Download Biological clock

大脑与节律
包爱民
浙江大学神经生物学系
Human Circadian Time Structure
Biological Rhythms
• Almost all land animals
coordinate their behavior
according to circadian
rhythms - the daily
cycles of daylight and
darkness that result from
the spin of the Earth.
(The term is from the
Latin circa,
“approximately,” and
dies,“day.”)
• In humans, there is an
approximately inverse
relationship between the
propensity（倾向、习性）
to sleep and body
temperature
Environmental
Light Intensity
Plasma Melatonin
Concentration
Sleep-Wake Cycle
Time of Day
Body Temperature
Plasma Cortisol
Concentration
• When the cycles of daylight and darkness are removed from an
animal’s environment, circadian rhythms continue on more or less the
same schedule - the primary clocks for circadian rhythms are not
astronomical (the sun and earth) but biological, in the brain.
• Brain clocks are imperfect and require occasional resetting.
• External stimuli, such as light and dark, or daily temperature changes,
help adjust the brain’s clocks to keep them synchronized with the
coming and going of the sunlight.
•
Brain clocks are an interesting example of the link between the
activity of specific neurons and behavior.
Biological clock
• The first evidence, a brainless organism - the mimosa: reacts to
sunlight, in some kind of reflex movement?
• In 1729, French physicist de Mairan: mimosa plants continued to raise
and lower their leaves in darkness, still sensing the sun’s movements?
• > 100 yrs later, Swiss botanist de Candolle: a similar plant in the
darkness moved its leaves up and down every 22, rather than 24, hrs,
implying the plant was not responding to the sun and very likely had
an internal biological clock.
What sets the Clock?
Zeitgeber: a stimulus that resets the biological clock (eg. bright light,
exercise, temperature)
The strongest zeitgeber, for both
plants and animals, is light.
Non-photic zeitgebers include
temperature, social interactions,
pharmacological manipulation,
exercise, and eating/drinking
patterns.
Biological clock
• Biological clock overrides （重写、无视）most
environmental cues.
• To maintain clock-environment synchrony, zeitgebers
induce changes in the concentrations of the molecular
components of the clock to levels consistent with the
appropriate stage in the 24-hr cycle, a process termed
entrainment.
• In the presence of zeitgebers, animals become entrained
to the day-night rhythm and maintain an activity cycle of
exactly 24 hrs.
Deprivation of zeitgebers: free-running
• Even small, consistent errors of
timing could not be tolerated for long
- a 24.5-hour cycle would, within 3
weeks, completely shift an animal
from daytime to nighttime activity.
• When mammals are completely
deprived of zeitgebers, they settle
into an activity-rest rhythm often with
a period more or less than 24 hrs, in
which case their rhythms are said to
freerun （自由运转）
• In mice, the natural free-running
period is about 23 hrs; hamsters, ~
24 hrs; humans, ~ 24.5–25.5 hrs
Biological clock
Deep caves, the sites for several isolation studies
People in caves, allowed to set their own schedules of activity for months,
they initially settle into roughly a 25-hr rhythm.
But after days to weeks, their activity may begin to free-run with a
surprisingly long period of 30–36 hrs: staying awake for about 20 hrs
straight, then sleep for about 12 hrs, and this pattern seems perfectly
normal to them at the time.
Biological clock
• In isolation experiments, behavior and physiology do not always continue
to cycle together: the rhythms of temperature and sleeping-waking, which
are normally synchronized to a 24-hr period, become desynchronized.
• One implication of this desynchronization is that the body has more than
one biological clock, uncoupled from one another.
• Desynchronization may occur temporarily - when we travel and force our
bodies suddenly into a new sleep-wake cycle: jet lag, and the best cure is
bright light, which helps resynchronize our biological clock.
What Reset the Clock?
Light
Synchronization of behavior and light-dark cycles - a photosensitive
mechanism for resetting the brain clock.
Mammals: a tiny pair of neuron clusters in the hypothalamus that serves as a
biological clock: the suprachiasmatic nuclei (SCN)
Retinal ganglion cells send direct projections to the SCN, i.e. the
retinohypothalamic tract
• light can also alter blood-borne factors
• SCN is highly vascularized
What Reset the Clock?
Melatonin: hormone of darkness
• secreted from the pineal gland
• increased levels of melatonin: one feels sleepy
• melatonin can act on receptors in the SCN to phase-advance the
biological clock
The circadian timing system
Superior cervical
ganglion
Axons from ganglion cells in the retina synapse directly on the dendrites of SCN
neurons. This input from the retina is necessary and sufficient to entrain sleeping
and waking cycles to night and day.
Pineal gland (to birds?) is unimportant, but to human melatonin may be important.
SCN as the biological clock: evidence
• When the SCN is stimulated electrically,
circadian rhythms can be shifted in a
predictable way
• Removal: abolishes the circadian
rhythmicity of physical activity, sleeping
and waking, and feeding and drinking.
• In hamsters, the transplantation of a
new SCN can restore rhythms within 2–
4 weeks.
• The brain’s internal rhythms never
return without an SCN.
SCN
Biological clock
Components of biological clock producing circadian rhythms:
Light-sensitive input pathway → Clock → Output pathway
One or more input pathways are sensitive to light and dark; the
clock continues to run and keep its basic rhythm even when
the input pathway is removed.
