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存在很大差异。具体而言，不同近交系之间锥体内和锥体下苔藓纤维 (IIPMF) 末端区域的大小相差约 4-5 倍。我们实验室早期的实验表明，这些变异在很大程度上是遗传性的，遗传力达到50%甚至更高。神经元回路的这些变化可以预测小鼠在径向迷宫中的空间学习任务中的表现：具有较大 IIPMF 预测的动物犯的错误较少。径向迷宫的表现也是可遗传的，遗传率为 25-30%。 IIPMF 大小与径向迷宫学习之间的遗传相关性约为 0.90，表明约 80% 的遗传变异是共享的。在此应用中，我们建议测试径向迷宫学习并测量 BXD 重组近交系 (RIS) 小鼠的 IIPMF 大小。直到最近，已有 34 个 BXD R1 菌株可用，但新开发了 45 个附加菌株，从而大大提高了使用该重组近交菌株组绘制数量性状基因座 (QTL) 的能力和精度。在目标 1 下，我们建议定位调节径向迷宫学习的 QTL。在目标 2 下，我们打算定位影响 IIPMF 大小的 QTL。在目标 3 下，我们将鉴定同时影响学习能力和海马结构的多效性 QTL。最后，我们将使用公开的基因表达数据，使用基于互联网的工具 WebQTL (www.webqtl.org) 进行转录组分析。这项工作的意义在于它将提供对正常认知变异原因的洞察。鉴于超过 99% 的基因在人类和小鼠之间都是保守的，这将增进我们对病理变异（例如智力低下和痴呆）原因的理解。