Light and some other stimuli are known to control the phase of circadian rhythms. A particular stimulus can advance, delay, or have no effect on the phase depending on when within the circadian cycle it is delivered. These responses can be characterized as phase response curves (PRC). PRCs for light pulses are different from PRCs to dark pulses or non- photic stimuli. The proposed research seeks to investigate the neural and neurochemical bases for these PRCs in a brain slice preparation which contains the suprachiasmatic nuclei, a known circadian clock in mammals. By sampling extracellular firing rates from many SCN cells over the course of several days, a circadian rhythm in firing frequency can be identified. The major goal of the proposed research is to establish which transmitter substances applied in vitro at 6 different times of day induce phase shifts in the population rhythm. One route by which light information is transmitted to the SCN is the retino-hypothalamic tract. The first experiment tests the hypothesis that EAA, believed to be transmitters in retino-hypothalamic neurons, phase shifts the SCN population rhythm like light pulses. Glutamate, acetylaspartyl-glutamate, aspartate, NMDA, quisqualate and kainate will be tested. If phase shifts are obtained, receptor blockers are used to identify postsynaptic receptor types. Based on recent results, histamine will also be tested. An indirect route from the eye to the SCN is via the intergeniculate leaflet, the geniculo-hypothalamic tract (GHT).Phase shifts obtained by stimulating this pathway mimic dark pulse or non- photic PRCs. A second experiment tests the putative transmitters of the GHT, namely, NPY, met-enk and GABA for phase shifting effects on SCN activity. Furthermore, RHT and GHT transmitters will be applied in combination to assess interactions among these transmitters (e.g., RHT transmitters may block or reduces the effects of GHT transmitters). Light pulses are known to induce c-fos and related immediate early genes in the SCN and intergeniculate leaflet, but not in other retino-recipient targets.
A second aim of the proposed research is to assess which transmitter substances have the capacity to induce c-fos expression in SCN neurons in vitro. The hypothesis is that only transmitters which mimic a light pulse PRC will induce c-fos.
A third aim of the proposed experiments is to assess direct effects of the transmitters used in aims 1 and 2 on the firing rate of SCN neurons. Neurochemical are given at 5 doses and at different times of day since a neuron's response may change throughout the circadian cycle.
The fourth aim i s to use whole cell patch clamping to measure the membrane potential of SCN neurons in response to different neurochemicals at different phases of the circadian cycle.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Biopsychology Study Section (BPO)
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Smith College
Schools of Arts and Sciences
United States
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Yannielli, P C; Brewer, J McKinley; Harrington, M E (2004) Blockade of the NPY Y5 receptor potentiates circadian responses to light: complementary in vivo and in vitro studies. Eur J Neurosci 19:891-7
Christian, Catherine A; Harrington, Mary E (2002) Three days of novel wheel access diminishes light-induced phase delays in vivo with no effect on per1 induction by light. Chronobiol Int 19:671-82
Brewer, Judy McKinley; Yannielli, Paola C; Harrington, Mary E (2002) Neuropeptide Y differentially suppresses per1 and per2 mRNA induced by light in the suprachiasmatic nuclei of the golden hamster. J Biol Rhythms 17:28-39