MOLECULAR NEUROBIOLOGY OF THE CIRCADIAN CLOCK

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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.