IBRO_Nairobi_2005: Lecture Circadian Rhythms and Behavior – HM Cooper
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LECTURE: CIRCADIAN RHYTHMS AND BEHAVIOR
Howard M. Cooper
Laboratory Brain and Vision,Department of Chronobiology, INSERM U37
Lyon France
All animals possess a central circadian clock which generates a daily rhythm
close to 24 hours. Output from the circadian system exerts profound effects on
numerous behavioral, physiological and endocrine processes: activity rhythms, sleepwake cycles, metabolism, vigilance states, cognitive processes, hormonal regulation,
etc. The basic function of the circadian timing system is to synchronize internal
physiological time to external factors of the environment in order to allow adjustment
to - and anticipation of - daily and yearly environmental cycles (food/water
availability, temperature cycles). It is advantageous for animals to predict, and not
merely react to changes in the environment. Along with synchronization to the outside
world (external synchronization), biological clocks also synchronize events within the
body (internal synchronization), for example to ensure that the time of hormone
release coincides with the time when the hormone receptor is available at the cell
membrane of the target tissue, etc. The process of synchronization of internal time to
external time is called entrainment and the environment cues allowing entrainment are
called zeitgebers (zeit = time, geber = giver, German). The main environmental cue for
synchronisation of the endogenous clock is the change in light levels associated with
the alternating day/night cycle. Other factors such as temperature, tidal cycle and
social interactions can also entrain biological rhythms in animals in which it is an
ecologically relevant cue.
Light or "photic" information is received by the retina and transmitted via a
direct pathway to the hypothalamic suprachiasmatic nucleus (SCN) which contains the
endogenous circadian clock. The endogenous clock generates a rhythm close to 24
hours which is derived from a molecular mechanism of clock genes and clock
regulated genes, involving several autoregulatory feedback-transcriptional loops. This
mechanism is endogenous, since SCN slices and individual neurons cultured outside
the brain in vitro are capable of functioning autonomously and express 24 hour
rhythms of gene expression, neuropeptide synthesis, and electrophysiological activity.
CIRCADIAN TIMING SYSTEM
Environmental
Cycle
Light Sensitive
Photoreceptor
Endogenous
Circadian Clock
Output
Rhythms
Light:Dark
FIGURE 1. Schematic diagram of the circadian system in mammals
The circadian timing system can be schematically represented as being
comprised of 3 components (Figure 1): (1) an input system sensitive to environmental
IBRO_Nairobi_2005: Lecture Circadian Rhythms and Behavior – HM Cooper
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light, which in mammals is comprised of the retinal photoreceptors, (2) the
endogenous circadian clock, located in the SCN, and (3) output effector systems which
control behavioral and physiological rhythms.
In a nocturnal animals such as the mouse and rat, the light cycle will
synchronize locomotor activity to the dark phase and their rest period to the light
phase. This daily rhythm is also seen in clock gene proteins, with the expression of
some proteins being higher during the day and others higher at night. The amplitude of
many physiological functions will also show daily patterns of variation, such as
temperature, metabolism and hormone levels (melatonin, cortisol). These internal
rhythms will all be synchronized by the SCN to the environmental light/dark cycle
with however, different phases (i.e. plasma melatonin levels are high at night while
cortisol levels are high during the day).
Locomotor activity is frequently used to monitor the internal state of the clock.
A typical recording of locomotor activity in the mouse is shown in the actogram below
(Figure 2). An actogram represents the distribution of activity over time. Each
horizontal line represents a successive 24 hour day. The vertical marks on each line
show the presence of locomotor activity, while the absence of the vertical marks show
a lack of activity. In the figure below exposure to a Light/Dark cycle (A) shows
"ACTIVITY" and "REST" periods which correspond to, respectively, the dark (shaded
area) and the light (un-shaded) phases of the light/dark cycle. This synchronisation of
activity to the light cycle is called entrainment.
B
LIGHT-DARK
CYCLE
CONSTANT
DARKNESS
C
NEW LIGHT
DARK CYCLE
D
CONSTANT
DARKNESS
ENTRAINED
RHYTHM
Successive Days
A
FREE-- RUNNING
RHYTHM
RE-- ENTRAINMENT
+ SHIFT
FREE- RUNNING
RHYTHM
0
12
24
TIME OF DAY
FIGURE 2. Actogram of locomotor activity in the mouse. Shaded areas
corrspond to the dark perios and unshaded areas to the light period. Recordings of
locomotor actvity are shown over successive days during and light/dark cycle
followed by a period of continuous darkness.
