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）：昼夜节律时钟的最重要功能是通过称为夹带的过程与24小时的灯光黑暗（LD）周期的身体活动同步。人类和动物研究都证明了夹带人类健康的至关重要。 LD周期的慢性相位移位会增加现实世界中的夹带过程，从而增加了许多疾病状态的发生率，包括癌症，心血管疾病和代谢疾病。了解夹带中断产生的疾病的病因如何需要理解控制位于上核核（SCN）中的昼夜节律中夹带的神经机制。 拟议研究的总体目标是确定导致SCN中昼夜节律夹带的神经机制。在理解背部SCN如何作为分子昼夜节律的功能以及腹外侧SCN如何响应光的情况下，已经取得了显着的进步，但是负责将这两个关键功能联系起来的神经机制尚不清楚。也许这是因为长期以来一直认为光线可以立即重置昼夜节律时钟（即非参数夹带），因此一般的假设是，SCN内的神经机制负责使核心时钟传达光的神经机制的持续时间很短。相比之下，我们建议将这两个重要的昼夜节律功能连接起来的神经机制在几个小时内运行，而GABA是关键的神经化学信使。 这些研究将检验以下假设：SCN中GABA受体的持续激活介导了光的相位转移效应，SCN内的时钟基因的诱导，并且GABA的作用是由GABA-A-TONIC介导的，而不是由GABA-A-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a介导。如果我们确认GABA受体在几个小时内的持续激活会介导SCN中的光的影响，则似乎同样类型的GABA受体激活GABA受体可能会介导其他CNS位点的特定功能。此外，这些研究将提供有关GABA受体亚型功能及其在整个中枢神经系统中应与GABA作用有关的可能相互作用的重要新信息。了解GABA在大脑中的作用在临床上非常重要，因为许多药物针对GABA受体的疾病，从癫痫病到焦虑。