The Pineal Gland and ________
The ______ gland or _______ synthesizes and secretes
_______, a structurally simple hormone that
communicates information about environmental
_________to various parts of the body.
Ultimately, melatonin has the ability to entrain biological
rhythms and has important effects on reproductive
function of many animals. The light-transducing ability
of the pineal gland has led some to call the pineal the
“_______".
Anatomy of the Pineal Gland
The pineal gland is a small organ shaped like a ______ (hence its
name). It is located on the midline, attached to the posterior end of
the roof of the third ventricle in the brain. The pineal varies in size
among species; in humans it is roughly 1 cm in length, whereas in
dogs it is only 1 mm long. To observe the pineal, reflect the cerebral
hemispheres laterally and look for a small grayish bump in front of
the cerebellum. The images below shows the pineal gland of a horse in relation to the brain.
Histologically, the pineal is composed of “__________" and glial
cells. In older animals, the pineal often contains calcium deposits
(“________").
How does the retina transmit information about light-dark
exposure to the pineal gland?
________ to the retina is first relayed to the
suprachiasmatic nucleus of the hypothalamus, an area of
the brain well known to coordinate ________clock
signals. Fibers from the hypothalamus descend to the
spinal cord and ultimately project to the superior
cervical ganglia, from which post-ganglionic neurons
ascend back to the pineal gland. Thus, the pineal is
similar to the adrenal medulla in the sense that it
transduces signals from the SNS into a hormonal signal.
Melatonin: Synthesis, Secretion and Receptors
The precursor to melatonin is _______, a neurotransmitter that
itself is derived from the amino acid _______. Within the pineal
gland, serotonin is acetylated and then methylated to yield ___.
_______ is the only hormone secreted by the pineal gland. Melatonin was discovered
in 1958 by Aaron B. Lerner and other researchers at Yale University. Melatonin is
produced in humans, other mammals, birds, reptiles, and amphibians.
It is present in very ____amounts in the human body.
Synthesis and secretion of melatonin is dramatically affected
by______ exposure to the _______.
The fundamental pattern observed is that serum concentrations of
melatonin are ____during the daylight hours, and increase to a peak
during the ____.
Examples of the
circadian rhythm in
melatonin secretion in
humans is depicted in
the figure to the right
(adapted from Vaughn, et al, J Clin
Endo Metab 42:752, 1976).
dark gray bars
represent night, and
serum melatonin levels
are shown for 2
individuals (yellow
Note that blood levels of melatonin are
versus light blue).
essentially undetectable during _______, but
rise sharply during the dark. Very similar
patterns are seen in other species. The
duration of melatonin secretion each day is
directly proportional to the length of the
night.
The mechanism behind this pattern of secretion
during the dark cycle is that activity of the ratelimiting enzyme in melatonin synthesis ______________________ (NAT) - is low
during daylight and peaks during the dark phase.
In some species, circadian changes in NAT
activity are tightly correlated with transcription
of the NAT messenger RNA, while in other
species, post-transcriptional regulation of NAT
activity is responsible.
Activity of the other enzyme involved in
synthesis of melatonin from serotonin - the
methyltransferase - does not show regulation by
pattern of light exposure.
2 __________receptors have been identified from
mammals (designated Mel1A and Mel1B) that are
differentially expressed in different tissues and
probably participate in implementing differing
biologic effects.
These are _________ cell surface receptors.
The highest density of receptors has been found
in the suprachiasmatic nucleus of the
________________, the anterior pituitary
(predominantly pars tuberalis) and the retina.
Receptors are also found in several other areas of
the ______.
Biological Effects of Melatonin
______ has important effects in
integrating photoperiod and affecting
circadian rhythms.
Consequently, it has been reported to
have significant effects on
reproduction, _____________ cycles
and other phenomena showing
circadian rhythm.
Effects on Reproductive Function
Seasonal changes in day length have profound
effects on _______ in many species. Melatonin is a
key player in controlling such events. In temperate
climates, animals like hamsters, horses and sheep
have distinct breeding season. During the nonbreeding season, the gonads become inactive
(males fail to produce sperm in any number), but
as the breeding season approaches-gonads must be
rejuvenated. _____ (length of day vs. night) is the
most important cue allowing animals to determine
which season it is. The pineal gland is able to
measure day length and adjust secretion of
melatonin accordingly. A hamster without a pineal
gland or with a lesion that prevents the pineal
from receiving photo information is not able to
prepare for the _______.
