NEURAL BASIS OF MAMMALIAN CIRCADIAN ORGANIZATION

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The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is part of a system that controls the near 24-hour (circadian) rhythms in many physiological processes and behaviors. This timing system generates circadian behaviors, synchronizes them to local time, sets an appropriate phase relationship between each behavior and daily environmental cycles, and sculpts the duration and amplitude of each behavior in response to particular environmental conditions (e.g., seasonal photoperiod). Although it is highly likely that individual SCN neurons generate circadian periodicities, it is uncertain whether these complex circadian behaviors arise at the level of single cells, through cellular interactions within the SCN tissue, or through interactions with other neural and/or non-neural systems. Furthermore, the pathways and mechanisms by which the SCN conveys timing information to other brain regions remain largely unexplored. The proposed experiments will examine the circadian properties and mechanisms of intercellular communication of neurons in vivo, and in cultured tissues and dispersals. Changes in the duration of the photoperiod or period of the light:dark cycle result in classically described changes in the time of activity onset, the duration of activity, or the expressed period of activity rhythms. Specific aim 1 will determine the level of cellular organization and mechanisms responsible for maintaining an appropriate phase relationship between the behavior and local time, the kinetics of resynchronization (e.g., phase shifting transients), and the control of circadian waveform by entraining stimulus parameters. Specific aim 2 will address the neural origins of plasticity in circadian behavior. We will determine whether changes in period and waveform are generated at the level of single SCN neurons, within the SCN or at other levels of neural organization. Finally, specific aim 3 will determine the locus of age-related deterioration of some of the behaviors examined in specific aims 1 and 2. These experiments will be aided greatly by the recent development of new technologies that enable recording of cellular rhythmicity for weeks in vitro. We will measure molecular rhythmicity by monitoring per1:luciferase activity in transgenic cells and electrical activity from individual neurons using multielectrode arrays. These procedures allow us to record from neurons taken from animals at least 9 months of age. Taken together, these studies will provide insights into how different levels of neural organization contribute to the generation and control of mammalian circadian behaviors.