MOLECULAR NEUROBIOLOGY OF THE CIRCADIAN CLOCK

描述（改编自摘要）：脊椎动物生物钟是 由多个昼夜节律振荡器组成， 稳定的明显节奏 这些组件的相对作用各不相同， 包括视交叉上核（SCN）、松果体 和眼睛，通过褪黑激素影响昼夜节律。 在 在鸟类中，褪黑激素起着特别重要的作用。 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 褪黑激素在鸟类SCN，vSCN和其他结构中的作用 使用碘化褪黑激素（IMEL）放射自显影的视觉系统。 结合是有节奏的，峰值在一天的后期。 (The主要 研究者和他的同事已经鉴定了两种褪黑激素受体， CKA和CKB，在膜受体的Gi蛋白组中， 药理学特征与IMEL结合相同， 在鸟类大脑中的分布类似）。最后，视觉系统功能是 通过褪黑激素的方式由生物钟调节，并且对激素敏感 主要是在后期主观的一天。 根据这些观察， 研究者假设：（1）鸟类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)大脑和视网膜对褪黑激素敏感， （4）这种对褪黑激素敏感的节律是由于平行节律 褪黑激素受体的数量;（5）褪黑激素的节律 灵敏度来自vSCN中的振荡;最后，（6）在 大脑中至少有一个褪黑激素作用的细胞部位位于 含有CKB褪黑素受体亚型的星形胶质细胞。 研究者建议确定视网膜电图中是否存在节律。 和大脑光敏感性通过记录视网膜电图（ERG）， 鸡脑视觉中枢的视觉诱发活动（VEP）， 不同的时间 他和他的同事将决定是否 预期的节律源自松果体和/或视网膜褪黑激素节律， 通过松果体切除术确定褪黑激素去除的效果，或 通过输注和注射的方式进行置换。 他们将决定是否 对褪黑激素敏感性的预期节律来自于 受体蛋白和/或mRNA的昼夜节律调节。 他们将决定 视觉敏感性、褪黑激素敏感性、 通过比较动物中的这些节律， vSCN已被破坏的人与接受假手术的人相比。 最后， 他们将研究褪黑激素在体内和体外对星形胶质细胞的影响。 在这些研究中，他们将解决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式， 褪黑激素作用的分子机制的研究， 在包括人类在内的许多脊椎动物中很重要。

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.