The effect of melatonin on reproductive systems can be
summarized by saying that it is ____________.
In other words, melatonin inhibits the secretion of the
gonadotropic hormones LH and FSH from the anterior
pituitary. Much of this inhibitory effect seems due to
inhibition of ______ from the hypothalamus, which is
necessary for secretion of the anterior pituitary
hormones.
One practical application of melatonin's role in
controlling seasonal reproduction is found in its use to
artificially manipulate cycles in seasonal breeders. For
example, sheep that normally breed only once per year
can be induced to have two breeding seasons by
treatment with melatonin.
Effects on ____ and Activity
Melatonin is probably not a major regulator of
normal ____ patterns, but undoubtedly has some
effect.
One topic that has garnered a large amount of
interest is using melatonin alone, or in
combination with phototherapy, to treat sleep
disorders.
There is some indication that _______levels are
lower in elderly insomniacs relative to age
matched non-insomniacs, and melatonin therapy
in such cases appears modestly beneficial in
correcting the problem.
Another sleep disorder is seen in _______, who often find
it difficult to adjust to working at night and sleeping
during the day.
The utility of melatonin therapy to alleviate this problem
is equivocal and appears not to be as effective as
phototherapy.
Still another condition involving disruption of circadian
rhythms is jet lag.
In this case, it has repeatedly been demonstrated that
taking _______ close to the target bedtime of the
destination can alleviate symptoms; it has the greatest
beneficial effect when jet lag is predicted to be worst (e.g.
crossing many time zones).
In various species including humans,
administration of ______ has been shown to
decrease motor activity, induce fatigue and lower
body temperature, particularly at high doses. The
effect on body temperature may play a significant
role in melatonin's ability to entrain sleep-wake
cycles, as in patients with _______.
Other Effects of Melatonin
One of the first experiments conducted to
elucidate the function of the pineal, extracts of
pineal glands from cattle were added to water
containing tadpoles.
Interestingly, the tadpoles responded by
becoming very light in color or almost
transparent due to alterations in melanin pigment
distribution.
Although such cutaneous effects of melatonin are
seen in a variety of "lower species", the hormone
does not have such effects in mammals or birds.
______ tumors
______ tumors are rare, occurring most often in children
and young adults. The most common of these are germ
cell tumors (germinomas and teratomas), which arise
from embryonic remnants of germ cells. These tumors
are malignant and invasive and may be life-threatening.
Tumors of pinealocytes also occur and vary in their
potential for malignant change.
_____tumors may cause headache, vomiting, and
seizures due to the increase in pressure within the head
that results from the enlarging tumor mass.
Pineal tumors
Endocrinologic effects may also be observed.
Some patients may become hypogonadal with regression
of secondary sex characteristics, while others may
undergo precocious puberty because of secretion of
___________.
___________ is frequently associated and is usually due
to tumor invasion of the hypothalamus and posterior
pituitary. Invasion of the pituitary stalk may interfere
with the ongoing inhibition of prolactin secretion by
dopamine from the hypothalamus, resulting in elevated
serum prolactin levels, a finding that may lead to a
mistaken diagnosis of prolactinoma. Treatment consists
of surgical relief of the increased intracranial pressure
and X-ray therapy.
Calcification of pineal begins in second decade of life
By Age 60, 70% is calcified
No evidence of change in gland activity
Descartes called “seat of the soul”
Continuous light, onset of sexual development
Remove pineal gland, prevent gonadal regression
Melatonin-Metabolized in liver for excretion
Eyes Wide Open
The United States Army Aeromedical Research Laboratory is
housed in a low orange brick building in Fort Rucker, Alabama,
Fort Rucker is the largest training base for helicopter pilots in the
United States.
Also where, for more than a decade, the sleep researchers John
and Lynn Caldwell have been conducting pioneering work on
sleep deprivation.