When the animal is then exposed to constant darkness (B), the locomotor
activity expresses a "free running rhythm" which in the mouse is shorter than 24 hrs
IBRO_Nairobi_2005: Lecture Circadian Rhythms and Behavior – HM Cooper
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(23.5 hrs). The onset of activity is thus observed to advance 30 minutes earlier each
day, and thus drifts to the left (arrow) – however the alternate periods of activity and
rest persist. Free running rhythms are expressed in constant conditions in complete
isolation from all time cues. In contrast, circadian rhythms are endogenous, i.e.,
generated by the organism itself and inherent (have a genetic basis). The period of
the free running rhythm is independent of temperature, i.e., it exhibits a phenomenon
called temperature compensation. Introduction of a new light/dark cycle (C) will
cause an immediate shift of nocturnal locomotor activity to the dark phase, and reentrainment of the rhythm. Re-exposure to constant darkness (D) leads to expression
of a new free-running rhythm of activity. Rhythms can also be studied by using
temperature recorders, analysis of plasma hormone levels (melatonin), brain activity,
heart rate variation, etc. A number of techniques using infrared detectors, activity
wheels, and transponders/telemetry have been developed to monitor daily changes in
rhythms. Some of these techniques will be demonstrated in the laboratory workshops.
Biological rhythms are also important in humans, and are frequently studied as
markers for disease or expression of altered physiology associated with different
pathological states. Significant alteration of physiological rhythms and sleep/wake
cycles occurs in major neuropathological diseases such as Alzheimer's, Parkinson's
disease, and seasonal depressive disorders. Loss of rhythmicity is also a major
complaint in the aged where sleep quality declines with age. Shift workers also suffer
from chronobiological dysynchronisation and increased susceptibility to diseases.
Recently, internal dysynchronisation of physiological rhythms has been recognized as
both a causal factor and early marker of disease in cancer patients. One of the major
challenges in the field of circadian biology is understanding the underlying
mechanisms of the circadian oscillator and the use of light as a synchronising factor
for developing strategies for light therapy of chronobiological disorders.
FURTHER INFORMATION: ON-LINE TUTORIALS:
NSF Centre for Biological Timing at the
University of Virginia
Biotiming Tutorial
HOWARD HUGHES MEDICAL INSTITUTE
Historical Background
The Human Clock
The Sleep-Wake Cycle
CIRCADIANA - CLOCK TUTORIALS
Clock Tutorial #7: Circadian Organization in Mammals
The principal mammalian circadian pacemaker is located in the
suprachiasmatic nuclei (SCN) of the hypothalamus. The general area was
first discovered in 1948 by Curt Richter who systematically lesioned a
number of endocrine glands and brain areas in rats.
http://www.hhmi.org/biointeractive/clocks/index.html
http://borazivkovic.blogspot.com/2005/01/clock-tutorials.html
http://template.bio.warwick.ac.uk/staff/amillar/andrewM/CBT%20tutori
al/TUTORIALMAIN.html
The only time he saw an effect on circadian rhythms was when he lesioned
a frontal part of hypothalamus (which is at the base of the brain)
immediatelly above the optic chiasm (the spot where two optic nerves
cross). Later studies in the 1970s narrowed the area to a small pair of
nuclei, each composed of about 10,000 neurons.
IBRO_Nairobi_2005: Lecture Circadian Rhythms and Behavior – HM Cooper
GLOSSARY OF TERMS...
biological clock--an internal timekeeping mechanism capable of driving or coordinating a circadian
rhythm.
biological rhythm--self-sustained cyclic change in a physiological process or behavioral function of an
organism that repeats at regular intervals.
circadian--taken from Latin words meaning "around" and "day"
circadian rhythm--a self-sustained biological rhythm which in an organism's natural environment
normally has a period of approximately 24 hours
circannual--a biological rhythm with a period of about one year
diurnal--performed in or belonging to the daytime; opposite of nocturnal
endogenous--self-sustained rhythm generated within an organism
entraining agent--an environmental time cue such as light that has the ability to reset a biological clock
exogenous--rhythm generated within or by an organism because of rhythmic environmental cues
that are external to the organism
free running--natural self-sustained rhythm that exists in the absence of all environmental cues.
When a human is free running, his/her cycle appears to be slightly longer than 24
hours.
hypothalamus--small area of the brain near the top of the brain stem; control site of behaviors such as
feeding or drinking, temperature regulation, secretion of hormones through its effect
on the pituitary gland
infradian--describes processes having periods much greater than 24 hours
melatonin--a hormone secreted by the pineal gland used as a marker of circadian rhythmicity in
humans
period--the time that elapses before a rhuthm starts to repeat itself
photoperiodism--the length of light in a light/dark cycle
tau--this term refers to an organism's period length
temporal--of or relating to time
ultradian--describes processes having periods much less than 24 hours
zeitgeber--taken from German words meaning "time givers"; an environmental time cue such as
sunlight, food, noise, or social interaction that usually helps reset the biological clock
to a 24-hour day
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