Section: Research

David Weaver, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Neurobiology

Other Affiliation(s):
   Interdisciplinary Graduate Program
   Program in Neuroscience

Molecular Physiology of Circadian Rhythms

Research Program Description. 

The major objective of our research program is to understand the molecular mechanisms for circadian rhythmicity, and the impact of circadian rhythms on physiology and behavior.

Molecular mechanisms of circadian rhythmicity.

Daily rhythms in activity levels, alertness/sleep, body temperature, and hormonal profiles will persist in constant conditions, with a cycle length of about 24 hours, demonstrating the presence of an internal time-keeping system. When exposed to a daily light-dark cycle, these rhythms are synchronized (entrained) to a 24-hour period. In mammals, a small area of the anterior hypothalamus called the suprachiasmatic nucleus (SCN) is the principal circadian pacemaker (for review see Weaver, 1998; Reppert & Weaver 2001).

How do SCN neurons measure out 24 hours? Work on the circadian clocks of species ranging from bacteria to fungi to fruit flies has revealed a common thread, that the molecular basis for circadian rhythmicity is the rhythmic synthesis of "clock" molecules. In each of these species, and in mammals, molecules are synthesized rhythmically, and these molecules then feed back to turn off their own synthesis. This forms what is called a "transcriptional-translational feedback loop." Mutations of specific genes within the feedback loop result in altered or disrupted rhythmicity. Recently, great advances have been made in identifying the components of the circadian feedback loop in mammals, and in defining the specific roles of individual gene products in the circadian clock (reviewed in Reppert & Weaver 2002). The aim of this research is to understand the molecular mechanisms underlying generation and entrainment of circadian rhythms in mammals.

Under my direction, the role of the Period genes in the central molecular oscillator was tested through targeted disruption of all three mPer genes. Targeted disruption of mPer3 causes only a very slight change in the cycle length of circadian rhythmicity, indicating that this gene, while controlled by the clock, is not central to its operation (Shearman et al., 2000).  In contrast, targeted disruption of either mPer1 or mPer2 produces gradual loss of rhythmicity, and animals with mutations of both genes lose rhythmicity immediately upon placement into constant conditions (Bae et al., 2001). Companion molecular analysis of mutant mice indicates that mPer1 and mPer2 gene products play distinct roles in the central circadian clock.

We have used genetically modified mice to investigation the mechanisms of clock resetting by light.  Alterations in Period gene expression occur coincident with exposure to clock-resetting light exposure, and some work suggests that mPer1 and mPer2 may be needed for clock resetting.  Mice with targeted disruption of either one these genes can still respond to light with phase delays and phase advances (Bae & Weaver, 2003).  We also examined an alternative possibility, that light-induced degradation of BMAL1 was involved in phase resetting by light.  Contrary to a previous study in the rat, however, we found no evidence for light-induced degradation of BMAL1 (von Gall et al., 2003). It appears that the mPer genes are involved in light-induced clock resetting, but that neither mPer1 nor mPer2 alone is absolutely needed.

Current Research Projects:

We are studying behavioral and molecular phenotypes of mice with genetic defects altering circadian behavior.  We continue to generate line of mice with targeted disruption of genes relevant to circadian rhythms.  Other areas of interest are to identify the effects of clock gene mutations on other behavioral and physiological processes, including sleep, and to understand the importance of local oscillators in tissues outside the brain.  Portions of these studies are done in collaboration with Dr. Steven Reppert, Professor and Chair of Neurobiology, and with members of his lab.

Studies in collaboration with Drs. Laura Smale and Tony Nunez (Michigan State University ) seek to characterize circadian gene expression rhythms in a diurnal mammal, the Nile grass rat, Arvicanthis niloticus. The broad objective is to identify how the temporal regulation of locomotor activity becomes reversed between nocturnal and diurnal species.

Studies in collaboration with Drs. William Schwartz and David Paydarfar (Department of Neurology, UMass Medical School ) seek to bring a mathematical modeling perspective to understanding questions of circadian clock function.

Circadian and Neuroendocrine Effects of Melatonin.

Melatonin is a hormone released at night by the mammalian pineal gland. Melatonin production is regulated by the suprachiasmatic circadian clock. Current studies related to the hormone melatonin are directed at understanding the role of melatonin receptor subtypes in the regulation of circadian rhythms. We are characterizing behavioral and neurochemical responses to melatonin in the SCN of mice with targeted disruption of the Mel1a and/or Mel1b receptor genes. Additional studies of melatonin receptor-deficient mice are aimed at revealing the receptor and molecular mechanisms for effects of melatonin on neuroendocrine function. These lines of investigation are being pursued in collaboration with the laboratories of Dr. Jorg Stehle and Charlotte von Gall (Frankfurt, Germany ).

Office: LRB 723
Phone: 508-856-2495
E-mail: David.Weaver@umassmed.edu
Keywords: Neurobiology, Suprachiasmatic Nucleus, Circadian Rhythms, Gene Expression, Organisms - mouse

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