BIOLOGICAL RHYTHMS - Dr.

Balanag
Outline:
II.
Biological Rhythms (Geophysical cycle)
III.
Characteristics of Biological Rhythms
IV.
Structural components of internal clock
i.
Suprachiasmatic Nucleus
ii.
Intergeniculate leaflet
iii.
Retina
iv.
Pineal glands
V.
Integration of the internal clock
i.
Generation of circadian rhythm
ii.
Entrainment of the internal clock
iii.
Coupling of the body to internal clock
VI.
Development and degeneration of the internal
clock
VII.
Circadian rhythms in practice
i.
Endocrine Rhythms
ii.
Cardiovascular rhythms
iii.
Respiratory rhythms
VIII.
Applications of Biological Rhythms
i.
Jet lag
ii.
. Altering Sleep-Wake Cycle
iii.
. Susceptibility to Noxious Agents
IX.
Effect of Disease on Biorhythms
Biological Rhythm
A. Circadian rhythm day and night: 24-hour cycle;
most important
is an internal biological clock that
regulates a variety of biological processes
according to an approximate 24-hour
period.
i. - sleep-wake cycle, the
temperature regulation system,
the endocrine system.
B. Circatidal the tides: high/low tide, cycle
C. Circalunar moon, cyclic, lunar cycle
D. Circannual seasons, seasonal cycle
circa-Greek for about
-

Biological rhythms have been retained by

organisms from the cellular level up to the organ
system level
The malfunctioning of a persons circadian system,
or biological clock, causes circadian rhythm
disorders.

When organism is isolated from the environment,

rhythm goes on even without inputs or signals from the
environment; oscillates independent from the
environment.
Independent oscillations approximate duration of
another day.
Things that follow a diurnal pattern:
In a study conducted to determine the diurnal
fluctuations of substances in the urine, it was found that

the activity, productions and excretion of the following

substances are greater during the day than night:
- K+
- Catecholamine
- Na+
- corticosteroids
- Ca2+
- other hormones
- Dopamine
- 17-hydroxycorticosteroids in the blood-follows
pattern opposite that of substances in the urine
greatest amount during early morning, goes down towards
midnight and rises just before waking up. Therefore, one
STRONGEST during the day
Others that follow diurnal pattern
- oxygen concentration - rises towards night
- venous pressure - rises towards night
- cardiac output - rises towards night
Phasic relationship of biological processes with functions
of the environment
Signals that direct biological rhythm:
1. Light and darkness
2. Temperature- cue utilized by organisms that
cannot see
i. Warm: day
ii. Cold: night
3. Social cues- actions of people, other organisms
people noisier during the day
Q: How does one prove that the biological rhythms are
independent of external signal and stimuli?
Experiment: more than 200 volunteers were isolated in the
underground chamber; no light and no sound
- Only means of communication was with the ones
conducting the experiment via written messages
Findings;
- When in an isolation, period of activity and rest
becomes a 25 hour cycle, may even reach 30-50 hrs
when period of isolation is lengthened rhythm may
be endogenous, independent from environment.
- In the isolated individual, the temp goes up with
the onset of rest, goes down at the end of the
activity phase.
- Rectal temperature peaks 2 hours after waking,
goes down when working and peaks again toward
the end of the day.
Characteristics of Biological Rhythms:
A. Environment-as long as there are ZEITGEBERS
(time givers), the rhythm of the organism is the
same as the environment
B. Organism (independent oscillations) the rhythm
continues to function in an organism independent
of the environment
C. Phasic rhythm as related to the other functions
of the organism
example:
temperature-rise in the morning
apex mid-afternoon

