In mammals, the sleep and circadian systems are intimately coupled and mutually essential for the proper coordination of physiological processes and behavior. The circadian clock located in the suprachiasmatic nucleus (SCN) provides for the temporal organization of sleep by promoting alertness during periods of high homeostatic sleep drive. In turn, the circadian program of sleep organization is synchronized to environmental rhythms through periodic adjustments of the phase and period of the circadian clock by ambient light. The neuroanatomical and neurophysiological mechanisms responsible for the imposition of circadian organization on the sleep process are only beginning to be understood. Furthermore, no mechanism has yet been described through which sleep-related processes might influence circadian timing. The current proposal seeks to delineate such a mechanism. The purine nucleoside, adenosine, has been implicated as a key component of the homeostatic sleep mechanism. Adenosine accumulates in the basal forebrain cholinergic area during sustained wakefulness, where it has been shown to promote sleep through an adenosine A1 receptor-dependent mechanism. Systemic administration of an adenosine A1 receptor agonist attenuates the magnitude of light-induced phase adjustments of the SCN circadian clock. We propose that adenosine provides information to the circadian clock regarding the state of fatigue of the organism, resulting in an altered response to light-induced phase adjustments. In the current proposal, we will test the hypothesis that increased adenosine production in the SCN region during sustained wakefulness attenuates light-induced adjustments in circadian phase by interacting with presynaptic A1 receptors located on RHT nerve terminals to reduce the release of glutamate. This work will reveal a novel and potentially important aspect of sleep and circadian regulation in mammals.
| Li, Da-Qiang; Pakala, Suresh B; Reddy, Sirigiri Divijendra Natha et al. (2013) Metastasis-associated protein 1 is an integral component of the circadian molecular machinery. Nat Commun 4:2545 |
| Sigworth, L A; Rea, M A (2003) Adenosine A1 receptors regulate the response of the mouse circadian clock to light. Brain Res 960:246-51 |
| Hallworth, Richard; Cato, Matthew; Colbert, Costa et al. (2002) Presynaptic adenosine A1 receptors regulate retinohypothalamic neurotransmission in the hamster suprachiasmatic nucleus. J Neurobiol 52:230-40 |
