Here, we review the history of the study of
circadian rhythms and highlight recent
observations indicating that the same mechanisms
that govern our central clock might be at
work in the cells of peripheral organs.
Peripheral clocks are proposed to synchronize
the activity of the organ, enhancing the
functional message of the central clock. We
speculate that peripheral visceral information
is then fed back to the same brain areas that
are directly controlled by the central clock.
Both clock mechanisms are proposed to have a
complementary function in the organization of
behaviour and hormone secretion. The rotation of
the earth exposes all organisms to a daily
change in light intensity. From algae to
mammals, nearly all organisms have adapted their
lifestyle to cycles of 24 hours.
Sunlight penetration has resulted in the
development of cellular mechanisms that are
sensitive to light and that allow the
anticipation of regular changes in the
environment; the evolutionary selection pressure
has been so strong that this property has been
retained in most species - from fungi to
mammals. Although most cells of all organisms
(including mammals) still have a molecular
mechanism able to drive a cellular clock, the
coupling of this mechanism to a biochemical
system capable of receiving and transducing
light has been retained in only a few tissues.
So, until recently, a common idea was that, from
lower invertebrates to mammals, the crucial
circadian clock elements had moved to the
central nervous system (CNS) and had become
concentrated close to or within the
light-transducing parts of the CNS. In mammals,
for example, the light signal can only reach the
CNS through glutamate secretion from retinal
terminals. However, recent findings have
refocused our attention on the circadian rhythms
of peripheral organ- organs that were thought to
have lost their rhythmic activity.
As a result of this shift in our thinking,
molecular clock mechanisms have been uncovered
in several peripheral organs. Together with the
older literature on the rhythmic functions of
such organs, these data indicate a
preservation of circadian functions outside
the CNS. Here, we review some of the earlier
literature on central and peripheral circadian
rhythms, and try to provide a tentative
functional link between central and peripheral
clocks. First, we describe some of the
experiments that led to the identification of
the suprachiasmatic nucleus (SCN) as the
central clock.We then consider the anatomical
and physiological evidence for the control that
the SCN exerts on peripheral-organ clocks and on
the autonomic nervous system. We conclude by
proposing a mechanism by which peripheral clocks
can feed back their circadian messageto the
brain, and point to some possible future
directions in this field. [...]
SCN and the autonomic nervous system :
The SCN-mediated control of the melatonin surge
indicates that autonomic control is at least one
important aspect of SCN function. Early data
showed a pronounced circadian change in the
sensitivity of the adrenal cortex to ACTH.
Transneuronal tracing and physiological
experiments provided proof that, in addition to
the classical neuroendocrine control of the
adrenal cortex by the release of CRH from the
PVN, and the subsequent release of ACTH, an
important neuronal SCNÐPVNÐsympathetic
nervous systemÐadrenal cortex axis also
determinesthe final levels of corticosterone
secretion from the adrenal gland. So, the SCN
uses a dual mechanism to provide an optimum
secretion of corticosterone: direct control of
the hypothalamic neuroendocrine neurons and of
neurons of the autonomic nervous system.We
propose that this is a general principle that
might hold, not only for endocrine glands but
for other organs as well. For example, recent
evidence indicates that, just before the onset
of activity, the SCN increases insulin
sensitivity, resulting in a physiologically
relevant increase in glucose uptake in muscle,
and simultaneously causes increased hepatic
glucose production. [...]
Peripheral and central clocks meet :
Despite the fact that cells of many organs have
the ability to retain a rhythmic function for a
few days, this property disappears without daily
enforcement (that is,without the SCN) . It is
interesting that soon after the SCN was
identified as the site of the biological clock,
other studies showed the capacity of an animal
to respond to a 24-hour rhythm of food
availability without an SCN. Although many
attempts were made to pinpoint the mechanism of
the observed anticipatory behaviour and
accompanying changes in hormone secretion, it
has remained enigmatic.However,we would like to
propose that peripheral clocks of different
organs, most notably of the liver, are essential
for this anticipatory behaviour.These peripheral
clocks, which lose their rhythm without the SCN,
can be entrained with food or hormone
stimulation.They are coupled to the metabolism
of the cell and, consequently, their
synchronized activity could send an important
signal to the brain. This hypothesis is
supported by several observations in relation to
the entrainment of behaviour in intact and
SCN-lesioned animals. One of the entrainment
properties of the SCN by light is that the clock
responds within certain limits, that is, a
22Ð28-hour period. If peripheral clocks have
a molecular mechanism similar to the central
clock, one might expect a similar limit of
entrainment as well. Interestingly, Stephan
showed more than 20 years ago that entrainment
to restricted feeding showed similar limits in
SCN-lesioned animals, an observation that led
this investigator to propose a multi-oscillatory
clock model in mammals. However, some
differences in the properties of central and
peripheral clocks exist. For example, in
contrast to the SCN, peripheral oscillators do
not seem to have a 'dead zone' for entrainment;
phase shifts can be induced at any time of the
lightÐdark cycle. On the basis of these
observations,we would like to suggest a role for
peripheral oscillators in synchronizing the
metabolic activity of the organ by their
signalling to the brain, mainly to the
hypothalamus.Visceral information could enter
the hypothalamus directly through hormones
and/or through axons from the nucleus of the
solitary tract (NTS), and indirectly through
projections from the parabrachial nucleus.As one
might expect, lesions of the vagus nerve or the
parabrachial nucleus lead to impaired
entrainment to feeding schedules. In this
regard, it is worth noting that the NTS and
parabrachial nucleus heavily target the same
hypothalamic structures that are innervated by
the SCN.These observations indicate a common
ground for the functioning of clock systems. In
our view, peripheralperipheral clocks, like the
central clock, control hypothalamic nuclei to
maintain a balance between body and brain.
Conclusions and future prospects
Although peripheral organs were first shown
to have a rhythm about 100 years ago, attention
quickly moved to the study of circadian rhythms
controlled by the CNS.Now the pendulum swings
back as we try to understand the interaction
between the central and peripheral clocks.
Evolution has equipped our organs with the
capacity to anticipate and adapt their activity
in relation to the activity pattern of the whole
organism.With hindsight, it is easy to see why
the function of the period (per) gene in the
circadian clock of Drosophila initially confused
scientists. As homogenates of the whole body
were used to detect circadian changes in per
mRNA concentrations, the rhythms of the
individual organs were masked by the conspicuous
noncycling nature of this transcript in the
female ovary. Similarly,we can now begin to
explain why clock rhythms in different mammalian
organs have a different momentum, and how they
relate to the pace of the central biological
clock. Organisms have to anticipate and adapt to
a changing external and internal environment.
Information from these two environments is
picked up by sensory and endogenous systems that
evolution has connected to cellular circadian
pacemakers. Information between these different
systems is constantly exchanged; in mammals,
this exchange takes place mainly within the
hypothalamus.Here, the physiological state of
the whole body is evaluated and the appropriate
hormonal and autonomic output is selected. This
idea is supported by several reports of
circadian rhythm disturbances in humans
suffering from chronic diseases - disturbances
that are manifest even before the onset of other
symptoms. Furthermore, these observations are
bolstered by correlated changes in the
anatomical integrity of the human SCN.We hope
that these insights will help to bridge the gap,
not only between body and brain, but also
between neurology and internal
medicine.
