NEUROPHARMACOLOGY OF THE CIRCADIAN TIMEKEEPING SYSTEM

本届医师科学家奖核心项目的目标是 应用于研究特定的神经递质受体 在生物钟计时系统中。有大量的 有证据表明，一个驱动昼夜节律的振荡器， 也许主振荡器，位于视交叉上 下丘脑的核(SCN)。然而尽管如此， 解剖学证据，神经化学基础的产生和 人们对昼夜节律的调节知之甚少。 多项研究表明，烟碱型胆碱能、伽马胆碱- 氨基丁酸(GABA)能、5-羟色胺能和β- 控制昼夜节律的肾上腺素能神经递质系统 节奏性。该项目的工作将调查 这四个系统的神经递质受体使用 定量放射自显影，一种允许 同时评估多个连续的脑区 可能在功能上是相互关联的，如在昼夜计时中 系统。 这些受体将在(1)SCN；(2)传出神经中进行研究 SCN的投射面积、室旁核 下丘脑；以及(3)大脑中没有直接参与的区域 昼夜节律计时，额顶皮质。我们会 研究这些受体本身是否表现出 其他昼夜节律所具有的特性。这个问题将是 通过评估两个定义明确的时代标杆的效果进行了研究 (时间提示)，光和松果体激素褪黑激素，在这些 感受器。由SCN控制的两个昼夜节律将是 在受体所在的同一动物体内进行监测 评估过了。对神经药理学基础的再认识 昼夜节律性的设计最终将允许 更有效地治疗抑郁症和躁郁症 疾病，其中这样的节律似乎被打乱，并可能计划 一个致病的角色。

The goal of the core project of this Physician Scientist Award application is to investigate specific neurotransmitter receptors in the circadian timekeeping system. There is substantial evidence that one oscillator which drives circadian rhythms, perhaps the master oscillator, is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. However, despite this anatomic evidence, the neurochemical basis of the generation and modulation of circadian rhythms is poorly understood. Several studies have implicated the nicotinic cholinergic, gamma- aminobutyric acid (GABA) ergic, serotonergic, and beta adrenergic neurotransmitter systems in the control of circadian rhythmicity. The work of this project will investigate the neurotransmitter receptors of these four systems using quantitative autoradiography, a technique which allows the simultaneous assessment of multiple contiguous brain areas which may be functionally interrelated, as in the circadian timekeeping system. These receptors will be studied in (1) the SCN; (2) an efferent projection area of the SCN, the paraventricular nuclei of the hypothalamus; and (3) an area of the brain not directly involved in circadian timekeeping, the frontoparietal cortex. We will investigate whether these receptors themselves manifest the properties expected of other circadian rhythms. This issue will be studied by assessing the effect of two well defined zeitgebers (time-cues), light and the pineal hormone melatonin, on these receptors. Two circadian rhythms controlled by the SCN will be monitored in the same animals in which the receptors are assessed. Further understanding of the neuropharmacologic basis of circadian rhythmicity will ultimately allow for the design of more effective treatments for depression and manic-depressive illness, in which such rhythms appear to be disrupted and may plan a pathogenic role.