Output pathways from the clock allow it to control brain and body
functions according to the timing of the clock.
Biological clock
• The retinal cells synchronizing the SCN are neither rods nor cones eyeless mice: cannot use light to reset their clocks
• mutant mice with intact retinas that lack rods and cones: can!
• David Berson et al. discovered a new photoreceptor: a very specialized
type of ganglion cell - light-sensitive, expressing a newly recognized
type of photopigment, melanopsin（视黑素）
• Melanopsin: not present in rods nor cones, very slowly excited by light,
axons sending a signal directly to the SCN to reset it.
?
Biological clock
• Output axons of the SCN mainly innervate nearby parts of the
hypothalamus, but some also go to the midbrain and other parts of the
diencephalon
• Because almost all SCN neurons use GABA as their primary
neurotransmitter, presumably they inhibit the neurons they innervate.
• In addition to the axonal output pathways, SCN neurons may
rhythmically secrete the peptide neuromodulator: vasopressin (AVP)
• How do neurons of the SCN keep time? no complete answer at the
molecular level, but it’s clear that each SCN cell is a minuscule（极小的
） clock.
Biological clock
SCN neurons in culture: rates of AP firing, glucose utilization, AVP
production, and protein synthesis continue to vary with rhythms of about
24 hrs.
Circadian rhythms of the SCN isolated from the rest of the brain. The activity of a clock gene
was monitored in 100 individual SCN neurons maintained in tissue culture. Each neuron
generates a strong circadian rhythm that is well coordinated with the neurons. (Fig 19.22)
Biological clock
• SCN cells in culture: no entrainment of light-dark cycles, but their basic
rhythmicity remains just as when being deprived of zeitgebers.
• SCN cells communicate their rhythmic message to the rest of the brain
through efferent axons, using Aps, and rates of SCN cell firing vary with
a circadian rhythm.
• APs are unnecessary for SCN neurons to maintain their rhythm tetrodotoxin (TTX，河豚毒) applied to SCN cells can block their APs but
no effect on the their rhythmicity. Removing TTX: APs resume firing with
the same phase and frequency they had.
• SCN APs are like the hands of a clock: removing the clock’s hands does
not stop the clock from working
Biological clock
• It is a molecular cycle based on gene expression – similar in
humans, mice, fruit flies, and bread mold
• in Drosophila and mice, the system involves clock genes known as
period (per), timeless (tim), and clock - ‘clock’ gene (circadian locomotor
output cycles kaput)
• The basic scheme is a negative feedback loop.
• A clock gene is transcribed to produce mRNA then translated into
proteins. - after a delay, the new proteins send feedback and somehow
interact with the transcription mechanism, causing a decrease in gene
expression, less protein produced, then gene expression again
increases to start the cycle anew.
• This entire cycle takes about 24 hrs, and thus it is a circadian rhythm
Biological clock
Clock genes.
In the SCN, clock genes
produce proteins that
inhibit further transcription.
Gene transcription and the
firing rate of individual SCN
neurons cycle up and down
over 24 hrs.
The cycles of many cells
are synchronized by light
exposure (input from the
retina) and by interactions
of the SCN neurons.
(Figure 19.23).
Biological clock
• The mechanism to coordinate the thousands of cellular clocks so that
the SCN transmits a single, clear message about time to the rest of the
brain.
• Light information from the retina serves to reset the clocks in the SCN
neurons each day, but the SCN neurons also communicate directly with
each other and seems to be independent of APs and normal synaptic
transmission: TTX; young rat before development of chemical synapses.
• In addition to classical chemical synapses, it may include other chemical
signals, gap junctions, or the participation of glia.
Types of Rhythms
• Circadian – fluctuate daily
– Sleep-wake, temperature, hormones, urine production,
gastrointestinal activity
– Cognitive and motor performance levels
• Infradian – less than once a day
– Hibernation, ovulation
• Ultradian – more than once a day
– Sleep cycles (REM and other sleep stages)
Multiple Pacemakers
• SCN cycles (affected by environment):
– Sleep-wake cycles
– Skin temperature
– Hormones in blood, calcium in urine.
• Cycles independent of SCN:
– Sleep cycles (REM)
– Internal body temperature
– Cortisol in blood, potassium in urine.
Rhythms and Disturbance
• Epilepsy
• Extreme synchronous behavior in which many neurons fire at once.
– Localized or global
– Upsets balance of excitation and inhibition among neurons
• Delayed sleep-phase insomnia
• Seasonal depression
Desynchronization between circadian rhythms, sleep and emotion
states may result in depression.
– Depression is almost invariably cyclic.
– Many depressed people enter REM sleep earlier than normal.
– Sleep deprivation may ease depression temporarily.
• Alzheimer’s disease
Alzheimer’s disease
Randomized Clinical trial:
Light & Melatonin 3.5 yr in up to 189 subjects in 12 homes for the
elderly, placebo-controlled.
- nocturnal restlessness - 22% by light & melatonin
- enhanced rhythms (activity, melatonin)
- 12% less depressive symptoms
- attenuated cognitive decline (3 MMSE points after 3.5 years
Melatonin and Light
Melatonin Only
Light Only
None
16
14
MMSE
MMSE change
12
10
8
Riemersma et al., JAMA,
299, 2642-2655, 2008
6
-0.5
0.0
0.5
1.0
1.5
2.0
Time (years)
2.5
3.0
3.5