drop a fternoon
nadir midnight
Rectal Temperature:
highest at the end of the day, lowest during the
night, rise again upon waking up
increase temperature towards the end of the day
represent the accumulation of metabolic
processes (consequently heat) in the individual
organ and cells
Circadian rhythm disorders can be caused by many factors,
1. Shift work
2. Pregnancy
3. Time zone changes
4. Medications
5. Changes in routine
Anatomical Basis of Biorhythms
a. Suprachiasmatic nucleus
Small paired nucleus in the anterior portion of the
hypothalamus, lateral to the third ventricle
o Ablation -> disrupted activity-sleep cycle,
but can discern night and day
Even if person can see, without SCN, activity-rest
cycle not preserved.
Rats drink in the dark when they are active
SCN lesion causes loss of drinking habits
*It seems that the suprachiasmatic nuclei is where genes
coding for biorhythm are transcribed.

The circadian "clock" in humans is located mainly in the

suprachiasmatic nucleus (SCN), which is a group of cells
located in the hypothalamus (a portion of the brain).

Suprachiasmatic nucleus
2 parts:
1. Dorsomedial
Vasopressinergic (AVP) cells - Maintains the
rhythm of SCN
Somatostatin
NE secreting neurons communicate the level
of activity since they originate from the
brainstem
2. Ventrolateral
VIP neurons receive connections from other
sites to adjust the rhythm of SCN; spread extra
SCN impulses to the rest of the nucleus
Gastrin- releasing neurons processing of
photic stimuli
Neurotensin, neuropeptide Y, glycine secreting
cells
SCN receives afferent connections from:
1. Retina - glutamate
2. IGL - NPY
3. midbrain raphe serotonin
their axons connect to the VIP cells of the ventrolateral
subnuclei for the implementation of the internal pacing
One of this sites ultimately lead to the pineal gland, the
master administrator of the SCN
Intergeniculate Leaflet
Distinct part of the lateral geniculate complex, the
thalamic component of the visual system
Role in stimulatory /feedback mechanism of
internal pacemaker
Efferent outputs;
GABA and NPY -> SCN
GABA and enkephalins -> contralateral IGL
? -> SCN
Receives impulse from retinal ganglion cells,
anterior hypothalamus, retrochiasmatic area,
brainstem (Ach)

Retina
Innermost layer of the eye; provides light, the most
important synchronizer of the internal clock
Glutamate and substance P -> retinohypothalamic
tract -> hypothalamus

3 levels of integration with outside world:

1. Generation of time signals by the SCN
2. Entrainment of the SCN
3. Coupling of the SCN to organs for timing
1.

Generation of Circadian rhythm

Cells express temporal changes in terms of
neuronal activity (peaks during daytime),
membrane potential, and sensitivity to
neuronal changes
Day: cAMP, 5-HT, NPY, melatonin
Night: cGMP, glutamate, NPY, melatonin
Among the cells in the SCN, vasopressinergic and
somatostatinergic cells show circadian rhythmicity

2.

Entrainment of Internal Clock

Process of adjusting SCN to the environment
- result: endogenous periodic events
- endogenous- from within the organism
which is periodic or cyclic
Light-> retina -> VIP cells (ventrolateral SCN)
and IGL

3.

Coupling of the body to the internal clock

Circadian rhythmicity of melatonin (peak at
night, low at photic stimulation) important as
SCN effector
NE is responsible for circadial rhythm of
melatonin
Impulse -> pineal glands -> NE -> melatonin

Pineal glands (epiphysis)

Hangs from the posterior end of the corpus
callosum, develops from the floor of the 3rd
ventricle,, connected by epiphyseal stalk
Pinealocytes melatonin
Receives input from SCN

Integration of the internal clock

Internal pacemaking is important in coordinating

activities, resides in SCN
Set at 25-hour cycle
Zero hour is at mid sleeping time, not 12 am
Zeitgebers light (most important), activity,
sleep, social interaction. Photic and non-photic
to protect the body from external dangers
brought about by an external world bound by
24-hour solar clock

