Showing posts with label sleep. Show all posts
Showing posts with label sleep. Show all posts

Wednesday, February 3, 2016

Plants That Don’t Sleep Will Take The Dirt Nap

Biology concepts – nastic movements, turgor pressure, evolutionary pressure, tropism, osmosis

If you don’t let a Mimosa pudica (sensitive plant) plant rest at night, it will wilt away to nothing. A plant that needs a good night’s sleep? Really? We have talked about how sleep revitalizes different brain functions, especially within the hypothalamus (The Best Cure For Insomnia Is To Get A Lot Of Sleep), but plants don’t have a hypothalamus or any brain for that matter. So why does it die if it can't rest; is it out of its mind?


The prayer plant on the left is how it looks during the day, but
on the right, the leaves have folded or curled up. They also stand
straight up, as if at attention. A tough way to spend the night, but
it must serve some purpose.
The prayer plant (Maranta leukoneura) folds up its leaves at night and tilts them upward. When morning comes, the leaves tilt back into their day position and unfold to catch as much sunlight as possible. The folded leaves might look like they are praying (hence the name), and it may appear that they are sleeping, but this is just anthropomorphism.

Humans have a need to feel connected to the rest of Earth’s life, and in the process, we tend to see the behaviors of other organisms in human terms, trying to assign some human motivation to them. So, is the plant sleeping? Does it need to rest? No. Sleep in animals implies inactivity and neural rearrangement, and these don’t occur in plants.


Charles Darwin performed crucial experiments
in plant movement in his later life, including the
identification that chemical signals moving in the
plant are responsible for growth toward the light
(heliotropism). Notice that his son got pretty good
billing as an assistant.
However, the fact that the plant carries out this activity every night suggests that it has evolved in response to some pressure, some need. Surprisingly little is known about why plants move their leaves at night, but there are a few hypotheses. Some scientists believe that changing the angle of the leaves helps funnel dewdrops and overnight rain down the trunk or stem to the roots. Charles Darwin published two books on these plant movements, his theory being that the behavior reduced the chance of chill or freezing.

Another hypothesis suggests that leaves fold up to keep the rain from pooling on them and promoting bacterial or fungal growth. Or perhaps, apposing one leaf closely to the opposite leaf reduces the amount of water lost overnight. However, aquatic plants don’t have to worry about loss of water, but some immersed plants, like Myriophyllum Mattogrossense, still fold up at night. It may be a holdover from their terrestrial days, as most of today’s aquatic plants evolved from terrestrial plants.

My personal favorite proposes that by folding up their leaves, the plants give nocturnal predators a better shot at seeing, hearing, and smelling nocturnal prey. By helping the predators, plants are indirectly protecting themselves from animals that would eat them- plants are sly little devils (more anthropomorphism). It is probable that different plants move for different reasons, so one hypothesis almost certainly won’t cut it for all organisms.

Plants have night moves other than folding leaves. Morning glories (Ipomoea violacea) close their flowers overnight. The reasons for this movement may be a little plainer. Dry pollen sticks to pollinators better than wet pollen, so closing off the stigma to rain or dew keeps the pollen dry. It also takes energy to maintain an open flower; this energy would be best spent when pollinators are around. If the plant’s pollinators are diurnal, they why leave the buffet open all night?


Just as animals have an internal clock, plants gauge
their movements according to the circadian period.
Often plants match their rhythms to pollinator animals
they depend on or to avoid the active periods of
predators. Anyway, I like the picture.
There are also flowers that have the exact opposite behavior, opening their flowers as the sun sets. Philodendron selloum (Is It Hot In Here Or Is It Just My Philodendron) is a classic example, with its spathe closing down in the early morning hours.

Moonflowers (Ipomoea alba) are another example.  At about 8:00 pm, the moonflower opens. A single flower can go from completely closed to fully open in less than a minute (http://www.moonlightsys.com/themoon/flower.html). The morning glories and the moonflowers are both of genus Ipomoea, but they have opposite behaviors – different pressures lead to different adaptations, even in closely related species.

