Genetic regulation of hippocampal anatomy and learning

海马解剖和学习的基因调控

• 批准号: 6968513
• 负责人: Wim E. Crusio
• 金额: $ 21.41万
• 依托单位: CNRS DELEGATION AQUITAINO-LIMOUEIN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968513
• 关键词: Internet; behavioral /social science research tag; behavioral genetics; biomarker; gene expression; genetic mapping; genetic strain; genetic transcription; genetically modified animals; hippocampus; inbreeding; laboratory mouse; learning; mossy fiber; neuroanatomy; performance; quantitative trait loci

DESCRIPTION (provided by applicant): Large variations exist in hippocampal neuroanatomy in mice. Specifically, the sizes of the intra-and infrapyramidal mossy fiber (IIPMF) terminal fields differ about 4-5 fold between different inbred strains. Earlier experiments from our laboratory have shown that these variations are hereditary to a large extent, with a heritability of 50% or larger. These variations in neuronal circuitry are predictive of the performance of mice in a spatial learning task in a radial maze: animals with larger IIPMF projections commit fewer errors. Radial maze performance is heritable, too, with heritabilities of 25-30%. The genetic correlation between the size of the IIPMF and radial maze learning is around 0.90, indicating that about 80% of the genetic variation is shared. In this application, we propose to test radial maze learning and measure IIPMF sizes in mice from the BXD Recombinant Inbred Strains (RIS). Up until recently, 34 BXD Rl strains were available, but 45 additional strains have newly been developed, thereby greatly enhancing the power and precision with which Quantitative Trait Loci (QTL) can be mapped using this recombinant inbred strain set. Under Aim 1, we propose to localize QTL regulating radial maze learning. Under Aim 2, we intend to localize QTL influencing IIPMF sizes. Under Aim 3, we will identify pleiotropically acting QTL that influence learning abilities and hippocampal structure simultaneously. Finally, we will use publicly available gene expression data to perform a transcriptome analysis using the Internet.based tool WebQTL (www.webqtl.org). The significance of this work lies in the insight it will provide into the causes of normal cognitive variation. Given the fact that over 99% of all genes are conserved between humans and mice, this will advance our understanding of the causes of pathological variation, such as mental retardation and dementia.

描述（由申请人提供）：小鼠海马神经解剖学中存在较大的变化。具体而言，在不同的近交菌株之间，内部和肾上腺膜状苔藓纤维（IIPMF）末端场的尺寸约为4-5倍。我们实验室的早期实验表明，这些变化在很大程度上是遗传性的，其遗传力为50％或更大。神经元电路中的这些变化可预测小鼠在径向迷宫中的空间学习任务中的性能：具有较大IIPMF投影的动物会造成更少的错误。径向迷宫的性能也是遗传性的，遗传性为25-30％。 IIPMF和径向迷宫学习之间的遗传相关性约为0.90，表明共享约80％的遗传变异。在此应用中，我们建议通过BXD重组近交菌株（RIS）测试小鼠的径向迷宫学习并测量IIPMF的大小。直到最近，还提供了34个BXD RL菌株，但新开发了45个额外的菌株，从而大大提高了可以使用此重组材料菌株绘制定量性状基因座（QTL）的功率和精度。在AIM 1下，我们建议定位调节径向迷宫学习的QTL。在AIM 2下，我们打算将影响IIPMF尺寸的QTL定位。在AIM 3下，我们将确定同时影响学习能力和海马结构的多效性QTL。最后，我们将使用公开可用的基因表达数据来使用Internet.toot.tool WebQTL（www.webqtl.org）执行转录组分析。这项工作的意义在于它将提供给正常认知变化的原因的见解。鉴于所有基因中有99％以上是人类和小鼠之间的保守，这将促进我们对病理变异的原因（例如智力低下和痴呆症）的理解。