Melatonin effects
Neuronal inhibition (negative feedback of SCN)
Increases SCN perception of ambient light
Body temperature (40% of the rhythm)
Decreases risk of hypertension and atherosclerosis
Immune response
Ovaries, spermatozoa, hormone production
Antioxidant -> delays aging
**Melatonin or 5-methoxy-N-acetyltryptamine

an important hormone that plays a role in

regulating the neuroendocrine system.
plays an important role in the regulation of the
circadian sleep-wake cycle
controls essential functions such as metabolism,
sex drive, reproduction, appetite, balance,
muscular coordination and immune system in
fighting off diseases triggered by bacteria, viruses,
chemical pollutants and excessive free radical
activity
normally released during the night in response to
environmental changes in light levels by the pineal
gland which is a tiny gland buried deep in the brain
behind the eyes of mammals.
pineal itself is controlled by a paired cluster of
nerve cells located just above the optic chiasm in
the hypothalamus. These cells are known as the
suprachiasmatic nuclei (SCN) and they contain the
circadian pacemaker. Each night the SCN send
impulses, via a series of neurons in the
hypothalamus and spinal cord, up to the pineal
gland to stimulate melatonin secretion. The timing
mechanism in the SCN itself is controlled by
sunlight that enters the retina and reaches the
SCN via the retinohypothalamic pathway
amount of melatonin circulating in the blood has
been shown to rise and fall during a day.

Development and Degeneration:

Development:
SCN already present at 18th week of gestation (20%
at birth)
Maternal timekeeping prenatally
Takes 12 weeks for infant to develop consistent
sleep-wake cycle, coincides with development of
circadian changes in melatonin secretion
Temperature is the first rhythm to develop

Degeneration:
Vasopressinergic cells decreases beyond 80 years
old, earlier in Alzheimers
Amplitude of fluctuation decreases as early as 50
years old
Retinal and pineal gland changes
Biologic clocks advance (sleeps and wakes up
early)
Circadian rhythm in practice
A. Endocrine rhythm
best exemplified in HPA
AM: ACTH peak; prolactin and GH, low
PM: ACTH low; Prolactin, GH, high
Increase in melatonin level inhibit dopaminergic
cells, increases prolactin
Cortisol rises in AM, falls at night, thus cortisol
treatment is given in AM
FSH/LH monthly menses
Nocturnal rise in gonadotropins -> wet dreams
Glucose: tolerance decreases during day
afternoon diabetes. OGTT abnormal late in the
day.
B. Cardiovascular
Myocardial infarction frequently in morning (8-12
am, peak 10AM)
o Catecholamines and sympathetic tone
increases
o HR and BP increases
o Blood volume decreases in am
o Increase GFR and water excretion
o Increase blood viscosity, HGB, platelet
activity
o Aspirin and cardiac drugs given in AM
Blood pressure
o Pressor hormones (catecholamines, RAA)
peak in AM (9-10 AM), trough at 3 PM
Stroke
o Early AM ischemic
o 9-10 am hemorrhagic stroke
C. Respiratory
Asthmatic attacks in PM
Allergen exposure
Supine position
Bronchodilator withdrawal
GER
Impaired mucociliary clearance
Airway cooling
Circadian Rhythm Disorder Causes
Sensitivity to zeitgebers ("time givers," such as
light and other environmental cues):
o most common cause of the circadian
rhythm disorder of the sleep-wake cycle.
o Light, higher noise levels, and elevated
room temperature are not conducive to
good sleep and are important variables to

consider in both shift workers and night

workers.
Disrupted pacemaker function
o A dysfunction may be present in the
internal coupling mechanisms of biological
pacemakers
o Ex: the coupling of the sleep-wake cycle
with the temperature cycle.