These movements of plant structures are independent of the direction of the stimulus, ie. they are not following the sun or being blown by a particularly wind, so they are called nastic movements. Nyctinasty (nyc = night or darkness, nastic = firm or pressed close) is the specific movement of leaves or flowers in a daily pattern, open during the day and closed at night. If directed by the position of a stimulus, the movements are called tropisms (heliotropism, thigmotropism, gravitropism).


The left picture shows that changes in the pulvinus shape could affect the direction of the entire petiole and all the leaves, or individual leaves (like on the sensitive plant). The middle cartoon indicates that filling the central vacuole with water can change the shape of the cell, pushing in one or more directions. The right image shows just how the extensor cells on the bottom must be inflated to lift the petiole, while turgidity in the flexor cells makes the leaf drop.
Nyctinastic movements are accomplished by the flow of water in and out of specific cells in the pulvini (swellings, singular is pulvinus) at the base of the petioles (the stalk that attaches the leaf blade to the stem). It is not unlike our muscle movements in that there is an extensor and a flexor pair. When K+ and Cl- are pumped into the extensor cells on the bottom of the pulvini, they become hypertonic and water follows the ions through osmosis. This causes the extensor cells to swell due to increased turgor pressure.

Turgor pressure refers to the pressure of the cell contents against the cell wall. This increased turgor pressure at the bottom of the petiole pushes the leaf up. In an opposite fashion, night causes a movement of ions to the flexor cells on the top of the petiole. Water flows out of the extensors and into the flexors by osmosis, causing the stem to droop. Flowers and leaves open and close by the same movements, with the extensor and flexor cells located at their bases.

Turgor pressure is the same mechanism which causes the venus flytrap (Dionaea muscipula) to snap closed its jaws of death when an insect disturbs its trigger hairs. These hairs are located on the nectar laden, red lobes of the trap. Touching just one trigger hair doesn’t spring the trap, two must be displaced within 20 seconds of each other. This saves energy and unnecessary trap closings; each trap snaps shut only four or five times, then dies. If you thought the moonflower moved fast, check out the venus flytrap (http://www.youtube.com/watch?v=ymnLpQNyI6g). I’m just surprised we can’t hear the water shooting into the flexor cells!


The venus flytrap supplements its diet of water and carbon
dioxide with proteins from the insects it catches and digests.
The bright surface with nectar draws them in, where they trigger the
mechanosensor hairs. The magnified image on the right shows a
trigger hair with its hinge that transmits a signal to the pulvini to
swell quickly and snap the trap shut.
The trigger hairs are mechanosensors. The stimulus that trips the trigger and causes the flow of ions and water in the extensor and flexor cells of the hinge region is directionally irrelevant; therefore, the snapping shut of the trap can be considered a nastic movement. In this case, as with the sensitive plant (Mimosa pudica), the movement is called haptonasty (hapto = touch).

A small percentage of plants have nyctinastic movements, so they are an exception to the rule that plants don’t move actively, but even a small percentage means that thousands of species do have these movements. This many exceptions underscores the point that nyctinasty must perform an important function.

Just as humans with fatal familial insomnia die from a lack of sleep (An Infectious, Genetic Disease), the sensitive plant has a much shorter lifespan when nyctinasty is prevented. A plant hormone that stimulates leaf opening was identified in 2006. When given to plants continuously, it caused the leaves to remain open. When nyctinasty was prevented in this way, the leaves were noticeably damaged within a few days, and the plant was dead in less than two weeks. It may not be sleep, but whatever it is, it is just as important.

Some plants are open during the day and some are open at night, just as some animals are active during the day and some during the night. And just as plants adapt to a time schedule to promote survival, animal adaptations are crucial to life in the light or the dark. But that doesn’t mean that some organisms won’t throw us a curve, as we will discover next time.


Ueda, M., & Nakamura, Y. (2006). Metabolites involved in plant movement and ?memory?: nyctinasty of legumes and trap movement in the Venus flytrap Natural Product Reports, 23 (4) DOI: 10.1039/b515708k





For more information, classroom activities or laboratories on nastic movements or turgor pressure, see:

nastic movements –

turgor pressure –

Wednesday, January 27, 2016

An Infectious, Genetic Disease? Better Sleep On It.

