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Molecular basis for emotional behavior

情绪行为的分子基础

基本信息

批准号：
11480234
负责人：
YAGI Takeshi
金额：
$ 8.7万
依托单位：
Osaka University (2000-2001)Okazaki National Research Institutes (1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

To understand molecular basis for emotional behavior in mammals, we used reverse genetics in mice. Previously produced gene-knockout mice in Fyn protein-tyrosine kinase had several behavior abnormalities for regulating emotional behaviors. Therefore in this research project, we placed Fyn molecule as emotional regulator in mammalian brain. This project has revealed that Fyn plays significant roles for regulating axonal guidance, myelin formation, synapse function and brain structure formation. In addition, cadherin-related neuronal receptor (CNR) family was5 initially identified as synaptic cadherins bound to Fyn-tyrosine kinase. To elucidate the molecular basis for regulating emotional behavior, we focused on CNR family bound to Fyn. The genomic organization of the CNR family genes, composed of variable and constant regions, is similar to that of immunoglobulin gene clusters. Fyn-deficient mice exhibited a disordered neuronal cell layer in the hippocampus and in the cerebral cortex. In mammals, CNR family proteins and Fyn were commonly expressed in the neurons of the cortical layer. The well-conserved first cadherin domain of CNR family protein plays a significant role in the interaction with Reelin protein during cortical layer development. Interestingly, among vertebrates, the gene clusters are phylogenetically different. Furthermore when we examined somatic regulation in CNR family gene during brain development, somatic mutation of CNR3 transcripts accumulated. High rate of replacement (amino acid exchange) mutations were detected in the first cadherin domain. The somatic alterations have interesting implications for the molecular basis-underlying establishment of somatic rearrangement of neuronal networks.

为了了解哺乳动物情绪行为的分子基础，我们在小鼠身上使用了反向遗传学。之前生产的 Fyn 蛋白酪氨酸激酶基因敲除小鼠在调节情绪行为方面存在多种行为异常。因此，在这个研究项目中，我们将Fyn分子作为哺乳动物大脑中的情绪调节剂。该项目揭示了 Fyn 在调节轴突引导、髓磷脂形成、突触功能和大脑结构形成方面发挥着重要作用。此外，钙粘蛋白相关神经元受体 (CNR) 家族最初被鉴定为与 Fyn 酪氨酸激酶结合的突触钙粘蛋白。为了阐明调节情绪行为的分子基础，我们重点关注与 Fyn 结合的 CNR 家族。 CNR 家族基因的基因组组织由可变区和恒定区组成，与免疫球蛋白基因簇的基因组组织相似。 Fyn 缺陷小鼠的海马体和大脑皮层神经元细胞层出现紊乱。在哺乳动物中，CNR 家族蛋白和 Fyn 通常在皮质层神经元中表达。 CNR 家族蛋白保守的第一个钙粘蛋白结构域在皮质层发育过程中与 Reelin 蛋白的相互作用中发挥着重要作用。有趣的是，在脊椎动物中，基因簇在系统发育上是不同的。此外，当我们检查大脑发育过程中 CNR 家族基因的体细胞调节时，CNR3 转录本的体细胞突变不断累积。在第一个钙粘蛋白结构域中检测到高替换率（氨基酸交换）突变。体细胞的改变对于神经元网络体细胞重排建立的分子基础具有有趣的意义。