Communication within the Suprachiasmatic Neural Circadian Network

描述（由申请人提供）：生物钟最重要的功能是通过称为夹带的过程使身体活动与 24 小时明暗 (LD) 周期同步。人类和动物研究都证明了夹带对人类健康的至关重要性。在现实世界中，通过轮班工作或实验性地通过 LD 循环的慢性相移产生的夹带过程的不同步会增加许多疾病状态的发生率，包括癌症、心血管疾病和代谢紊乱。了解夹带中断如何产生疾病的病因学需要了解位于视交叉上核 (SCN) 的主生物钟中控制夹带的神经机制。 本研究的总体目标是确定 SCN 中负责控制昼夜节律的神经机制。在理解背内侧 SCN 如何发挥分子生物钟功能以及腹外侧 SCN 如何响应光方面已经取得了显着进展，但负责连接这两个关键功能的神经机制仍不清楚。也许这是因为光长期以来一直被认为可以立即重置生物钟（即非参数夹带），从而导致人们普遍认为 SCN 内负责将光传递给核心时钟的神经机制的持续时间非常短。相比之下，我们认为连接这两个重要昼夜节律功能的神经机制会在几个小时内运作，并且 GABA 是关键的神经化学信使。 这些研究将检验以下假设：SCN 内 GABA 受体的持续激活介导光的相移效应、SCN 内时钟基因的诱导，以及 GABA 的作用是由 GABA-A-TONIC 而不是由 GABA-A-PHASIC 或 GABA-B 受体介导的。如果我们确认 GABA 受体在几个小时内的持续激活介导了 SCN 中的光效应，那么 GABA 受体的这种相同类型的持续激活似乎也可能介导其他 CNS 部位的特定功能。此外，这些研究将提供有关 GABA 受体亚型功能及其可能的相互作用的重要新信息，这些相互作用应与 GABA 在整个 CNS 中的作用相关。了解 GABA 在大脑中的作用在临床上极为重要，因为许多药物都针对 GABA 受体，用于治疗从癫痫到焦虑等疾病。

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.