Biology concepts – thermoregulation, sleep, genetic disease, infectious disease, central dogma of molecular biology, form follows function


Even rats have to get some sleep. It was nice to have the sleeping cap,
but unnecessary for a sleep deprivation study. Not a good use of
research dollars.
“I’m dying for a good night’s sleep.” Is this just hyperbole, or an impending warning of death? For laboratory rats, sleep deprivation does kill. During their insomniac downward spiral, the rats tend to get hot and can’t cool down – you know, they can't thermoregulate (see Can’t We Just Go With The Flow). This doesn’t mean that a loss of the ability to thermoregulate is what kills the rats, but it does suggest a connection between sleep deprivation and the hypothalamus.

We looked at the hypothalamus in our story of endothermy. This evolutionarily old brain structure implements a set point temperature for the body and receives information about the temperature of different parts of the body. When the body temperature deviates from the set point, the hypothalamus initiates bodily mechanisms to normalize the temperature.


Apparently one of the effects of sleep deprivation is that you
become semi-transparent.
People with severe insomnia tend to sweat more and have higher core temperatures even though they say they are cold. They also have extreme high blood pressure, pulse, and appetite. These symptoms suggest that sleep deprivation messes with the hypothalamus, since functions of the hypothalamus include themoregulation, sleep, hunger, thirst, reproductive readiness in females, and stress responses. What scientists don’t know yet is just how sleep deprivation actually kills the rats or harms people.

Dying from a lack of sleep is not just a rat problem, a few very unlucky humans die from it as well. Fatal familial insomnia (FFI) is a very rare genetic disorder; it has been reported in only 40 families worldwide. Before describing the truly horrible way these patients die, let’s look at what causes the disease.

FFI is caused by a point mutation in the gene for the prion protein PrPc. A point mutation means that one nucleotide on the DNA is changed, which leads to a change in the protein coded for by the DNA. Three unit (nucleotides) segments of the RNA (made from the DNA template) work together (called a codon) to code for one protein building block (amino acid). In the case of FFI, the amino acid called aspartic acid is changed to one called asparagine, and this changes the protein’s shape. 


The left image shows mRNA bases recognized in sets of three
(codons) by tRNAs with amino acids attached (Ser = serine, tyr =
tyrosine). The amino acids are linked to because proteins. The
lower section is the genetic code, showing which amino acids are
coded for by which codons. The right image shows how proteins
fold. The primary structure is the amino acid sequence. The
secondary structure comes from interactions of adjacent amino acids,
including spirals called helices or sheets. The tertiary structure comes
from the folding up of the entire protein, while the quaternary
structure comes from the interaction of different proteins into a
larger complex.
PrPc is made up of 250 amino acids linked together in a chain. Each different amino acid carries a different shape and charge and will interact with every other amino acid differently. The sequence of amino acids in a protein cause it to fold into a specific shape. It is the protein’s conformation (shape) that determines its function. This is the opposite of what we determined for evolved organism characteristics, where form follows function (see Do You Have To Be Ugly To Hear Well?). With proteins – function follows form!

Mutation of that single amino acid at position 178 (aspartic acid is negatively charged, while asparagine is positive) causes the folding, and therefore the function, of the protein to change. Aspartic acid is sometimes abbreviated "D", while asparagine is called "N"; therefore, the mutation is often indicated as D178N (D at position 178 is changed to N).

Many genetic mutations result in no change in amino acid, or a change that bring a large enough change the shape to cause a change in function. But when it does, good or bad things can happen. On one hand, the altered protein might confer an advantage to the organism, one that promotes survival in the environment or after an environmental change.This positive selection through reproductive advantage become the new normal – and this is evolution

On the other hand, the change in amino acid sequence, form, and function could be destructive. Disease might be the result, or perhaps a change in the organism that reduces reproductive success. One of these two results is what occurs with the FFI mutation of the prion protein.

When the mutated prion folds differently, it forgets its day job and moonlights as a sinister evil force. Every other prion protein it contacts, WHETHER MUTATED OR NOT, is coaxed into changing its shape. The new prions turn to the dark side, then change other prion proteins they contact, multiplying the effect. The poorly folded prion proteins will stick together, come out of solution, and form solids (plaques) where they settle out. In different prion protein diseases, this settling out occurs in different parts of the brain. In FFI, it is the hypothalamus.