Their laboratory contains an elaborate flight simulator with
wraparound projected images mimic the visual experience of
flight. “It’s not like sitting at a video monitor or a computer
screen,” John Caldwell said recently. “It’s as close to the real thing
as you can get.”
Eyes Wide Open
Kept 6 helicopter pilots, in full combat garb were kept
awake continuously for two 40h periods-separated by
one night of recovery sleep.
Detailed performance evaluations were conducted at
regular intervals. The pilots were ordered to execute
precision maneuvers: Caldwells assessed how sleep
deprivation affected the pilots performance.
Eyes Wide Open
The military has a practical interest in such matters.
In last several year, bombing mission in Afghanistan and Iraq that
require the 2-man crew of a B-2 stealth plane to fly there from
Missouri without stopping -- a trip halfway around the world.
In ordinary circumstances- sleep-deprived pilots make more
errors and respond more slowly. Yet some of the pilots in the
Caldwells’ study were little affected by the loss of sleep. These
were pilots who had been given the compound 2-(diphenylmethyl)sulfinylacetamide, also known as modafinil. “Drugs are a tactical
necessity for sleep deprivation,” John Caldwell says.
_____, approved by the FDA for the treatment of ______,
is not a conventional stimulant, and has almost no
detectable effect on people who are already fully alert.
Yet the drug is at the center of a burgeoning new area of
research into the neurochemistry of sleep and wakefulness,
which promises to transform the treatment of sleep
disorders.
At the same time, scientists are exploring the prospect that
people may be able to sustain a state of poised and
productive alertness for days on end.
Some have even raised the question of whether advances in
biopharmacology will ultimately make regular sleep
unnecessary.
Several years ago, scientists in Texas identified a new family of
neurotransmitters called ________.
_____ are proteins produced by a remarkably small
number of nerve cells -- a few thousand, at most -- in a
single area of the hypothalamus.
scientists created “knockout” mice, which lacked the
orexin gene The genetically engineered mice seemed
normal in all respects but one: they had trouble staying
awake.
The scientists got in touch with scientists in Boston who
confirmed that orexin regulated the sleep-wake cycle.
“If you think about a normal day, 98% of the time is
spent either awake or asleep,” Saper says. “There is a
very short transition period between the two. The brain
seems to have a flip-flop switch that changes the state
from wakefulness to sleep, and orexin acts like the
thumb that keeps this switch in the ‘on’ position.”
A deficiency of orexin causes narcolepsy.
A research team dissected the hypothalamus of a________. The
hypothalamus appeared normal: it was the size of a plum, and had
the color and consistency of tofu.
They performed immunohistochemistry
No orexin was found
What had happened to the orexin neurons?
Unlike the knockout mice, the majority of human narcoleptics
have normal genes for producing orexin proteins and receptors.
Researchers believe that the orexin neurons are destroyed as part
of an autoimmune reaction.
Until recently, the only “countermeasures” to sleepiness
have been conventional stimulants, most notably
amphetamines like Dexedrine. Dexedrine has been the
standard treatment for narcolepsy, and it has had military
applications as well: the US Air Force supplied it to most
air crews during the Persian Gulf War. More than 60% of
the pilots who used the drug said it was “essential” to
accomplishing their mission.
Unfortunately, amphetamines, in addition to a high
potential for addiction, cause jitteriness, hypertension,
rapid and irregular heartbeat, overconfidence, and a
negative “rebound” effect -- nonrestorative sleep -- when
they wear off.
What scientists have sought instead is something that
would boost wakefulness by replicating the brain
chemistry of healthy, well-rested people.
Like many drugs, ________ was discovered before its
mode of action was understood.
In the early 1980s-, a French pharmaceutical company,
was exploring new treatments for somnolence by
injecting hundreds of compounds into lab animals and
observing the results.
In rats and then in humans, modafinil was found to
cause wakefulness, yet, unlike stimulants, it did not give
rise to hyperactivity.
In clinical trials conducted by Cephalon, a Pennsylvaniabased company that licensed the drug, modafinil was
demonstrated to be a safe and effective treatment for
narcolepsy. Somehow, it made up for the missing orexin.
