Research Topics
Departments of Cell & Structural Biology, Physiology and College of Medicine
Ph.D. (1976) University of Toronto
Research Topics
Research Interests The suprachiasmatic nuclei (SCN) of the hypothalamus are endogenous oscillators that serve a critical role in the generation and entrainment of the daily (circadian) rhythms of mammals. Our broad research objective is to understand mechanisms by which the SCN keep 24-hr time. The SCN pacemaker (or clock) survives intact for at least 3 days in rat hypothalamic brain slices where it is accessible to experiments aimed at dissecting cellular mechanisms. Conventional neurophysical techniques that measure the circadian rhythm of neuronal activity and biochemical analyses that measure cyclic nucleotide levels, enzyme activities, protein/phosphoprotein profiles and DNA-protein interactions are being used.
Our present research program has two interrelated major thrusts. The first is aimed at elucidating mechanisms underlying the clock. We have shown that the spontaneous SCN rhythm of neuronal firing rate can be reset in the brain slice by treatments affecting cAMP or cGMP pathways. The rhythm is reset by cAMP only in the donor's day, and by cGMP or high K during the donor's night. The specific aims of this line of research include: a) to more fully explore the role of cAMP in SCN function; b) to examine the nature of the effect of cGMP analogs at night; and, c) to identify the mechanism by which melatonin regulates the SCN pacemaker at dusk and dawn.
The second thrust of our research is to use this in vitro system to examine the organization and regulation of the circadian time-keeping system within the SCN. Specific lines of inquiry include: a) determining whether pacemaking properties are distributed throughout the nucleus and whether the clock is located within the single cells or circuits (using biocompatible electrodes); b) determining the effects of extrinsic and intrinsic neurotransmitters or modulators upon the clock; and c) determining the transduction mechanisms mediating effects of neuroactive substances on the clock.
Ultimately, we should understand how the neurons and glia within the SCN keep 24-hr time, the way in which this biological clock is differentially regulated in day vs night by various inputs and the role of intrinsic neurotransmitters and modulators in information processing. This information is fundamental to determining the mechanisms responsible for SCN circadian rhythmicity, its regulation by the environment, and its influence upon mental state, physiology and behavior. Further, it has applied relevance for developing environmental or drug interventions to ameliorate dysfunctions due to jet lag and shift work, as well as biological clock and sleep disorders.
Key Words Cellular Immunology, Monoclonal Antibodies, Hormones, Animal Cell and/or Tissue Culture, Image Analysis, Pharmaceuticals, Neurobiology, Protein Purification and Characterization, Active Sites and Receptors, DNA-Protein Interaction, Bioengineering,
Molecular Biology, Electrophysiology
Current Research Funding NIH, AFOSR