In the top image, the PrPc on the left is properly folded. The green
represents alpha helices and the blue arrows represent beta-pleated
sheets. The right image shows the malfolded version of PrPsc. It is a
tighter structure, which partially explains why protein-degrading
enzymes don’t work on it. . The lower cartoon shows that the PrPsc
can force the PrPc to assume the improper form, and these then
aggregate into plaques.
The prion plaques are longer lived then the regular prion protein; normal cellular enzymes whose job it is to degrade proteins won’t work on prion plaques. And worse, if some of the malfolded protein is transferred to another animal, the recipient will develop plaques and disease as well. That makes this an infectious disease that isn’t caused by a bacteria, fungus, parasite, or virus. The prion is an infectious protein! What a terrible exception to the rules of infectious diseases.

We see here a protein that can replicate itself (not by building more of themselves, but by changing the form of normal proteins), and that makes it a repository of biologic information. This is an exception to the central dogma of molecular biology, which says that DNA is the sole information storing material.

FFI moves from person to person through heredity, but if a non-affected person comes into contact with some brain material from an FFI patient and that material entered their bloodstream, it can be transmitted this way as well. A prion protein disease called Kuru is famous for being transmitted from person to person.

The Fore tribe in Papua New Guinea once observed a ritual wherein they honored a dead tribe member by eating part of their brain (called ritualistic mortuary cannibalism - gasp!). Because of this, there was an epidemic of Kuru in this tribe in the early 1900’s. Over a period of 3-6 months victims would become unsteady, irrational with bouts of laughter, and then degrade mentally and physically to the point of death. There are more than twenty known prion diseases (mad cow disease, Creutzfeldt-Jakob, scrapie, etc.), and Kuru suggests that some might have no genetic component, only person to person transmission.


A member of the Fore tribe is shown on the left. This tribe used
to celebrate the lives of departed members by eating their brains.
This spread a prion protein disease called Kuru, a protein disease
that is infectious! The Fore tribe still lives in Papua New Guinea,
although there are fewer of them than before Kuru.
The differences between the various prion diseases are based on the specific prion protein mutation, what part of the brain is attacked, and how potent the prion is at refolding normal prion proteins. For instance, the D178N mutation in FFI also occurs in Creutzfeldt-Jakob Disease (CJD), but a normal polymorphism (an amino acid change that doesn’t change form or function) at position 129 determines the fate. If amino acid 129 is methionine, the the person gets FFI, if it is valine, then they get CJD. 

The families that suffer from FFI have the D178N mutation, and also pass on the polymorphism for methionine (M) at position 129. Even more gruesome, some cases of prion protein diseases can be sporadic, not associated with either an inherited mutation or transmission. The malfolded prion can very rarely arise out of nowhere in isolated individuals.

The mutated PrPc is passed on via inheritance. You get one copy of each chromosome from each of your parents, so for an individual gene, you might get two normal copies, 1 mutant copy and 1 normal copy, or 2 mutant copies. Some diseases require that you must inherit two mutant copies for symptoms to show (recessive), but other require only one mutant copy (dominant, it dominates the trait from the other parent).

FFI is autosomal dominant (not associated with the X or Y sex chromosomes), so the chance of getting a mutant copy and the disease if one parent has it is 1 in 2; these are bad odds. But, if everyone with FFI dies, then why is the disease still showing up in families. Remember that we said above that some genetic diseases can, but don't have to, affect reproductive success. Unfortunately for those with FFI, the symptoms appear in the victims’ fifties, after they have had children. Natural selection doesn’t eliminate FFI from the population because FFI doesn’t appear affect reproduction.

The first symptoms of FFI include sweating while feeling cold. Later, the ability to get a good night’s sleep is lost, followed closely by the inability to nap. As the disease progresses, there are panic attacks, phobias, and no sleep whatsoever. After 4-6 months, mental abilities start to degrade. In its final stages unresponsiveness precedes death. 

This is especially sad way to die, because during the majority of the disease course the patient is aware of everything going on. At least with middle to late Alzheimer’s disease the patient is blissfully unaware of their dementia.


