Genetic Dissection of a Motor Central Pattern Generator

描述（由申请人提供）：中枢模式发生器（cpg）是有节奏的活跃神经网络，是许多刻板和重复的随意肌肉运动（如搅拌或舔液体）的基础。啮齿动物的液体舔舐是CPG的一个有希望的简单模型：这是一种高度刻板的行为，以有节奏的舌头和下巴运动为特征，并且被认为是由分布在脑干髓质网状结构中的神经基质控制的。在初步观察中，我们已经证明小鼠是研究舔舐CPG遗传基础的一个极好的物种选择-常见的近交系C57BL/6J （B6）和DBA/2J （D2）在舔舐率方面具有强大的，非重叠的表型差异。对舔舐率差异的基因鉴定将为CPGs的研究带来巨大的回报。然后，可以用基因靶向缺失或插入来创建小鼠，从而允许进行特定的生理或解剖研究。我们建议利用一个新增加的资源来进行舔的遗传解剖：BXD高级重组自交系（Rl）菌株集。这些小鼠将允许对行为特征基础上的数量性状位点（QTL）进行精确的遗传定位。我们提出了一种新的高通量舔舐率测定方法，对一组-80个BXD Rl菌株进行了测试，并高精度地绘制了菌株舔舐率变化的数量性状位点（qtl）。相关性：像人类这样的复杂动物具有许多运动反应，这些反应在本质上是刻板的和/或重复的。比较模式化重复运动与可塑性行为的基因和机制将为涉及异常重复运动的许多人类CMS疾病提供相关信息。

DESCRIPTION (provided by applicant): Central pattern generators (CPGs) are rhythmically active neural networks that underlie many stereotyped and repetitive voluntary muscle movements such as whisking or fluid licking. Fluid licking in rodents is an example of a promising, simple model of a CPG: It is a highly stereotyped behavior characterized by rhythmic tongue and jaw movements, and it is thought to be controlled by a neural substrate distributed in the medullary reticular formation in the brainstem. In preliminary observations, we have demonstrated that mice are a superb species choice for investigating the genetic basis of the licking CPG - the common inbred strains C57BL/6J (B6) and DBA/2J (D2) have a robust, non-overlapping phenotypic difference in lick rate. The identification of genes underlying differences in lick rate should have a huge payout for the study of CPGs. Mice can then created with gene-targeted deletions or insertions, allowing for specific physiological or anatomical investigation. We propose to take advantage of a newly augmented resource for our genetic dissection of licking: The BXD advanced recombinant inbred (Rl) strain set. These mice will allow for precision genetic mapping of quantitative trait loci (QTL) that underlie behavioral traits. We propose to use a novel high-throughput assay for lick rate to test a set of -80 BXD Rl strains, and map quantitative trait loci (QTLs) with high precision that underlie strain variation in lick rate. Relevance: Complex animals such as humans possess a number of motor responses that are stereotypic and/or repetitive in nature. Comparison of the genes and mechanisms underlying stereotyped repetitive movements versus plastic behaviors will be a source of information relevant for a number of human CMS disorders involving abnormal repetitive movements.