Communication within the Suprachiasmatic Neural Circadian Network

描述(申请人提供)：生物钟最重要的功能是通过一种称为夹带的过程，使身体活动与24小时的光-暗(LD)周期同步。人类和动物研究都证明了夹带对人类健康的关键重要性。在现实世界中，由于轮班工作或实验上由于LD周期的慢性相移而产生的卷吸过程的去同步化，增加了许多疾病状态的发生率，包括癌症、心血管疾病和代谢紊乱。要了解夹带中断引起的疾病的病因学，需要了解位于视交叉上核(SCN)的主昼夜节律钟中控制夹带的神经机制。这项拟议研究的总体目标是确定在SCN中负责携带昼夜节律的神经机制。在理解背内侧SCN如何作为分子生物钟以及腹外侧型SCN如何对光作出反应方面已经取得了显着的进展，但负责连接这两个关键功能的神经机制仍不清楚。也许这是因为长期以来，人们一直认为光可以瞬间重置生物钟(即非参数缠绕)，导致人们普遍认为，SCN内负责将光传递给核心时钟的神经机制持续时间非常短。相反，我们认为连接这两个重要的昼夜节律功能的神经机制运行几个小时，GABA是关键的神经化学信使。这些研究将检验这样的假设：SCN内GABA受体的持续激活介导了光的相移效应，SCN内时钟基因的诱导，以及GABA的作用是由GABA-A紧张性而不是通过GABA-A相或GABA-B受体介导的。如果我们证实GABA受体在几个小时内的持续激活在SCN中介导了光的效应，那么这种相同类型的GABA受体的持续激活似乎也可能在其他中枢神经系统部位调节特定的功能。此外，这些研究将提供关于GABA受体亚型的功能及其可能的相互作用的重要新信息，这些信息应该与整个中枢神经系统的GABA作用相关。了解GABA在大脑中的作用在临床上极其重要，因为有许多药物针对从癫痫到焦虑等疾病的GABA受体。 公共卫生相关性：人类和动物研究发现，身体时间组织的不同步会产生广泛的健康问题，包括癌症、心血管疾病和影响数百万人的睡眠-唤醒障碍的发病率增加。由于这些去同步化通常是由昼夜节律夹带过程中的干扰引起的，因此了解位于视交叉上核的主昼夜节律钟夹带的机制至关重要。该项目旨在确定这些机制，从而提供对昼夜去同步化如何产生这些病理的理解。

DESCRIPTION (provided by applicant): The most important function of circadian clocks is the synchronization of bodily activities with the 24 hr light-dark (LD) cycle through a process called entrainment. The critical importance of entrainment to human health has been demonstrated in both human and animal studies. Desynchrony of the entrainment process produced in the real world by shift work or experimentally by chronic phase shifts of the LD cycle increases the incidence of many disease states including cancer, cardiovascular disease and metabolic disorders. Understanding how the etiology of the disorders produced by disruptions in entrainment will require understanding the neural mechanisms controlling entrainment in the master circadian clock located in the suprachiasmatic nucleus (SCN). The overall goal of the proposed research is to identify the neural mechanisms responsible for entrainment of circadian rhythms in the SCN. Remarkable progress has been made in understanding how the dorsomedial SCN functions as a molecular circadian clock as well as how the ventrolateral SCN responds to light however the neural mechanisms responsible for linking these two critical functions remains unclear. Perhaps this is because light has long been considered to reset the circadian clock instantaneously (i.e., non-parametric entrainment), resulting in the general assumption that the neural mechanisms within the SCN responsible for communicating light to the clock in the core would be of a very short duration. In contrast, we propose that the neural mechanisms that link these two important circadian functions operate over several hours and that GABA is the critical neurochemical messenger. These studies will test the hypotheses that the sustained activation of GABA receptors within the SCN mediates the phase shifting effects of light, the induction of clock genes within the SCN, and that the effects of GABA are mediated by GABA-A-TONIC and not by GABA-A-PHASIC or GABA-B receptors. If we confirm that the sustained activation of GABA receptors over several hours mediates the effects of light in the SCN, it seems likely that this same type of sustained activation of GABA receptors might mediate specific functions in other CNS sites as well. In addition, these studies will provide important new information on functions of GABA receptor subtypes and their possible interactions that should be relevant to GABA action throughout the CNS. Understanding how GABA acts in the brain is extremely important clinically because of the many drugs that target GABA receptors for diseases ranging from epilepsy to anxiety. PUBLIC HEALTH RELEVANCE: Human and animal research have found that desynchrony of the temporal organization of the body produces a wide range of health problems including increased incidence of cancer, cardiovascular disease and sleep-wake disorders that affect millions of people. Since these desynchronies often result from disruptions in the process of circadian entrainment it is critical to understand the mechanisms that underlie entrainment in the master circadian clock located in the suprachiasmatic nucleus. This project aims to identify these mechanisms and thereby provide an understanding of how circadian desynchrony can produce these pathologies.