Physiological Substrates of a Circadian Oscillator

昼夜节律振荡器的生理基础

• 批准号: 6639383
• 负责人: Martha U Gillette
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-15 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639383
• 关键词: RNase protection assay; central neural pathway /tract; circadian rhythms; cyclic AMP; enzyme activity; glutamates; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; neural transmission; neuropeptide receptor; neuropeptides; protein isoforms; protein kinase A; receptor expression; retina; suprachiasmatic nucleus; visual stimulus

DESCRIPTION (applicant's abstract): Our objective is to understand mechanisms whereby interacting chemical messengers transduce light information from the eye via the retinohypothalamic tract (RHT) to the circadian clock in the suprachiasmatic nucleus (SCN). This process decodes photic information from external light in the context of internal state. Under the present award, we discovered that the chemical signal from the RHT is more complex than previously thought. Pituitary adenyl cyclase-activating peptide (PACAP) and glutamate (Glu) co-localize within terminals of retinal ganglion cells innervating the SCN. We found evidence for functional interaction both in vivo and in vitro: in early night, PACAP potentiated Glu-induced phase delay of SCN rhythms, while in late night it blocked Glu-induced phase advance. Thus, responses to these signals are state-dependent and clock-controlled. How does PACAP interact with Glu to encode light signals at the SCN? What cellular processes integrate combinatorial signaling events to modulate amplitude and direction of phase resetting differentially in early vs. late night? We will evaluate PACAP and Glu actions and interactions during photic signaling in vivo, release from the RHT, signal transduction(s) and consequent molecular events in early vs. late night. Hypotheses to be tested are that: 1) the light signal contains both Glu- and PACAP-ergic components that interact producing graded changes in clock phase, and 2) the clock's responses to PACAP and Glu change between early and late night due to differential effects of clock-gated cAMP/PKA signaling and the state of the molecular clockworks. Multiple indices of change will be measured: rhythms of behavior, oscillation of SCN neuronal activity, and levels/localizations of putative clock elements in rodent models. This multidisciplinary approach will provide insights into classical (Glu) and modulatory (PACAP) neurotransmission, cellular and molecular mechanisms of signal integration, and decision-making processes that alter neuronal state. These are fundamental issues in neuroscience. Signal transduction is a cellular process, and by identifying the relevant neurotransmitters, receptors, second messenger systems and targets, we will be able to understand the causal mechanisms the mediate differential state changes in the clock. This research is basic to understanding integrative brain function. It has applied relevance for strategies in drug chronotherapeutics and will facilitate developing rationally-based therapies for timing disorders, including internal desynchronizations manifested as disordered patterns of sleep, cognitive and autonomic function, neurological impairment in aging and depressive states.

描述（申请人的摘要）：我们的目标是理解机制 通过相互作用的化学信使来转换来自光的信息 眼睛通过视网膜下丘脑束（RHT）到达生物钟 视交叉上核（SCN）。该过程解码来自 内部状态背景下的外部光。根据目前的奖项，我们 发现来自 RHT 的化学信号比 之前以为。垂体腺苷酸环化酶激活肽 (PACAP) 和 谷氨酸 (Glu) 共定位于视网膜神经节细胞末端 支配 SCN。我们发现了体内功能相互作用的证据 体外：在清晨，PACAP 增强了 Glu 诱导的 SCN 相位延迟 节律，而在深夜它会阻止谷氨酸诱导的相位提前。因此， 对这些信号的响应是状态相关且受时钟控制的。怎么样 PACAP 与 Glu 相互作用以编码 SCN 处的光信号？什么蜂窝 过程整合组合信号事件来调节幅度和 清晨和深夜的相位重置方向有差异吗？我们将 评估 PACAP 和 Glu 在光信号传导过程中的作用和相互作用 体内、RHT 释放、信号转导和后续分子 清晨与深夜的事件。需要检验的假设是：1）光 信号包含 Glu 和 PACAP 能成分，它们相互作用产生 时钟相位的分级变化，以及 2) 时钟对 PACAP 和 Glu 的响应 由于时钟门控的差异效应，清晨和深夜之间的变化 cAMP/PKA 信号传导和分子发条的状态。多重指数 将测量变化：行为节律、SCN 神经元的振荡 啮齿动物模型中假定的时钟元件的活动和水平/定位。 这种多学科方法将提供对经典 (Glu) 和 调节（PACAP）神经传递，细胞和分子机制 信号整合和改变神经元状态的决策过程。 这些是神经科学的基本问题。信号转导是一种细胞 过程，并通过识别相关的神经递质、受体，第二 信使系统和目标，我们将能够理解因果关系 机制调节时钟中的中间差分状态变化。这项研究 是理解大脑综合功能的基础。它已应用相关性 药物时间治疗策略并将促进开发 针对时间障碍的理性疗法，包括内部治疗 去同步化表现为睡眠、认知和认知模式紊乱 自主神经功能、衰老和抑郁状态下的神经损伤。