NEUROPHARMACOLOGY OF THE CIRCADIAN TIMEKEEPING SYSTEM

本次医师科学家奖核心项目的目标 应用是研究特定的神经递质受体 在昼夜节律计时系统中。 有大量 有证据表明，一个驱动昼夜节律的振荡器， 也许是主振荡器，位于视交叉上 下丘脑核（SCN）。 不过尽管如此 解剖学证据，产生的神经化学基础， 对昼夜节律的调节知之甚少。 几项研究表明，尼古丁胆碱能，γ- 氨基丁酸（GABA）能、孕酮能和β 肾上腺素能神经递质系统对昼夜节律的控制 节奏性 该项目的工作将调查 这四个系统的神经递质受体， 定量放射自显影，一种允许 同时评估多个相邻的大脑区域， 可能在功能上相互关联，如昼夜节律计时 系统 这些受体将在（1）SCN中进行研究;（2）传出 SCN的投射区，室旁核， 下丘脑;和（3）不直接参与的大脑区域 昼夜节律计时，额顶叶皮层 我们将 研究这些受体本身是否表现出 其他昼夜节律的预期特性。 这个问题将 通过评估两个明确定义的授时因子的影响来研究 （时间线索），光和松果体激素褪黑激素，对这些 受体。 由SCN控制的两种昼夜节律将被 在相同的动物中监测， 评估。 进一步了解神经药理学基础 昼夜节律的设计最终将允许 更有效的治疗抑郁症和躁狂抑郁症 疾病，其中这种节奏似乎被打乱，并可能计划 致病作用。

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.