BEHAVIORAL ANALYSIS OF A MOUSE MODEL OF DOWN SYNDROME

6Ts65Dn唐氏综合征小鼠模型已证实为行为 表型与人类DS表型的某些方面一致。目标 这一建议首先要继续确定行为 这个有趣的模型的表型和第二个开始确定 过度表达的基因产生神经和行为的机制 表型。因为DS是一种复杂的疾病，没有一个大脑区域是 对认知表型负责。同样，在这款Ts65Dn模型中， 到目前为止的发现涉及到多个大脑区域，即 前额叶皮质、海马体、小脑，也许还有杏仁核。 了解这多个地区的赤字是如何相互作用产生的 DS表型将需要彻底探索行为 表型。我们将使用情景和暗示的恐惧条件作用，熟练 到达，连锁行为，参考和工作记忆，延迟和 交替和一系列眨眼条件反射范例。我们的方法 在这个目标上，从一开始就以研究和理论化为指导 我们的同事(Pennington和Nadel)参与了项目8。在新的赠款中 期间，我们已经设计了并行实验，并将在未来 能够利用他们在人类身上的发现来设计测试 动物模型。此外，有关神经系统参与DS的假说 从人类工作中衍生出来的东西可以在动物身上进行测试。假说 关于DS的神经参与，需要测试的是基底前脑 内侧隔区胆碱能神经元参与前额叶和 这个小鼠模型中的海马区缺失。这将由以下人员测试 用一个成熟的产前来操纵这些胆碱能系统 胆碱补充与胆碱能神经元数和大小的检测 海马神经元和皮质神经元上的神经元和树突。角色 胆碱能神经元中干扰素受体的过度产生 通过将Ts65Dn小鼠与基因敲除小鼠杂交来测试表型 使这些受体的拷贝数正常化。此外，我们还将 利用其他项目生产的转基因和基因敲除小鼠 可以用来确定其他个体基因和基因的作用 DS认知表型中的区域。

6The Ts65Dn mouse model of Down syndrome has demonstrated as behavioral phenotype consistent with aspects of the human phenotype of DS. The aims of this proposal are first to continue to determine the behavioral phenotype of this interesting model and second to begin to determine the mechanisms by which over-expressed genes produce the neural and behavioral phenotype. Because DS is a complex disorder, no one brain region is responsible for the cognitive phenotype. Similarly, in this Ts65Dn model, multiple brain regions are implicated by the findings to date, namely the prefrontal cortex, hippocampus, cerebellum and perhaps amygdala. Understanding how deficits in these multiple regions interact to produce the DS phenotype will require a thorough exploration of the behavioral phenotype. We will use contextual and cued fear conditioning, skilled reaching, chaining behavior, reference and working memory, delayed and alternation and a range of eyeblink conditioning paradigms. Our approaches in this aim have from the start been guided by the research and theorizing of our colleagues (Pennington and Nadel) on Project 8. In the new grant period, we have designed experiments in parallel, and in future will be able to make use of their findings with humans to design tests for the animal models. In addition, hypothesis about neural systems involved in DS that derive from the human work can be tested in animals. The hypothesis to be tested regarding neural involvement in DS is that basal forebrain and medial septal cholinergic neurons are involved in the prefrontal and hippocampal deficits in this mouse model. This will be testing by manipulating these cholinergic systems with a well-established prenatal choline supplementation and examining number and size of cholinergic neurons and dendritic spins on hippocampal and cortical neurons. The role of the over production of interferon receptors in the cholinergic phenotype will be tested by crossing the Ts65Dn mice with knockout mice for these receptors to normalize their copy number. In addition, we will make use of transgenic and knockout mice produced by other projects that can be used to determine the role of other individual genes and gene regions in the cognitive phenotype of DS.