Communication within the Suprachiasmatic Neural Circadian Network

视交叉上神经昼夜节律网络内的通信

• 批准号: 8686095
• 负责人: H. Elliott Albers
• 金额: $ 32.05万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686095
• 关键词: Affect; Animal Experimentation; Animals; Anxiety; Behavior; Brain; Cardiovascular Diseases; Chronic Phase; Circadian Rhythms; Communication; Data; Disease; Drug Targeting; Epilepsy; Etiology; GABA Agonists; GABA Antagonists; GABA Receptor; GABA-B Receptor; Gene Expression; Genes; Goals; Health; Hour; Human; Incidence; Knowledge; Light; Lighting; Link; Malignant Neoplasms; Mediating; Messenger RNA; Metabolic Diseases; Molecular; Pathology; Phase; Physiology; Population; Process; Receptor Activation; Research; Site; Sleep; System; Testing; Time; Work; cancer risk; circadian pacemaker; gamma-Aminobutyric Acid; insight; light effects; neurochemistry; neuromechanism; neurotransmission; novel; relating to nervous system; research study; shift work; suprachiasmatic nucleus; theories

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.

描述（由申请人提供）：生物钟最重要的功能是通过一个称为夹带的过程使身体活动与24小时光暗（LD）周期同步。夹带对人类健康的重要性已在人类和动物研究中得到证实。在真实的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确定性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。了解如何产生的疾病的病因中断夹带将需要了解的神经机制，控制夹带在主生物钟位于视交叉上核（SCN）。 这项研究的总体目标是确定SCN中昼夜节律夹带的神经机制。在理解背内侧SCN如何作为分子生物钟以及腹外侧SCN如何对光响应方面已经取得了显着进展，但是负责连接这两个关键功能的神经机制仍然不清楚。也许这是因为长期以来人们认为光可以瞬间重置生物钟（即，非参数夹带），导致一般假设SCN内负责将光传递到核心时钟的神经机制的持续时间非常短。相比之下，我们提出，这两个重要的昼夜节律功能的神经机制，运作超过几个小时，GABA是关键的神经化学信使。 这些研究将测试以下假设：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的作用由GABA-A-TONIC介导，而不是由GABA-A-PHASIC或GABA-B受体介导。如果我们证实GABA受体在几个小时内的持续激活介导了SCN中的光效应，那么这种GABA受体的持续激活似乎也可能介导其他CNS部位的特定功能。此外，这些研究将提供重要的GABA受体亚型的功能和它们可能的相互作用，应该是相关的GABA行动在整个中枢神经系统的新信息。了解GABA在大脑中的作用在临床上非常重要，因为许多药物都是针对GABA受体的，从癫痫到焦虑症。