“Modafinil is a key to understanding biologically what it
means for us to be awake,”
Miller believes that through evolution we have developed
2 different systems in the brain which previously were
lumped together under the broad term of wakefulness.
The first system is associated with vigilance, where one is
tensely alert to potential threats in the environment.
The physiology of vigilance seems to involve the
dopamine, NE and serotonin pathways: stimulating
these pathways results in hyperactivity and a reduction
of reaction time.
The second system is the “calm” type of wakefulness,
where one is attentive and engaged in so-called
“executive functions” -- able to focus on cognitive tasks.
Such wakefulness may involve the histamine pathways.
“the trouble with conventional stimulants -- caffeine and cocaine,
as well as amphetamines -- is that they indiscriminately activate
all the wakefulness-promoting neurons throughout the brain.
Modafinil, by contrast, promotes the more selective firing of
neuronal circuits in the cerebrum, particularly in the prefrontal
cortex, where many of the higher executive functions of cognition
and emotion seem to lie.
For narcoleptics, the results can be dramatic.
Modafinil preserves normal “sleep
architecture.” Unlike stimulants, modafinil
seems to have no potential for addiction; nor
have users been known to develop tolerance.
Indeed, because of modafinil’s effectiveness
and safety, many physicians are experimenting
with it for patients with other disorders;
modafinil has been shown, for instance, to
alleviate drowsiness and fatigue associated
with multiple sclerosis, Parkinson’s, and
depression.
Of course, one of the reasons so many Americans have trouble staying
awake is that they have trouble falling asleep.
Estimated that 30% of the population has significant insomnia on
occasion
10-15%, it is a regular condition.
Some researchers believe that the orexin pathway may point toward a
new-generation sleeping pill that would not have the disadvantages of
conventional sleeping pills, which almost always degrade the quality
of the sleep they induce.
A drug that blocked orexin might replicate the sort of rapid transition
to sleep that narcoleptics experience. “But there is still a lot we don’t
know about the kind of sleep that might result,” Thomas Scammell,
the Boston sleep researcher, warns. “If it meant prolonging REM
sleep, you might have 8h of intense dreams with an erection.”
Paradoxically, some investigators speculate that modafinil itself could
be helpful for insomniacs, since they report low energy during the day.
A more alert, fruitful day could usher in a night of restorative sleep.
Even as sleep disorders increase, firms are pushing their
employees to disrupt their normal sleep patterns in order to
provide services around the clock.
A fitness center that is open twenty-four hours a day, or a
restaurant that can deliver in the early morning. Etc.
Are at least 237 Home Depots and nearly 1300 Wal-Marts
that never close.
A health-club chain called 24 Hour Fitness has more than
430 places; - spends an extra 5 million dollars a year to stay
open all the time
extended hours generate an estimated 50 million
In the corporate world, of course, to be able to get by on 5
hours of sleep or less is a badge of honor, .
The military’s sleep research is going far beyond shift-worker
experiments and flight-simulator studies.
Department of Defense Advanced Research Projects Agency, or
DARPA, does studies on“innovative research and development
proposals in the prevention of degradation of cognitive performance
due to sleep deprivation.”
The capability to resist the mental and physiological effects of sleep
deprivation will fundamentally change current military concepts of
“operational tempo” and contemporary orders of battle for the military
services.
In short, the capability to operate effectively, without sleep, is no less
than a 21st Century revolution in military affairs.... As combat systems
become more and more sophisticated and reliable, the major limiting
factor for operational dominance in a conflict is the warfighter.
Eliminating the need for sleep while maintaining the high level of both
cognitive and physical performance of the individual will create a
fundamental change in warfighting and force employment.
One study, at Sea World, focuses on dolphins, which never
go fully to sleep.
“If these dolphins fell asleep, they could die in the water,”
“As mammals, they have to surface regularly for oxygen, so
they’ve had to adapt.”
In dolphins, only one cerebral hemisphere sleeps at a time:
when the left hemisphere is asleep, the right one is awake,
and vice versa.
Carney believes that working out how the dolphin
hemispheres shift between wakefulness and sleep while the
animal maintains a basic level of alertness may lead to
methods by which cognitive performance might be sustained
in human beings.
