Optimal
biological functioning requires the precise temporal coordination among
countless biological systems. For instance, females with irregular work cycles such as shift
workers, airline pilots, and medical residents, experience abnormal menstrual cycles, reduced fertility, and an
increased spontaneous abortion rate. Male and female shift workers have a
dramatically increased risk of cardiovascular problems, diabetes, obesity,
and gastrointestinal problem. Additionally, results from over 78,000 subjects participating in the Nurses
Health Study indicate that women on rotating shifts or night work are at
increased risk for breast cancer. In animals studies, destruction of
the circadian clock in the brain accelerates tumor growth, and experimental
jet lag profoundly accelerates malignant tumor progression. Importantly,
tumor cells themselves show marked daily fluctuations in mitotic index (an
measure of cell division). Because chemotherapy targets cells that are
rapidly dividing, knowledge of the peak of tumor cell mitosis along with the
cellular mechanisms responsible for this rhythm generation can be used to
create more effective chemotherapy delivery regimens. Collectively, these studies indicate the
importance of proper endocrine timing in health and disease and underscore
the significance of investigating the interactions between the neuroendocrine and endogenous timing systems. |
Mechanisms
of Circadian Rhythm Generation:
Circadian
(about a day) rhythms in physiology and behavior are generated and
maintained by a biological clock located in the suprachiasmatic nucleus
(SCN) of the anterior hypothalamus. These rhythms are endogenously generated and
maintained in the absence of environmental time cues. Circadian rhythms are
not only necessary to coordinate thousands of biochemical and physiological
processes on a daily schedule, but also to coordinate these processes in
time relative to one another, so that each physiological process can occur
during an optimal time of day. |
Temporal
Regulation of Endocrine Function:
Because hormones are
secreted into the bloodstream, this mode of communication represents an
important means by which the circadian system can communicate to widespread
systems in the brain and body. Research in the lab
focuses on the neural and endocrine mechanisms by which the SCN communicates
with target systems to maintain homeostasis and promote optimal biological functioning
and avoid disease states. We are currently using the reproductive system
as a model system by which to investigate this question, with specific emphasis on
the hierarchy of clock control from brain to peripheral glands.
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Mechanisms of Seasonal Changes in Reproduction: In order to cope with the energetic challenges of winter, species inhabiting nontropical and boreal latitudes inhibit reproduction and other energetically costly processes. Inhibition of reproduction occurs in anticipation of winter in response to decreasing day lengths. Day length information is transmitted from the retina, interpreted by the SCN, and communicated to the pineal gland. The duration of melatonin secretion codes day length and drives seasonal changes in reproduction. However, the neural pathways on which melatonin acts to inhibit reproduction remain elusive. Theoretically, melatonin should communicate either directly or indirectly to the gonadotropin-releasing hormone neuronal (GnRH) to regulate season changes in reproduction. This melatonin-sensitive pathway likely requires input from the SCN to control seasonal responsiveness to SCN signals. Our lab is currently investigating a novel inhibitory system projecting to the GnRH system that is in a key position to modulate seasonal changes in reproduction.
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