Adaptation to Jet Lag in Animal Models

描述(申请人提供)：昼夜节律每天由中央起搏器引导到24小时的环境光-暗(LD)周期。随着LD周期的改变(当跨越时区旅行时)，在倒班工作中，以及在睡眠剥夺之后，缠绕的节奏被打乱。人们普遍认为，人类如何应对昼夜节律的中断存在很大的个体间差异。虽然有许多因素决定了昼夜节律在这种干扰后恢复的速度，但目前尚不清楚昼夜节律计时系统的哪些参数决定了适应的速度。使用松果体褪黑素作为时钟标记，研究了啮齿动物被扰乱的节律对新时区的适应。我们发现：(1)再捕获到延迟的LD周期是一个缓慢的过程；(2)在外交动物中，在携带条件下褪黑素的开始时间存在很大的个体间差异；(3)褪黑素开始的时间是光周期(光周期长度)的函数；(4)在远交大鼠中，随着LD周期的延迟转移，再捕获速率存在很大的个体间差异。值得注意的是，我们发现褪黑素出现的时间和再夹带的速度之间存在密切的联系。在这项修订的提案中，我们计划进一步研究啮齿动物褪黑激素分泌时间和再夹带率之间的关系。目标1将验证这一假设，即褪黑素开始得越早，动物在LD周期的延迟转移后重新进入的速度就越快，而不管这种转移的幅度有多大。在目标2中，我们将确定褪黑素分泌的开始时间与啮齿动物的内在周期之间的关系，并检验这样的假设，即昼夜节律周期越短，个体在LD周期延迟移位后重入的速度就越快，而不管移位的幅度如何。目的3将研究在短光周期和长光周期中褪黑素再携带速率与褪黑素开始时间之间的关系，以检验这样的假设，即夜间越短，个体在LD周期延迟移动后重新携带的速度就越快，而不考虑这种移动的幅度。其目的是在褪黑素再夹带速率和起效时间之间建立明确的关系。这项拟议的研究将影响我们对昼夜节律再牵引的基本理解，并将有助于我们理解人类如何应对时差、倒班工作和睡眠剥夺等昼夜节律中断。

DESCRIPTION (provided by applicant): Circadian rhythms are entrained daily to the environmental light-dark (LD) cycle of 24h by a central pacemaker. The entrained rhythms are disrupted following a shift of the LD cycle (when traveling across time zones), in shiftwork, and following sleep deprivations. It is widely recognized that large inter-individual variations exist in how humans cope with disruptions of circadian rhythms. While a large number of factors contribute to how fast circadian rhythms reentrain following such disruptions, it is not known what parameters of the circadian timing system determine the rate of adaptation. Adaptation of disrupted rhythms to a new time zone was investigated in rodents using pineal melatonin as a clock marker. We have found that (1) reentrainment to a delayed LD cycle is a slow process; (2) a large inter-individual variation exists in timings of melatonin onset under entrained conditions in outbred animals; (3) the timing of melatonin onset is a function of photoperiod (length of the light period); and (4) a large inter-individual variation exists in rate of reentrainment following a delay shift of the LD cycle in outbred rats. Remarkably, we have discovered a tight association between the timing of melatonin onset and the rate of reentrainment. In this revised proposal, we plan to further investigate the relationship between timings of melatonin secretion and rate of reentrainment in rodents. Aim 1 will test the hypothesis that the earlier the melatonin onset, the faster animals reentrain following a delay shift of the LD cycle, regardless the magnitude of the shift. In Aim 2, we will determine the relationship between onset timings of melatonin secretion and intrinsic period of rodents and test the hypothesis that shorter the circadian period, faster the individual reentrains following a delay shift of the LD cycle, regardless the magnitude of the shift. Aim 3 will examine the relationship between rate of reentrainment and timing of melatonin onset in both short and long photoperiod to test the hypothesis that the shorter the night period, the faster the individual reentrains following a delay shift of the LD cycle, regardless the magnitude of the shift. The goal is to establish an unambiguous relationship between the rate of reentrainment and timing of melatonin onset. The proposed studies will impact our basic understanding of circadian rhythm reentrainment, and will benefit our understanding of how humans cope with circadian disruptions such as jet lag, shift work, and sleep deprivations.