For both the gross and microscopic images, the left example is from prion protein disease victim, while the right example is from a normal brain. The brains on the left show how great the loss of tissue can be in Creutzfeldt-Jakob disease. The microscopic image from the diseased brain shows the plaques and the resulting holes in the brain structure. The small gaps in the normal brain on the right are a result of shrinking of tissue after it was on the slide.
On autopsy, the hypothalmus of an FFI sufferer looks like it has been hit with a shotgun blast. Holes are present in the tissue, representing areas where neurons have been lost due to inflammation and triggered cell death. The affected area of the brain takes on a spongy appearance, so prion protein diseases are lumped together and called transmissable spongiform encephalopathies (encephalon = brain and pathy = disease). Unfortunately, there are no cure, treatments, or vaccines for any of these prion diseases.

It is the hypothalamus' control of sleep cycles and circadian rhythms that promotes survival in animals. But what about plants? They don’t have a hypothalamus. Can they suffer from loss of circadian activity? In a word – yes!  And this will be our starting point next time.


For more information or classroom activities on prion proteins, central dogma, infectious or genetic disease, the genetic code or protein structure, see:

Prion protein and diseases –

central dogma of molecular biology –

infectious disease –

genetic disease –

genetic code –

protein structure –
nwabr.org/sites/default/files/learn/bioinformatics/AdvL5.pdf
 

Wednesday, January 13, 2016

Exercise Puts Me To Sleep – You Too

Biology concepts – sleep induction, circadian cycle, narcolepsy, insomnia, anterior hypothalamus, neurotransmitters, cytokines, inflammation


Harriet Tubman gained the respect of all after the Civil
War, including that of William Seward, Secretary of State
of the United States (he’s the guy that bought Alaska).
Despite this respect, she ended up penniless. Seward
provided her with a two story brick house in Auburn,
New York where she could live out her days in
relative comfort.
Harriet Tubman was a narcoleptic. No, she didn’t steal things from the Woolworth, that’s kleptomania. She led hundreds of slave to freedom in the years before the American Civil War despite fighting off the urge to go to sleep at any given moment.

Narcolepsy is a sleep disorder that affects 1 in 2000 Americans, and causes them to have episodes of extreme fatigue. They fall asleep at odd times, and are very hard to awaken. In addition, they may also suffer from wakeful dreams, and cataplexy, a condition similar to temporary paralysis. This can’t have instilled confidence in Harriet’s passengers, but she got the job done.

Narcolepsy is basically too much sleep induction, while insomnia is too little. Many people suffer from insomnia, and it can be brought on by many different conditions. Could your New Year’s resolution to start exercising end up helping both narcolepsy and insomnia. Let’s find out.

You wake up in the morning determined to wear yourself out on the treadmill sometime today. You’re going to run to exhaustion in the hopes that you will get a good night’s sleep as a result. Your doctor did say that working out would help you sleep – but is this what he meant? You run until you’re out of energy and then you sleep to refill the gas tank?

Exhaustion from exercise may play a role in inducing sleep, but there’s much more. Exercise helps in insomnia in the elderly according to some reports. Exercise also helps with narcolepsy in children and adults. But how does it help?

There are two competing hypotheses for exercise’s effects on sleep via your brain. They use two different sensors, but they both run through the brain. But first we need to know a little bit more about the sleep center of the brain to explain how exercise is affecting us.

Sleep was the subject of a series of posts a couple of years ago, starting with this post. But we didn’t talk much about the induction of sleep. Sleep used to be considered a passive process; you slept when the stimulatory inputs to the brain were diminished.


Here is the hypothalamus, home of the sleep centers of the
brain. One the left you can see where the hypothalamus is
relative to the rest of the brain structures. On the right is a
cartoon showing the hypothalamus closer, including the
VLPO, the SCN, the LHA for wakefulness, and the MPO
for heat regulation.
Sleep is now known to be an active process, controlled by the anterior hypothalamus and preoptic nucleus. See the picture to help you locate this area of the brain. In the anterior hypothalamus and the preoptic nucleus, stimulation of GABAergic neurons promote sleep induction and maintenance. GABA is a neurotransmitter that is inhibitory, it stops some of neurons from firing. In this case, the neurons it inhibits are the ones that produce orexin/hypocretin. This is another neurotransmitter, but this one stimulates wakefulness.

Orexin is one neurotransmitter with two names. It was discovered by two different groups at just about the same time, and each group named it something different. Scientists haven’t decided yet which name to go with, so they use both.

