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: 8852717
• 负责人: H. Elliott Albers
• 金额: $ 32.38万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852717
• 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种被称为“携带”的过程，使身体活动与24小时的光暗（LD）周期同步。娱乐对人类健康的极端重要性已在人类和动物研究中得到证实。在现实世界中，由于轮班工作或实验中由于LD周期的慢性相移而产生的夹带过程的不同步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。要了解由夹带性神经紊乱引起的疾病的病因，就需要了解位于视交叉上核（SCN）的主生物钟中控制夹带性神经机制。拟议研究的总体目标是确定负责SCN中昼夜节律的神经机制。在了解背内侧SCN如何作为分子生物钟以及腹外侧SCN如何对光作出反应方面取得了显着进展，但负责连接这两个关键功能的神经机制仍不清楚。也许这是因为长期以来人们一直认为光可以瞬间重置生物钟（即，非参数干扰），从而导致一般假设，SCN内负责将光传递给核心时钟的神经机制将持续很短的时间。相反，我们认为连接这两个重要昼夜节律功能的神经机制在几个小时内运行，GABA是关键的神经化学信使。这些研究将验证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GABA- a - phasic或GABA- b受体介导的假设。如果我们证实GABA受体在几个小时内的持续激活介导了SCN中光的作用，那么GABA受体的这种类型的持续激活可能也介导了CNS其他部位的特定功能。此外，这些研究将为GABA受体亚型的功能及其可能的相互作用提供重要的新信息，这些相互作用应该与GABA在整个中枢神经系统中的作用有关。了解GABA如何在大脑中起作用在临床上是极其重要的，因为许多针对GABA受体的药物治疗从癫痫到焦虑等疾病。