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Circadian Rhythms
Horton, T. |
Takahashi, J. |
Turek, F.W.
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Teresa H. Horton, Ph.D.
Department of Neurobiology and Physiology
Ph.D., University of Utah
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The ability to reproduce successfully requires that an organism coordinate gonadal function
with behavioral, physiological and environmental conditions conducive to the survival of
the resulting young. My primary research area investigates the mechanisms by which the
central nervous system integrates these multiple sources of information to regulate
reproductive function in mammals. The central focus of my research is the mechanism by
which secretion of the releasing hormone, gonadotropin releasing hormone (GnRH), from the
hypothalamus is regulated. GnRH controls the release of the gonadotropic hormones
(luteinizing hormone (LH) and follicle stimulating hormone (FSH)) from the anterior
pituitary; in turn, LH and FSH regulate the development of the gonads and germ cells. GnRH
has also been shown to function as a neurotransmitter to regulate reproductive behavior.
This dual function of GnRH facilitates the coordination of reproductive behavior with the
presence of mature gametes. The neurons that innervate the GnRH neurons form a complex
network providing for the integration of many forms of information. Thus the GnRH neurons
can be thought of as a nodal point in a complex information processing system. On going
research projects fall into three categories: 1) the role of the circadian system and
photoperiod in the regulation of GnRH secretion; 2) the mechanisms by which responses to
environmental and endocrine stimuli are altered during development and aging, and 3) the
mechanism by which seasonal changes in photoperiod regulate the ability of mammals to
release GnRH in response to other environmental stimuli, specifically pheromones from
potential mates. A wide variety of molecular biological, neurobiological,
endocrinological, and behavioral methods are used to study these problems.
Serum levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in male
Siberian hamsters following exposure to a female (arrow). Males housed in short
photoperiod (SD controls) do not release LH upon exposure to a female, but males housed in
long days do (LD controls). The ability of a female to elicit release of LH from a male is
apparent after he has been returned to a long photoperiod for as few as four days (SD >
LD (4 days)) and is well developed after eleven days in long days (SD > LD (11 days)).
An increase in circulating FSH is stimulated by exposure to long photoperiods, but not by
exposure to a female. These data indicate that the secretion of LH and FSH are
differentially regulated by environmental factors. (Data from Anand, Olson, Turek, and
Horton, unpublished).
Recent References:
Bernard, D.J., I.Y. Merzlyak, T.H. Horton, and F.W. Turek. 2000. Differential
regulation of pituitary gonadotropin subunit messenger ribonucleic acid levels in
photostimulated Siberian hamsters. Biol. Reprod. 62: 155-161.
Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS. Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol. 2004 Aug 10;14(15):1367-73.
Anand S, Turek FW, Horton TH. Chemosensory stimulation of luteinizing hormone secretion in male Siberian hamsters (Phodopus sungorus). Biol Reprod. 2004 Apr;70(4):1033-40.
I also co-direct the Science and Engineering Research and Teaching Synthesis Program (SERTS). Click here to
visit the SERTS web site.
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Joseph S. Takahashi, Ph.D.
Department of Neurobiology and Physiology
Ph.D., University of Oregon
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The long-term objective of the research in the Takahashi laboratory is to understand the
cellular and molecular mechanisms that regulate circadian rhythms. Our approach to
studying the mechanisms of circadian clocks has been threefold. First, we have developed
cellular model systems that express oscillations in vitro. Second, we have analyzed
the role of gene expression in the control of circadian rhythms. Finally, we have isolated
and identified clock mutants in mammals using classical and molecular genetics. At
present, our group is analyzing a number of vertebrate systems that fall into four areas
of research: (1) mechanisms of circadian oscillations in chick pineal cells; (2) circadian
and photic regulation of photoreceptor gene expression; (3) regulation of cellular
immediate early genes in the suprachiasmatic nucleus; and (4) molecular genetics of
circadian clock mutants in the mouse and hamster.
In future work, we seek to
identify the set of genes and gene products involved in the clock mechanism. Among
vertebrates this will require the use of model systems that are amenable to molecular
genetic approaches. The isolation of clock mutants, the molecular genetic analysis of
clock genes, and the creation of immortalized cell lines that express circadian
oscillations will ultimately be required to identify elements of the clock system. Once
fundamental elements are identified, we will be in a position to analyze the dynamics of
the oscillator in order to describe its mechanism.
Recent Publications:
Takahashi JS. Finding new clock components: past and future. J Biol Rhythms. 2004 Oct;19(5):339-47.
Lowrey PL, Takahashi JS. Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu Rev Genomics Hum Genet. 2004;5:407-41.
Solberg LC, Baum AE, Ahmadiyeh N, Shimomura K, Li R, Turek FW, Churchill GA, Takahashi JS, Redei EE. Sex- and lineage-specific inheritance of depression-like behavior in the rat. Mamm Genome. 2004 Aug;15(8):648-62.
Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS. Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol. 2004 Aug 10;14(15):1367-73.
Ahmadiyeh N, Slone-Wilcoxon JL, Takahashi JS, Redei EE. Maternal behavior modulates X-linked inheritance of behavioral coping in the defensive burying test. Biol Psychiatry. 2004 Jun 1;55(11):1069-74.
Bult C, Kibbe WA, Snoddy J, Vitaterna M, Swanson D, Pretel S, Li Y, Hohman MM, Rinchik E, Takahashi JS, Frankel WN, Goldowitz D. A genome end-game: understanding gene function in the nervous system. Nat Neurosci. 2004 May;7(5):484-5.
Kolker DE, Vitaterna MH, Fruechte EM, Takahashi JS, Turek FW. Effects of age on circadian rhythms are similar in wild-type and heterozygous Clock mutant mice. Neurobiol Aging. 2004 Apr;25(4):517-23.
Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong HK, Oh WJ, Yoo OJ, Menaker M, Takahashi JS. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues.Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5339-46.
Hong HK, Chakravarti A, Takahashi JS. The gene for soluble N-ethylmaleimide sensitive factor attachment protein alpha is mutated in hydrocephaly with hop gait (hyh) mice. Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1748-53.
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Fred W. Turek, Ph.D.
Department of Neurobiology and Physiology
Ph.D., Stanford University
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My research program is focused on the study of circadian and seasonal rhythms in mammals,
primarily in rodents. Ongoing work on circadian rhythms includes an investigation of:
- the neurochemical molecular and cellular events involved in the entrainment, generation suprachiasmatic nucleus (SCN) of the hypothalamus,
- the role of melatonin in modulating circadian rhythms and pulsatile hormone release,
- the interaction between ultradian and circadian rhythm generating centers in the regulation of endocrine and behavioral events,
- the genetics of the circadian clock system,
- the feedback effects of the sleep-wake cycle on the circadian clock regulating the timing of that cycle, and
- the effects of advanced age on the expression of behavioral and endocrine rhythms.
Of particular interest
is the role of the circadian system in measuring the annual change in daylength;
information which is used in the photoperiodic regulation of the seasonal reproductive
cycle. Other studies on the photic regulation of reproductive cycles involve:
- examining hypothalamic GnRH secretion under different photoperiodic conditions,
- determining the role of the pineal gland and melatonin in the regulation of hypothalamic-pituitary-gonadal activity,
- identifying the neural events which mediate the effects of light on neuroendocrine-gonadal activity,
- identifying early gene products in the brain, pituitary gland and gonads that are induced in response to a change in the length of the day.
A variety of neurobiological and endocrinological approaches are
being utilized to address these problems. In addition, to our work on rodents, we have
established extensive collaborations with clinical researchers. Studies in humans are
aimed at shifting the human clock in an attempt to alleviate mental and physical problems
that are associated with disorders in circadian time-keeping, particularly in the elderly
and in shift-workers. In addition, we are using both pharmacological and
non-pharmacological approaches to determine if we can reverse the effects of aging on the
circadian clock system of both rodents and humans.
Recent Publications:
Turek FW. Circadian rhythms: from the bench to the bedside and falling asleep. Sleep. 2004 Dec 15;27(8):1600-2.
Easton A, Meerlo P, Bergmann B, Turek FW. The suprachiasmatic nucleus regulates sleep timing and amount in mice. Sleep. 2004 Nov 1;27(7):1307-18.
Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med. 2004 Nov;5(6):523-32.
Solberg LC, Baum AE, Ahmadiyeh N, Shimomura K, Li R, Turek FW, Churchill GA, Takahashi JS, Redei EE. Sex- and lineage-specific inheritance of depression-like behavior in the rat. Mamm Genome. 2004 Aug;15(8):648-62.
Meerlo P, Westerveld P, Turek FW, Koehl M. Effects of gamma-hydroxybutyrate (GHB) on vigilance states and EEG in mice. Sleep. 2004 Aug 1;27(5):899-904.
Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS. Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol. 2004 Aug 10;14(15):1367-73.
Kolker DE, Vitaterna MH, Fruechte EM, Takahashi JS, Turek FW. Effects of age on circadian rhythms are similar in wild-type and heterozygous Clock mutant mice. Neurobiol Aging. 2004 Apr;25(4):517-23.
Challet E, Malan A, Turek FW, Van Reeth O. Daily variations of blood glucose, acid-base state and PCO2 in rats: effect of light exposure. Neurosci Lett. 2004 Jan 23;355(1-2):131-5.
Anand S, Turek FW, Horton TH. Chemosensory stimulation of luteinizing hormone secretion in male Siberian hamsters (Phodopus sungorus). Biol Reprod. 2004 Apr;70(4):1033-40.
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