疾病基因，可以测试这些联系。通过制造具有人类疾病等位基因的小鼠，神经科学家可以研究这种疾病的行为、发育、解剖、细胞和生化水平。这种方法使研究人员能够定义这些基因的正常功能。这种方法已经被用于为NIH IRP的许多研究项目以及与校外项目的合作者提供动物模型。这些实验的细节在调查人员自己的报告中有描述。 以下是转基因核心在过去一年中进行的部分研究项目。核心设施生产的动物模型使广泛的调查领域受益。这些项目可以在特定分子、基因表达、细胞生物学、神经回路、学习或复杂行为的水平上阐明功能，并包括对特定疾病的研究。 精神分裂症：具有类似精神分裂症的行为特征的小鼠是通过核心设施的效应鼠与反应鼠交配而产生的。后者进行了有条件的NMDA受体的消融。这些交配的后代被设计成在皮质边缘中间神经元的子集中缺乏NMDA受体。它们在正常交配、筑巢和类似焦虑的行为上表现出行为缺陷。在这些动物身上也发现了记忆功能障碍。 压力：一种特定的基因(卡巴胆碱-O-甲基转移酶)在压力易感性中的作用在转基因小鼠中被证明是降低了该基因的水平。 学习和记忆： 研究了特定和严格控制的蛋白质合成对学习和记忆的影响。此外，转基因小鼠模型已经被用来显示特定的多肽表达细胞在影响恐惧、行为和学习之间的联系方面所起的作用。 操纵电路：已经为两个独立的实验室制造了小鼠，这两个实验室有特定的神经元，这些神经元可以通过光激活的离子通道暂时不活动。这些实验室正在研究活跃在学习和成瘾中的不同神经回路。 药物成瘾：在核心设施中产生了转基因大鼠系，这些转基因大鼠在传入输入激活FOS基因的情况下表达GFP。布鲁斯·霍普斯在NIDA的实验室正在使用这些老鼠来研究对成瘾药物做出反应的神经活动模式。 神经发生：已经产生了转基因小鼠和最近的转基因大鼠，以研究成年神经发生的作用。从妊娠中期到老年，大脑中会产生新的神经元。在成人中出现的新细胞的作用特别有趣，这表明它在学习和记忆中具有功能，并可能治疗神经退行性疾病。 自闭症和费兰-麦克德米德综合征：在核心设施中正在制造小鼠，在那里可以操纵SHANK3基因的表达。SHANK3是唯一与自闭症谱系障碍有确凿联系的基因。 粘脂症IV：这种疾病的小鼠模型是与斯拉根豪普特实验室长期合作的结果，并继续取得成果，包括对可能与这种疾病相关的神经病变的描述。核心设施继续分发这些动物。 家族性自主神经障碍：与斯拉根豪普特实验室的另一项合作导致了这种疾病的模型。携带人类正常或疾病基因的品系正在核心中被创造出来。这些品系被交叉成一个空品系，用与人类疾病等同的内源性IKBKAP基因替换。 神经胶质活性报告：核心产生了一个转基因小鼠品系，表明神经胶质细胞中钙的浓度。通过其荧光性质的变化，已经证实了这些细胞中的钙浓度和相关活性。 报告和效应小鼠和大鼠：在特定的时间和空间间隔产生了几个表达效应分子(如Cre重组酶)的线条。核心还创建了其他用于报告这些重组酶和其他重组酶活性的品系。 小鼠，如来自Gensat项目的小鼠，被重新衍生并出口。