MOLECULAR NEUROBIOLOGY OF THE CIRCADIAN CLOCK

描述(改编自摘要)：脊椎动物的生物钟是 由多个昼夜节律振荡器组成的，它们的相互作用是关键的 对于稳定的公开节奏感。这些组件的相对角色各不相同 在物种中，包括视交叉上核(SCN)、松果体 还有眼睛，它们通过褪黑激素影响昼夜节律。在……里面 在鸟类中，褪黑素起着特别关键的作用。移除 褪黑激素信号极大地影响许多人的昼夜节律 生理功能。最近的研究已经确定了 褪黑素在禽类SCN、vSCN和其他结构中的作用 视觉系统使用碘化褪黑素(IMEL)放射自显影。 结合是有节律性的，峰值出现在傍晚。(校长 调查员和他的同事已经确定了两个褪黑素受体的特征， Cka和CkB，在其膜受体的Gi-蛋白质组中， 药理配置文件与Imel绑定相同， 类似地分布在鸟类的大脑中。)最后，视觉系统的功能是 由时钟通过褪黑激素调节，对激素敏感 主要是在主观上的最后一天。基于这些观察， 研究人员假设：(1)鸟类的视觉系统是有节奏的 它对光的反应；(2)这种节律是由于褪黑素的节律； (3)主观晚期大脑和视网膜对褪黑素敏感。 这种对褪黑激素敏感的节律是由于一种平行的节律 褪黑素受体的数量；(5)褪黑素的节律 灵敏度由vSCN中的振荡得到；最后，(6)在 大脑中至少有一个褪黑素作用的细胞部位在 含有CKB褪黑素受体亚型的星形胶质细胞。 研究人员建议确定视网膜是否存在节律 通过记录视网膜电信号(ERG)和 鸡脑视觉中枢的视觉诱发活动(VEP) 一天中不同的时间。他和他的同伙将决定是否 预期节律源自松果体和/或视网膜褪黑激素节律 确定通过松果体切除术去除褪黑素的效果，或 通过输液和注射的方式进行替换。他们将决定是否 褪黑素敏感性的预期节律来自一种 受体蛋白和/或信使核糖核酸的昼夜调节。他们将决定 无论节律的视觉敏感度、褪黑素敏感度、感受器 通过比较动物的这些节律，蛋白质和mrna来自vSCN。 他们的vSCN已经被摧毁了，而那些做了假手术的人。最后， 他们将在体内和体外研究褪黑素对星形胶质细胞的影响。 在这些研究中，他们将研究一种新的神经调节形式 重要的感觉系统--视觉。他们将提供一个很好的模型 褪黑素作用的分子机制研究 在包括人类在内的许多脊椎动物物种中都很重要。

DESCRIPTION (Adapted from the Abstract): The vertebrate circadian clock is composed of multiple circadian oscillators whose interactions are critical for stable overt rhythmicity. These components, whose relative roles vary among species, include the suprachiasmatic nucleus (SCN), the pineal gland and eyes, which influence circadian rhythms via the hormone melatonin. In birds, melatonin plays a particularly critical role. Removal of the melatonin signal dramatically affects the circadian rhythms of many physiological functions. Recent research has identified the sites of melatonin's action in the avian SCN, the vSCN, and other structures within the visual system using autoradiography of iodinated melatonin (IMEL). Binding is rhythmic, with peak values in the late day. (The Principal Investigator and his associates have characterized two melatonin receptors, CKA and CKB, in the Gi-protein group of membrane receptors whose pharmacological profiles are identical to IMEL binding and which are distributed in avian brain similarly.) Finally, visual system function is regulated by the clock by way of melatonin and is sensitive to the hormone primarily during the late subjective day. Based on these observations, the Investigator hypothesizes that: (1) the avian visual system is rhythmic in its response to light; (2) this rhythm is due to the rhythm of melatonin; (3) brain and retinae are sensitive to melatonin during the late subjective day; (4) this rhythm of sensitivity to melatonin is due to a parallel rhythm in the number of melatonin receptors; (5) the rhythm of melatonin sensitivity is derived from oscillations in the vSCN; and, finally, (6) at least one cellular site of melatonin action in the brain is within astrocytes containing the CKB melatonin receptor subtype. The Investigator proposes to determine whether a rhythm exists in retinal and brain photic sensitivities by recording electroretinograms (ERG) and visually evoked activity (VEP) from visual centers of the chick brain at different times of day. He and his associates will determine whether the anticipated rhythms derive from pineal and/or retinal melatonin rhythms by determining the effects of melatonin removal, by way of pinealectomy, or replacement by way of infusion and injection. They will determine whether the anticipated rhythm in the sensitivity to melatonin derives from a circadian regulation of receptor protein and/or mRNA. They will determine whether the rhythms of visual sensitivity, melatonin sensitivity, receptor protein and mRNA derive from the vSCN by comparing these rhythms in animals whose vSCN have been destroyed versus those with sham surgeries. Finally, they will study the effects of melatonin on astrocytes in vivo and in vitro. In these studies they will address a novel form of neuromodulation in an important sensory system-vision. They will provide an excellent model for the study of the molecular mechanisms of melatonin action, which is important in many species of vertebrates including humans.