Genetics of rest:activity behavior in the mouse

描述（由申请人提供）：我们研究的长期目标是确定参与调节小鼠休息活动行为的分子事件的遗传因素。我们采用前向遗传学方法来确定导致活动水平或休息组织的总体变化的单基因突变：活动周期。这些变化可能是由于一般的代谢或发育缺陷，或由神经生物学过程的异常引起的，如昼夜节律系统和睡眠调节。我们已经建立了一个完整的和嵌套的表型协议，这将使我们能够在几个层面上表征新的突变；分子，神经病理，电生理和行为学。我们的目标是：目标1)通过随机ENU （n -乙基-n -亚硝基脲）诱变鉴定的休息/活性突变体的遗传特征、定位和定位克隆；1)目的2)选定休息时睡眠模式的特征：活动突变体；目的3)确定休息的特异性：活动障碍；目的4)微阵列分析将用于确定被突变基因破坏的下游途径。最初，该项目包括两个突变的遗传和表型特征，一个影响昼夜节律（Rooster），另一个是Bedlam，与昼夜节律幅度下降有关。

DESCRIPTION (provided by applicant): The long term goal of our studies is to identify genetic factors that underlie molecular events involved in the regulation of rest:activity behavior in the mouse. We employed forward genetics approach to identify single gene mutations that cause gross changes in activity levels or organization of rest:activity cycles. These changes may be due to general metabolic or developmental defects, or caused by anomalies in neurobiological processes, such as the circadian system and regulation of sleep. We have established an integrated and nested phenotypic protocol, which will allow us to characterize novel mutations on several levels; molecular, neuropathological, electrophysiological and behavioral. Our aims are: Aim 1) Genetic characterization, mapping and positional cloning of rest/activity mutants, identified by random ENU (N-ethyl-N-nitrosourea) mutagenesis; 1) Aim 2) Characterization of sleep patterns in selected rest:activity mutants; Aim 3) Determination of the specificity of rest:activity disturbances; Aim 4) Microarray analysis will be used to define downstream pathways disrupted by the mutant gene. Initially, this project includes genetic and phenotypic characterization of two mutations, one with an effect on circadian period (Rooster), and second, Bedlam, associated with a decreased amplitude of the circadian rhythms. Our hypothesis is that a subset of rest:activity mutations will uncover novel genes involved in the regulation of sleep and their interaction with the other neurobiological processes, such as those that underlie learning and memory or circadian system. Human orthologs of loci defined by these single gene mutations may represent additive or interactive contributions to the polygenic component of inherited psychiatric and sleep disorders.