The long-term goal of the project is to identify signals that mediate the circadian regulation of behavior. Twenty-four hour (circadian) rhythms are strongly expressed in the behavior of animals and humans. For example, the homeostatic regulation of sleep is modulated by circadian output so that sleep is consolidated and phased to occur at a particular time of day. A circadian pacemaker in the hypothalamus, the suprachiasmatic nucleus (SCN), drives the circadian modulation of sleep as well as rhythms in other behaviors and in neuroendocrine and metabolic functions. The phasing of these rhythms is regulated by light via entrainment of the SCN and retinal projections that are distinct from the visual system. Non-visual projections also mediate acute effects of light on behavior and neuroendocrine function. Little is known about the output mechanisms for the circadian regulation of behavior or for the acute, non-visual effects of light. SCN transplant experiments show that an SCN signal can affect downstream targets for the control of activity by diffusion from the third ventricle. Previously, we infused candidate molecules into the third ventricle of hamsters, and found that an SCN peptide, transforming growth factor alpha (TGFalpha) strongly inhibits wheel-running activity. TGF-alpha could mediate both the acute effects of light on behavior as well as the circadian modulation of behavior. In this project we will test two hypotheses: 1. That TGFalpha is a physiologically important output signal of the SCN, and 2. That a specific hypothalamic structure, the subparaventricular zone, is an essential target for SCN output and the acute effects of light. In addition, the same methods used to identify TGFalpha will be used to evaluate the role of other SCN peptides as output signals. An understanding of SCN output may allow the development of therapies for the treatment of abnormal sleep timing and consolidation. In addition, identifying mechanisms for the acute effects of light may lead to a better understanding of light therapy that is commonly used to treat mood disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH068796-02
Application #
6914877
Study Section
Special Emphasis Panel (ZRG1-IFCN-D (04))
Program Officer
Vicentic, Aleksandra
Project Start
2004-07-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$283,140
Indirect Cost
Name
Northeastern University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Wreschnig, Daniel; Dolatshad, Hamid; Davis, Fred C (2014) Embryonic development of circadian oscillations in the mouse hypothalamus. J Biol Rhythms 29:299-310
Pantazopoulos, Harry; Dolatshad, Hamid; Davis, Fred C (2010) Chronic stimulation of the hypothalamic vasoactive intestinal peptide receptor lengthens circadian period in mice and hamsters. Am J Physiol Regul Integr Comp Physiol 299:R379-85
Dolatshad, Hamid; Cary, Andrew J; Davis, Fred C (2010) Differential expression of the circadian clock in maternal and embryonic tissues of mice. PLoS One 5:e9855
Gilbert, Jenifer; Davis, Fred C (2009) Behavioral effects of systemic transforming growth factor-alpha in Syrian hamsters. Behav Brain Res 198:440-8
Li, Xiaodong; Gilbert, Jenifer; Davis, Fred C (2005) Disruption of masking by hypothalamic lesions in Syrian hamsters. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 191:23-30
Snodgrass-Belt, Pamela; Gilbert, Jenifer L; Davis, Fred C (2005) Central administration of transforming growth factor-alpha and neuregulin-1 suppress active behaviors and cause weight loss in hamsters. Brain Res 1038:171-82