The Pentagon wants soldiers who can be
awake and high-functioning for up to a full
week, even in circumstances where a single
error can have disastrous consequences.
And for civilian society, too, the prospect of
gaining control over the cycles of sleep and
wakefulness has great appeal; lost productivity
caused by sleep disorders costs an estimated
18 billion dollars every year.
But will biology permit it?
But will biology permit it?
The widespread assumption that sleep is necessary
was supported by early studies of sleep-deprived
rats: they suffered deterioration not only in behavior
but in body metabolism and immune defenses.
As repeated experiments have verified, when rodents
are prevented from sleeping they often die of sepsis,
with some succumbing after only 5d, the hardiest
lasting a full month.
surprisingly, there is very little hard data showing
that prolonged sleep deprivation truly has deleterious
effects on humans
.
A record for documented continuous wakefulness was set in
1964,-a high-school student kept himself awake for 12 days.
rate of thinking and response slowed- no dramatic
physiological problems.
More systematic work on the effects of prolonged wakefulness
28 people kept continuously awake for 4 days, and found that
the major consequence was the expected decline in cognitive
functioning. Other studies of chronic sleep deprivation, where
subjects are allowed to sleep for 4h and are kept awake for 20,
found temporary changes in glucose metabolism, with an
increase in insulin resistance, a condition seen in early
diabetes.
Some of the sleep-deprived subjects also had about a 25%
increase in the number of circulating WBC.
clinical significance of such changes is unclear.
Many researchers believe that sleep is
necessary for the brain to replenish its
energy stores, the hypothesis remains
unproved.
In the absence of such basic medical
knowledge, sleep experts caution about the use
of drugs like modafinil as a substitute for sleep.
They worry that high-achieving types may be
tempted to take them in order to stay awake 2-3
days a week throughout the year.
And they worry about abuse among students
cramming for exams.
In fact, the medical consequences of such regular onoff sleep behavior are simply not known, and probably
will not be known for a long time.
Modafinil is the most tempting drug for our society to come along in
decades,” “It promises to satisfy our relentless desire to control time.”
Is caffeine a mirror of society’s craving, and its view of sleep as a
dispensable commodity.
“For years, coffee was taken in small doses, but the growth of Starbucks
says it all,” he says. “A venti” -20 ounces of coffee -- “is loaded with the
drug. It’s the beverage of choice in America. In middle school, it’s
Mountain Dew, which is also packed with caffeine.”
But research has shown how limited caffeine’s effects are. When his
team studied people kept awake for 88 hours, caffeine turned out to be
effective for only some 20 hours.
“Modafinil looks much better than caffeine,”
“Wakefulness becomes effortless.”
It’s a prospect that is both exciting and
disturbing.
The hypocretins (orexins) are a newly identified
peptide family comprised of two peptides,
hypocretin-1 and hypocretin-2.
These peptides play a role in the regulation of
behavioral state.
-when infused into the lateral ventricles in
awake animals, hypocretin-1 elicits increased
duration of waking beyond that observed in
vehicle-treated animals. Same true for
Hypocretin-2, but less potent
-rapidly emerging as functionally important
neurotransmitters.
(Hcrt-1/OXA,
Hcrt-2/OXB) encoded by the same
precursor gene and 2 G-protein coupled receptors
(Hcrtr1/OXR1, Hcrtr2/OXR2) are currently known.
Alterations in hypocretin neurotransmission causes the
sleep disorder narcolepsy in mice, dogs and humans.
Effects on appetite, neuroendocrine and energy
metabolism regulation are also suggested by other
studies. Hypocretins are uniquely positioned to link
sleep, appetite and neuroendocrine control, three
behaviors of major importance in psychiatry.
Orexin-A and B were identified as endogenous ligands for the orexin-1
(HCRT1) and orexin-2 (HCRT2) G-protein coupled receptors
These peptides are identical to 2 hypothalamic peptides that share a high
degree of homology with secretin, designated hypocretin-1 and
hypocretin-2.
ICV administration of orexin-A and B stimulated food intake in rats.
reports suggest a role in the sleep-wake cycle.