Circadian rhythms are cyclical changes in physiology, gene
expression, and behavior that run on a cycle of approximately
one day (even in conditions of constant light or darkness).
Schibler's talk focused on the observation that many peripheral
organs in the body appear to have their own molecular clocks
that are reset daily by exposure to daylight. A central
clock which, in mammals, is located in the Suprachiasmatic
Nucleus (or SCN, a region of the hypothalamus) coordinates
the resetting of the peripheral clocks.
Some examples of output from these clocks are the daily
rhythmic changes in body temperature, blood pressure, heart
rate, concentrations of melatonin and glucocorticoids, urine
production, acid secretion in the gastrointestinal tract,
and changes in liver metabolism. In the case of the liver,
its molecular clock drives the production of enzymes at
specific times during the day (or night, in the case of
rats) in anticipation of food consumption.
Schibler pointed out that much of the work done elucidating
the mechanisms that produce the molecular oscillations generating
circadian rhythms has been done here at Brandeis in the
labs of Michael Rosbash
(lab website) and
Jeffrey Hall. Specific
transcriptional regulators, genes discovered first in Drosophila
with their homologs later identified in mammals, are shown
to drive these molecular oscillations based on negative
feedback loops of gene expression. Measuring levels of transcribed
MRNA for these clock genes at different times during the
day is another way to quantify the timing of a clock at
the cellular level.
Individual cells in culture can be induced to produce rhythmic
gene expression, and these rhythms persist running on their
own for days. The central (SCN) and peripheral (liver) clocks
have different entrainment properties, which means their
rhythms can be differentially effected by changes in environment.
For example, if you shift the feeding time for a mouse from
night to day, it will shift the peripheral clock in its
liver over a period of days to anticipate the new feeding
time, thus completely inverting the original phase relationship.
However, the central clock will not shift in its rhythmic
transcription of circadian genes.
Recent findings from the Schibler lab suggest a role for
glucocorticoids as a signal from the SCN to the liver. The
absence of glucocorticoid signaling results in a much faster
phase-shifting in response to daytime feeding in mice. Therefore,
one iole of this signal seems to be to slow the phase shifting
in peripheral clocks in response to changes in feeding time.
Thus, if you decide to have a large, late night snack,
it would not be sufficient to shift the circadian clock
in your liver, due in part to release of glucocorticoids
from the SCN. Other potential signals from the SCN have
yet to be uncovered and the mechanism by which the SCN resets
peripheral clocks needs to be explored in further detail.