There are only 10,000-20,000 neurons which produce orexin/hypocretin, so damage to any part of this area of the brain could induce narcolepsy. This may have been what happened to Harriet Tubman after her master hit her in the head when she was 12 years old. On the other hand, the brain trauma may have resulted in too much VLPO and AH sleep promotion. Either way, she was a professional napper.

So stimulating the POAH and the VLPO lead to sleep at least in part by inhibiting the production of orexin/hypocretin. But what stimulates the POAH and VLPO? Knowing nature as you do, you can bet there are several pathways. One way is certainly routed through the circadian clock. We have talked before about the sleep cycle controlled by the clock.


Yet another picture of the brain, this time highlighting the
pineal gland, where melatonin is made. The left side suggests
that light affects the pineal, but it ain’t the way the yellow
arrow shows. The right figure shows the true pathway much
more realistically. The pineolocyte is the cell type found in the
pineal gland. The melatonin is made from tryptophan and
serotonin is an intermediate structure, so you can make it
from serotonin itself.
Different hormones (like melatonin) and neural inputs/outputs stimulate the sleep and wake centers of the brain to create a semi-regular day/night cycle. Many things can mess with the cycle of melatonin and other day/night rhythms, including exercise. Now we can talk about different ways this may occur.

Temperature hypothesis:
The temperature hypothesis for sleep induction states that a one-degree decrease in your core temperature is enough to trigger sleep induction pathways on the brain. How could these two factors be linked? Well, the temperature sensing and regulating centers of your brain are located in the anterior hypothalamus, right next to the sleep centers (POAH and VLPO).

Reducing temperature is a way of saving energy by the body; this is probably an evolutionary holdover from when calories were hard to come by. Decreasing temperature signaled the brain that less activity was going on, so the body induced sleep to further reduce temperature and save energy for the next day.

It so happens that activity also decreases when the sun goes down, or at least it did before Thomas Edison and the electric light. This strengthened the link between temperature and the circadian sleep/wake cycle. To illustrate this point, a 2013 study measured the effects of drugs on both the circadian patterns and temperature. Drugs that altered the light responses in the SCN, including caffeine, also altered core temperature.


GABA (Gamma-aminobutyric acid) is a neurotransmitter
release at the synaptic cleft of some neurons. It is inhibitory
for some wakefulness neurons, so it promotes sleep. On the
other hand, noradrenaline is stimulatory for the orexin
producing neurons so it promotes being awake. In the middle
is adenosine, you know the player in DNA, RNA, and ATP. It
also happens to be a neuromodulatory and can inhibit the
GABA, NA, and orexin neurons.
In the same study, the same responses that reinforced circadian cycle (spontaneous sleep about 16 hours after light stimulation) also reduced the core temperature at the same time. Drugs that inhibited one, stopped the other as well. It would appear that temperature and day/night cycles are very much linked for sleep.

That then brings up the question of how exercise helps you go to sleep just by messing with your temperature. You exercise - you get hot - the blood vessels in your skin dilate and you sweat to dissipate some of the heat. But sweating isn’t 100% effective, your core temperature does go up. After you finish exercising, your temperature goes down slowly over time.

This decrease in temperature is the cue for your body to begin sleep. Your anterior hypothalamic temperature-regulating center can’t tell the difference between this decrease and the decrease brought about by circadian rhythms. So you may get sleepy a few hours after exercising, as your temperature comes down.

So, is right before bed the best time to exercise? Nope. Exercising stimulates your brain and cardiovascular system as well as raises your temperature. Trying to sleep right after exercise will probably be harder than normal, just because you are firing on all cylinders in your brain and heart.

The best time to exercise to help you get to sleep is about five hours or so before you plan on retiring for the evening. Your temperature goes up while exercising, and then will start to drop just about the same time you are ready for bed. This will reinforce the circadian cycles and give you the best shot at good sleep.


