Neurobiology of Circadian Dysrhythmias

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DESCRIPTION (provided by applicant): Daily rhythms are governed by endogenous circadian clocks, and, in mammals, by the suprachiasmatic nucleus (SCN). The circadian system is complex, with an SCN tissue pacemaker containing multiple, coupled single-cell oscillators and a system composed of interlocking and nested auto-regulatory feedback loops. Advances have been made in delineating the main elements of this network, and we can now begin to analyze its stimulus-response properties at the molecular, cellular, tissue, and behavioral levels. What we are finding is that the system's output after a given input may not be linear, with striking consequences for animal behavior. Notable examples of this are some of the effects of constant light (LL) - "splitting" in golden hamsters and circadian rhythmicity in genetically-deficient mice - that dramatically reorganize the circadian system. We propose to study these phenomena experimentally, but from a perspective that is not traditionally applied in research on hamsters and mice. It is known that complex systems often exhibit two or more stable states - like split & unsplit, or rhythm & no rhythm - that are accessible by small, properly timed perturbations. The preferred state of such systems may switch under certain conditions, e.g., if the outside environment or a system component is altered. Using hamsters and mice, we present preliminary evidence for the potential bi-stability of the rodent circadian system and outline an experimental program for investigating its neurobiology. In Aim 1, we test our hypothesis that bi-stability in the hamster circadian system is revealed in split hamsters that are transferred from LL to darkness, a condition in which the normally favored unsplit state becomes less robust and more vulnerable to being switched to the split state. In Aim 2, we test our hypothesis that LL fosters splitting by introducing an element of noise into an inherently bi-stable circadian system, ultimately propelling the switch from an unsplit to split state. We also test our hypothesis that the running wheel itself is a necessary part of the splitting process. In Aim 3, we test our hypothesis that genetically-deficient murine circadian systems, being less robust than wild type in the circadian domain, are vulnerable to being switched to alternative rhythmic or quiescent states, [especially] by the tonic or noisy inputs in LL. We predict that our studies will provide new insights on the organization of complex circadian systems, on their vulnerability to imperfections in system components and environmental changes, and perhaps even on our views of circadian dysrhythmias and how they might be repaired.