Research Interests

     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 Nurse’s 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.
     The temporal relationship among rhythms is critical for optimal body functioning; rhythmic disruption is associated with a number of endocrine abnormalities, rate of cancer progression and outcome, and numerous cardiovascular and gastrointestinal pathologies.  A great deal of progress has been made in uncovering the cellular and molecular mechanisms governing circadian rhythm generation. My laboratory is interested in how sustained rhythmicity is generated within the SCN at the cellular, molecular, and network levels, and how this information is communicated to target systems in the CNS and periphery.  To accomplish this goal, we use a variety of pharmacological, neuroantomical, and behavioral techniques in order to study this question from gene to behavior. 


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. 
     To date, this work has uncovered that the same clock genes necessary for rhythm generation in the SCN are also found in neuroendocrine cells.  Importantly, this research reveals that the neuroendocrine system has the cellular machinery necessary to generate daily rhythms and does not simply passively respond to cues from the SCN.  This finding has important implications for uncovering the the cellular mechanisms responsible for other cell types that show pronounced rhythms such as carcinomas. 
     The endocrine system provides an ideal opportunity to investigate the mechanisms and pathways by which the SCN exerts control over peripheral physiology and behavior. The cells in the brain that regulate endocrine function have been well characterized and there are abundant data available on the mechanisms by which the neuroendocrine axis is controlled hierarchically. Combined, these pieces of information allow for discovering general principles of circadian regulation of physiological functioning using a tractable system.  For this line of research, several neuroanatomical methods are used including monosynaptic and viral tract tracing, double-label immunocytochemistry, in situ hybridization, blotting techniques, and conventional and confocal microscopy. 


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.