Insomnia is found in a number of conditions. It is
becoming a serious problem in the elderly, with people
living longer and unfortunately becoming more sedentary.
Complications are shown in the cartoon. You see that the
effects are varied, including the ability to fight off
disease. Who knew that not sleeping could lead
to diabetes!
The above plan applies to most of us, but perhaps not all of us. Very well-trained athletes might be less affected by the changes in body temperature for sleep induction. One 2013 study looked at exercise time, temperature manipulation and sleep patterns in professional and highly trained amateur cyclists. The results showed that evening exercise had no affect on sleep patterns, even if combined with a cold water dunk after the cycling routine (brrr!). Neither exercise nor exercise + decreasing temperature brought on a decreased time to spontaneous sleep. So – they sleep well because they wear themselves out each day.

Cytokine hypothesis:
The other system that may be important for inducing sleep after exercise is the immune system. Cytokines are chemical messages that influence many different parts of the immune system. They come into play when you have an infection, or cancer, or allergy; basically any insult to your system.

There are many different cytokines, and they perform many different jobs. Certain cytokines can even mediate opposing pathways, depending on the stimulus that starts their production and release. Some promote inflammation (pro-inflammatory) when one specific injury is sense, but inhibit inflammation (anti-inflammatory) if a different insult occurs.

Exercise can be seen as a stress to the body. It can injure muscles; in fact, that's how you build muscle. You tear them down a bit through work, and they grow back bigger and stronger. This is an insult that results in cytokine production and release into the bloodstream. But the more you train, the less of an insult your body registers.

IL-1beta, TNF-alpha and IL-10 are cytokines that have been associated with sleep induction. Plasma levels of IL-1beta are highest just as sleep is induced; this is one of the things controlled by the circadian system. But prolonged IL-1beta or TNF-alpha results in short sleep, and it is easy to wake you up.


Cytokines have big roles in the brain, even if they
act indirectly. Second messengers trigger pro-
inflammatory cytokines through the brainstem
which control fever and other symptoms,
including sleepiness. You think it’s a coincidence
that you sleep more when you’re sick?
On the other hand, IL-10 is anti-inflammatory and is higher with physical training over time. A 2012 study showed that in the elderly with insomnia, moderate training over months resulted in lower IL-1beta, lower TNF-a, and higher IL-10. These were also associated with better sleep patterns.

The neurons of the sleep center are sensitive to pro-inflammatory cytokines; inflammation signals disrupt the restful sleep patterns we are looking for. This involves the pro-inflammatory stimulation of cortisol, the stress hormone, so exercise’s help in sleep may be again related to a reduction of stress effects. This is a complicated system, but the take home message is, more exercise results in less pro-inflammatory cytokine action on the brain.

Chronic fatigue is also linked to high levels of pro-inflammatory cytokines in the brain that are unhooked from the decrease induced by training for some time. In the opposite direction, narcolepsy is aided by exercise, perhaps by reducing the cytokines that would inhibit orexin/hypocretin domination (wakefulness) in the anterior hypothalamus.

A 2007 study showed that in mice that don’t make orexin/hypocretin (have narcoplepsy), running on the wheel helped them stay awake more during the day. Of course, it also led to more episodes of cataplexy, so the story is not complete.

Next week, another brain effect of exercise – it can actually build your brain and make you smarter. Start running before that next AP quiz.


For a good resource on the structures of the brain, see Open College's Interactive Brain map.



Vivanco P, Studholme KM, & Morin LP (2013). Drugs that prevent mouse sleep also block light-induced locomotor suppression, circadian rhythm phase shifts and the drop in core temperature. Neuroscience, 254, 98-109 PMID: 24056197

Robey E, Dawson B, Halson S, Gregson W, King S, Goodman C, & Eastwood P (2013). Effect of evening postexercise cold water immersion on subsequent sleep. Medicine and science in sports and exercise, 45 (7), 1394-402 PMID: 23377833

Santos RV, Viana VA, Boscolo RA, Marques VG, Santana MG, Lira FS, Tufik S, & de Mello MT (2012). Moderate exercise training modulates cytokine profile and sleep in elderly people. Cytokine, 60 (3), 731-5 PMID: 22917967

EspaƱa RA, McCormack SL, Mochizuki T, & Scammell TE (2007). Running promotes wakefulness and increases cataplexy in orexin knockout mice. Sleep, 30 (11), 1417-25 PMID: 18041476
For more information or classroom activities, see:



Exercise and sleep –

Narcolepsy –

Orexin/hypocretin –

VLPO and sleep –