NEURAL BASIS OF BIOLOGICAL RHYTHMS

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Circadian rhythms are internally generated rhythms in behavior and physiology with periods of about 24 hours. Awareness of underlying circadian rhythmicity is essential for all pharmacological treatments. Circadian rhythms can be used to advantage in medical treatments, for example, by timing drug delivery to minimize toxic side effects. Internal rhythms must be reset to maintain synchrony with the external cycle of 24 h. Better understanding of the resetting mechanisms will allow advances in the treatment of discomforts associated with jet lag and shift work, as well as a variety of depressive disorders. Several types of stimuli are able to phase shift the circadian clock. Light produces phase shifts mainly during the subjective night, with a characteristic phase response curve (PRC), the "LPRC." Other stimuli, including dark pulses, activity within a novel running wheel, and benzodiazepine injections, produce phase shifts mainly during the subjective day, in the "DPRC" pattern. The mammalian circadian pacemaker is localized to the hypothalamic suprachiasmatic nuclei (SCN). I am proposing to measure circadian oscillations from the SCN maintained in vitro and to study the phase shifts induced by various neurotransmitters. I will use this model to study the cellular events which accompany phase shifts of the circadian clock in either the LPRC or DPRC pattern. Following characterization of the stimuli associated with either of these PRCs, I will then determine effects of these stimuli on (a) induction of immediate early genes, (b) extracellular firing rate, and (c) membrane potential of SCN neurons. This work will lead to a better understanding of resetting and rhythm- generating mechanisms underlying mammalian circadian rhythmicity.