Jet Lag syndrome

o Physiologic and mental, not pathological.
o The severity is related to the direction of travel and
is more frequently seen in individuals traveling in
an eastward direction.
o The number of time zones crossed also has an
effect on the severity of jet lag, with
most individuals experiencing jet lag if they cross 5
or more time zones.
o The rate of adjustment is 1.5 hours per day after a
westward flight and 1 hour per day after an
eastward flight.
o Desynchronization between internal pacemaker
and zeitgebers in the new time zone
Difficulty sleeping in the new sleeping time, daytime
sleepiness and fatigue, irritability, headaches
- traveling from EAST to WEST; faster
normalization of strength, oxygen
consumption and temperature
It takes: 2 days to adjust to sleep-wake cycle
5 days to recover body temperature
8 days for other rhythms to adjust to time
zone
Q: What is the medical application of all these?
A: One is more prone to develop illness while or after
traveling. Hence it is not
advisable to:
1. undergo operation few days after traveling
2. have a vaccination after a long flight
3. Sexual function are lowered, hence dont have
sex right after a long flight.
Recommendations: adjust sleeping time before long trips,
high protein diet and caffeine to promote awakening, high
carbohydrate diet to promote sleep.
Neurological disease:
Alzheimers disease
Sundowning - common in persons with Alzheimer disease,
is characterized by sleep disruptions with awakenings and
confusion.
Shift work:
Rapid shift changes and shift changes in the
counterclockwise direction are most likely to cause
symptoms of a circadian rhythm disorder.
Epileptics, asthmatics, those on chronic medications and
elderly are at risk.
Lifestyle and social pressure to stay up late
can exacerbate a circadian rhythm disorder
B. Altering Sleep-wake cycle

Q: Is studying at night (or engaging in other nighttime

activities) and sleeping during the day (sa oras ng lecture)
deleterious to your health?
Study conducted on blow flies (life span approximately 125
days)
Control group expose to normal light-dark pattern to
approximate day-night shift lived for only 100 days
YES, altering the normal sleep-wake cycle is deleterious to
your health and life because It goes against the natural
course of things
C. Susceptibility to noxious stimuli
Sensitivity to noxious agents depend on time this agents
are encountered
histamine : greatest susceptibility at the
end of the day
17-hydoxycorticosteroid activity: higher at
6-8 am then goes down; lowest at
the end of the
day
The most profound allergic reactions occur during dark,
hence body is more susceptible to allergens then. This
susceptibility is probably phasically related to the biological
rhythm of adrenocortical activity. Low 17 OH
corticosteroids, increased susceptibility to allergens
Q: What is the clinical substance of this?
A: An infection acquired at night could be worse than one
acquire during the day
Most resistant: when corticosteroid level is highest
Most susceptible: when corticosteroid is lowest
Chronic disorders
- Delayed sleep-phase syndrome (DSPS)
persistent (that is, lasting longer than 6 months) inability to
fall asleep and awaken at socially acceptable times.
fall asleep late (for example, in the early morning hours)
and wake up late (for example, in the late morning hours or
in the early afternoon hours).
Once asleep, however, persons with DSPS are able to
maintain their sleep and have normal total sleep times.
In contrast, persons without DSPS who are unable to sleep
because of difficulties initiating and maintaining sleep have
a lower than normal total sleep time than persons with
DSPS.
- Advanced sleep-phase syndrome (ASPS)
- persistent early evening sleep
onset time (between 6:00 pm and 9:00
pm) and an early morning wake-up time
(between 3:00 am and 5:00 am).
- less frequent, most commonly seen in
elderly and depressed individuals.
How Are Circadian Rhythm Disorders Treated?
The goal is to fit a persons sleep pattern into a schedule
that can allow the person to meet the demands of a desired
lifestyle.
Proper sleep hygiene techniques and external stimulus
therapy such as bright light therapy or chronotherapy.

Chronotherapy is a behavioral technique in which the

bedtime is gradually and systematically adjusted until a
desired bedtime is achieved.
Bright-light therapy is designed to reset a persons circadian
rhythm to a desired pattern. When combined, these
therapies may produce significant results in people with
circadian rhythm disorders.