Stress and Circadian Rhythms

描述（由申请人提供）：基本上所有多细胞生物都表现出生理和行为的昼夜节律。这些节律（通过特定的相位关系）维持生物体与外部世界之间的同步，以及生理功能之间的内部同步。昼夜周期的快速变化改变了机体与外界之间的相位关系，通常需要几天到几周的时间才能完全恢复，在此期间，个体的内部同步被打乱。在人类中，这种现象被称为时差反应，它与身体、情绪和精神问题有关，如溃疡、抑郁和情绪困扰。这在轮班工人和长途旅行者中很常见。这一建议探讨了哺乳动物体内和外部昼夜节律同步恢复的延迟（反映在活动和皮质醇节律上），与褪黑激素携带（被认为最能反映SCN功能）的恢复相比，部分原因是由于光周期转移导致下丘脑-垂体-肾上腺轴（应激轴）的激活。我们假设中央昼夜节律机制，如褪黑激素节奏所反映的那样，比活动或皮质醇节奏更快地重新进入，并且褪黑激素节奏重新进入与压力轴无关。其次，我们预计，通过操纵压力轴来提高或减少压力，会同时增加或延迟相移后的活动和皮质醇节律的恢复速度，但褪黑激素的再携带将不受影响。为了验证这些假设，我们将使用微透析每小时测量一次皮质醇和褪黑激素，同时避免小型哺乳动物的失血问题。具体目标1将在一系列4个实验中确定再夹带率与皮质醇浓度和/或皮质醇昼夜节律之间的关系，这些实验在测量其他变量的同时独立操纵夹带率或皮质醇水平。具体目标2将确定褪黑激素、皮质醇和活动节律之间的关系，以验证褪黑激素节律以及中枢振荡器机制比其他节律恢复得更快的假设。更好地了解压力和昼夜节律系统之间的相互作用，将有助于对昼夜节律不同步的病理进行更彻底的研究，并可能导致减少不同步的治疗。

DESCRIPTION (provided by applicant): Essentially all multicellular organisms demonstrate circadian rhythms of physiology and behavior. These rhythms maintain synchrony (via specific phase relationships) between the organism and the outside world, as well as internal synchrony between physiological functions. A rapid change in the light:dark cycle alters the phase relationship between the organism and the outside world, typically requiring days to weeks for full recovery, during which time the internal synchrony of the individual is disordered. In humans, this phenomenon is referred to as jet lag and has been linked to physical, emotional, and psychiatric problems such as ulcers, depression, and emotional distress. It is common in shift workers and long-distance travelers. This proposal explores the possibility that the delay in recovery of internal and external circadian synchrony in mammals (reflected in activity and cortisol rhythms), as compared with the recovery of melatonin entrainment (thought to best reflect SCN function), is in part due to the activation of the hypothalamic-pituitary-adrenal axis (stress axis) as a result of the shifted light cycle. We hypothesize that the central circadian mechanism, as reflected in the melatonin rhythm, re-entrains faster than activity or cortisol rhythms, and that melatonin rhythm re-entrainment is independent of the stress axis. Secondarily, we expect that manipulating the stress axis so as to elevate or reduce stress will concomitantly increase or delay recovery rates of activity and cortisol rhythms after phase shifts, but that melatonin re-entrainment will be unaffected. To test these hypotheses we will use microdialysis to measure cortisol and melatonin at hourly intervals while avoiding the blood-loss problems for a small mammal. Specific Aim 1 will determine the relationship between re-entrainment rate and cortisol concentrations and/or circadian cortisol rhythm in a series of 4 experiments which independently manipulate entrainment rate or cortisol levels while measuring the other variable. Specific Aim 2 will determine the relationship between melatonin, cortisol and activity rhythms during re-entrainment to test the hypothesis that melatonin rhythm, and therefore the central oscillator mechanism, recovers more rapidly than other rhythms. Providing a better understanding of the interactions between stress and the circadian system will allow for a more thorough investigation of the pathology of desynchronized circadian rhythms and may lead to treatments to reduce the desynchrony.