Transgenic animal models for neuroscience research

人类基因和精神障碍之间的潜在联系正在被越来越多地发现。但随着这些联系的出现，人们明显缺乏对这些基因在患病的、甚至可能是正常的大脑中如何发挥作用的了解。通过创造具有相同基因变化的动物，甚至一些携带人类疾病基因的动物，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。通过这种方法，可以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。 以下是我们的研究项目的部分清单，这些项目表明了从核心设施生产的动物模型中受益的调查领域的范围。这些项目涵盖了广泛的神经科学实验，涉及特定分子、基因表达、细胞生物学、神经回路、学习、复杂行为，并包括对特定疾病的研究。 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：在过去的一年里，转基因小鼠模型被用来展示特定蛋白质合成在学习和记忆中的作用。其他转基因小鼠模型已经被用来展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的作用。 神经发生：从妊娠中期到老年，大脑中产生新的神经元。这些出现在成年人身上的新细胞的作用特别有趣，它表明了一种学习和记忆功能，以及可能治疗神经退行性疾病的方法。 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。它们被交叉成一条空线，用与人类疾病等同的内源性IKBKAP基因取代。CORE今年生产了几个新的品系，以测试该基因的多个副本的效果。 神经胶质细胞的活性：核心产生了一个转基因小鼠系，表明神经胶质细胞中钙的浓度。通过其荧光性质的变化，已经证明了这些细胞中的钙浓度和相关的活性。 操纵电路：在两个不同的实验室中，已经产生了可以使特定神经元暂时处于不活动状态的小鼠。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。 报告和效应小鼠：产生了几个在特定的时间和空间间隔表达效应器分子如Cre重组酶的品系。用于报告这些重组酶和其他重组酶活性的其他品系也被创建。老鼠，例如来自Gensat项目的老鼠被重新衍生并出口。 转基因大鼠：技术开发项目已经允许核心为三个NIH内部研究所的研究人员生产转基因大鼠。

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 presumably normal brain. By creating animals with the same genetic changes and even some carrying 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. From this approach the normal function of these genes can be defined. This approach 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 our research projects that suggests the scope of the areas of investigations that have benefited from animal models produced by the core facility. These projects cover a wide range of neuroscience experiments at the level of specific molecules, gene expression, cell biology, neural circuits, learning, complex behavior, and include studies of specific diseases. 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: In the past year transgenic mouse models have been used to show the role of specific protein synthesis on learning and memory. Other 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. Neurogenesis: From mid-gestation and into old age, new neurons are produced in the brain. The role of these new cells that appear in adults is especially interesting, and suggests a function in learning and memory and potential treatments for neurodegenerative disorders. 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. The lines that carry either a human normal or disease gene are being created in the core. Those are crossed into a null line to replace the endogenous IKBKAP gene with its human disease equivalent. The core produced several new lines this year to test the effect of multiple copies of the gene. Activity in glial cells: 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. Manipulating circuitry: Mice in which specific neurons could be rendered transiently inactive have been produced for two separate laboratories. Those laboratories are investigating different neural circuits that are active in learning and addiction. Reporter and effector mice: Several lines that express effector molecules like CRE recombinase at specific temporal and spatial compartments were produced. Other lines that were used to report the activity of these and other recombinases were created. Mice, such as those from the Gensat project were rederived and exported. Transgenic rats: Technological development projects have allowed the core to produce transgenic rats for investigators in three NIH intramural institutes.