GENETIC VARIATION INFLUENCING SLEEP REGULATION

这项提议试图确定与小鼠睡眠和睡眠脑电的正常表达和调节有关的基因。在近交系小鼠中，我们已经确定了几种与睡眠和脑电相关的表型，这些表型随着基因的不同而变化很大。在这项建议中，我们打算在这些表型差异最大的近交系的分离后代中遵循这些候选表型。我们建议首先研究从两个祖先品系(即AKR x DBA/2)衍生的21个重组近交系(RI)小鼠的“候选”表型的分离。随后对杂交后代和/或回交后代的表型和基因分型将产生关于基因组定位的更详细的信息，这些信息可用于解释感兴趣性状的基因变异(QTL定位和连锁分析)。此外，我们可以利用睡眠中这些自发的物种内差异来回答基本的睡眠生理学问题。这些问题涉及SWS和REMS的动态平衡调节，它们之间的相互作用以及与脑温度的相互作用，以及通过EEG增量功率测量SWS强度的神经生理基础。我们发现AKR和DBA/2的SWS增量功率随觉醒增加的时间常数的巨大差异是特别有趣的，因为这表明睡眠需求的积累是受基因控制的。识别睡眠和睡眠脑电正常表达和调节的遗传因素将进一步加深我们对支配睡眠的神经生理机制的理解，并可能对一般睡眠障碍，特别是那些具有遗传易感性的睡眠障碍产生重大影响。

This proposal seeks to identify genes implicated in the normal expression and regulation of sleep and the sleep EEG in mice. We have identified several sleep and EEG related phenotypes that strongly vary with genotype in inbred strains of mice. In this proposal, we intend to follow these candidate phenotypes in segregating progeny derived from the inbred strains for which these phenotypes differed the most. We propose to first study the segregation of "candidate" phenotypes in a set of 21 recombinant inbred (RI) strains of mice that were derived from two progenitor strains (i.e. AKR x DBA/2). Subsequent pheno- and genotyping of inter-and/or backcross progeny will yield more detailed information on genomic localizations that may be used to explain genotypic variance in the traits of interest (QTL-mapping and linkage analysis). Furthermore, we can make use of these spontaneous intra-species differences in sleep to answer basic sleep physiology issues. These issues concern the homeostatic regulation of SWS and REMS, their interaction with each other and with brain temperature, and the neurophysiological substrate of SWS intensity measured by EEG delta power. The large difference in the time constant of the wakefulness-dependent increase in SWS delta power between AKR and DBA/2 that we have found, is of special interest because it suggests that the accumulation of sleep need is under genetic control. Identifying genetic factors underlying the normal expression and regulation of sleep and the sleep EEG will further our understanding of the neurophysiological mechanisms that govern sleep and will potentially have large implications for sleep disorders in general and those with a genetic predisposition in particular.