BEHAVIORAL ANALYSIS OF A MOUSE MODEL OF DOWN SYNDROME

6唐氏综合征Ts65Dn小鼠模型表现出行为学特征， 表型与DS的人表型的方面一致。目标 这一建议首先是继续确定行为 表型，然后开始确定 过度表达的基因产生神经和行为功能的机制 表型因为DS是一种复杂的疾病，没有一个大脑区域 负责认知表型。同样，在这个Ts65Dn模型中， 迄今为止的发现涉及多个大脑区域，即 前额皮质海马体小脑也许还有杏仁核 了解这些多个区域的缺陷如何相互作用， DS表型将需要彻底探索 表型。我们将使用情境和线索恐惧条件反射，熟练 到达，链接行为，参考和工作记忆，延迟和 交替和一系列眨眼条件反射模式。我们的方法 从一开始就以研究和理论化为指导， 我们的同事（彭宁顿和纳德尔）在项目8。在新的补助金中 在此期间，我们已经设计了平行实验，未来将 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，关于神经系统参与DS的假说 可以在动物身上进行测试。的假设 关于神经参与DS的测试是，基底前脑 和内侧隔胆碱能神经元参与了前额叶和 海马缺陷的小鼠模型。这将是测试， 通过一个完善的产前控制系统来控制这些胆碱能系统， 补充胆碱和检查胆碱能神经的数量和大小 海马和皮质神经元上的神经元和树突自旋。的作用 干扰素受体在胆碱能神经系统中的过度产生 将通过Ts65Dn小鼠与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，我们将 利用其他项目生产的转基因和基因敲除小鼠， 可用于确定其他单个基因和基因 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.