Mammalian circadian rhythms are generated by a molecular clock located within individual neurons of the suprachiasmatic nucleus (SCN). The molecular clock drives the activity of SCN neurons which fire action potentials at a higher frequency during the day than during the night. The mechanisms underlying this activity are unknown, but must involve circadian regulation of ion channels involved in the generation of action potentials. Our hypothesis is that neurotransmitters which alter SCN neuronal activity and phase shift circadian rhythms also modulate the activity of ion channels which are necessary for the rhythmic firing of SCN neurons. In the SCN these questions are complicated by the heterogeneity of neuronal phenotypes and differences in signal transduction coupling at different times of the circadian day. Electrophysiological and morphological techniques will be used to investigate neurotransmitter signal transduction in SCN neurons.
The specific aims of the proposal are to: 1) Examine the mechanisms coupling neurotransmitter receptors to ion channels which are important for action potential generation in SCN neurons. 2) Determine the role of circadian time in the coupling of neurotransmitter receptors to ion channels. 3) Investigate how melatonin receptors modulate the activity of other neurotransmitter receptors in the SCN. 4) Catalogue the morphological cell types which respond to specific neurotransmitters. Identification of unique ion conductances and signal transduction pathways in the SCN will provide new targets for clinical treatment of sleep and circadian disorders.
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