The Function of Sleep
The primary function of the insulin system is to maintain a steady blood glucose supply to the brain. The brain does not need insulin in order to take up sugar from the blood the way other body cells do, so by turning insulin on and off the body can allocate energy to the nervous system. When a muscle or body part needs more fuel it can increase blood flow to that area, but this takes time. In the meantime muscles and tissues have reserves of energy which can exist as fat or as glycogen. A glycogen molecule is a long branched chain of glucose molecules. In the brain glycogen is made and stored in cells called glia. The two primary types of cells in the brain are neurons and glia, and there are about 9 glia for each neuron (this is where the erroneous myth that we only use 10% of our brains comes form). The hypothesis for this lecture is that the function of sleep is to restore the glycogen reserves in the brain. This idea is supported by the fact that a buildup of adenosine leads to sleep, and adenosine builds up as energy is depleted. Adenosine opens potassium channels. The injection of a chemical that mimics adenosine into the brain of animals causes them to go into deep slow-wave sleep.
Glycogen breakdown, known as glycogenolysis, is done by an enzyme called glycogen phosphorylase. Glycogen is made by glycogen synthase. The neurochemicals that promote wakefulness activate the glycogen breakdown enzyme, and inhibit the glycogen synthesis enzyme. When the levels of these neurochemicals goes down at the onset of sleep, glycogen synthase is activated and the glycogen breakdown enzyme is inhibited. ATP inhibits the glycogen breakdown enzyme. Experiments found that sleep deprivation caused the most decrease in glycogen levels in the cortex, and the least in the brain stem. Areas of the brain that work harder, sleep harder; also supporting the idea that sleep has the function of restoring depleted energy reserves. Glia cells provide energy from glycogen to neurons in the form of lactate.
The Timing and Function of REM Sleep
The first part of the night is dominated by non-REM sleep, and the second half of the night sees more REM sleep. All mammals show cycling between non-REM and REM sleep. Is it possible that wakefulness creates the need for non-REM sleep, and non-REM sleep creates the need for REM sleep somehow? In studies of sleep deprivation, non-REM sleep comes first still, except in some extreme cases of total sleep deprivation, in which sleep-onset REM (SOREM) is seen. When rats are deprived of all sleep, serious failures of major physiological systems occurs. In studies that attempt to deprive the rats of only REM sleep, those same failures occur, just more slowly. The selectively REM-deprived rats became much more aggressive (possible sign of hallucinations?). Since REM deprivation has a significant impact on the quality of non-REM sleep, studies that attempt to study only REM deprivation must be viewed as studies of total sleep disruption.
Is there a homeostatic relationship between non-REM and REM sleep, that explains why they cycle? REM need builds up during non-REM sleep, as it builds up it is more likely to interrupt non-REM sleep (could the dysfunctional REM sleep onsets in narcolepsy be driven by an unmet need for REM sleep at night?). Human sleep studies also show that the length of REM sleep episodes corresponds to the length of the preceding non-REM sleep period, which supports the homeostatic model in humans well.
What about SOREM, or sleep-onset REM? This occurs in people who are very sleep deprived, such as those with sleep apnea or narcolepsy. Two possible explanations are that people with excessive daytime sleepiness tend to nap, and that high-density EEGs show that episodes of slow-wave sleep occur in regions of their brains during wakefulness. So maybe REM sleep need is building up in people who are having non-REM sleep processes during their awake phases. Obstructive Apnea events are more likely to occur during REM than non-REM sleep, which means that these people will have an accumulating REM need that is not being met.
How could non-REM sleep create a need for REM sleep? What does REM sleep do for non-REM sleep processes? Non-REM sleep is characterized by slow waves, which result from hyper-polarization of the neurons, which results from the leakage of potassium ions. The membrane potential is more negative during non-REM sleep than it is during REM sleep. The composition of the extra cellular fluids, where the potassium builds up, is controlled bu the glial cells. The glia take up the excess potassium ions from the extra cellular fluid- is it possible that REM sleep is when these potassium ions are moved back into the neurons? In a study that limited the leaking of potassium from neurons during non-REM sleep, it was found that REM sleep was eliminated. When the drug wore off REM sleep returned but there was no rebound effect which suggests that the drug was not simply masking the need for REM sleep but actually eliminating it. Interestingly, the drug used was apamine, which is in honeybee stings, and which blocks potassium channels, which depolarizes the neurons, making them more sensitive and more likely ton fire. (So, could narcolepsy be caused by an inability to regulate potassium ions in the brain?).
Sleep state misperception is when someone has brain activity that is such that they think that they are awake when they are actually asleep.
Sleep apnea is the partial or complete lack of breathing during sleep. In central sleep apnea, the part of the brain that controls breathing takes a break, so the lack of breathing is not accompanied by an effort to breathe. Central sleep apnea is thought to be one possible cause of SIDS. The other kind is called Obstructive Sleep Apnea, which is when the person is trying to breath but the breathing is blocked. The person will awaken just enough to breath, which is very disruptive to sleep patterns through the night. It is said to be like watching someone choke. The person with sleep apnea does not remember these awakenings and is not aware that this is happening. Obstructive sleep apnea occurs when the soft tissues of the throat collapse during sleep. This is more likely to happen in cases of obesity or certain facial structures. People with small lower jaws or receding chins are much more likely to develop sleep apnea (what about connective tissue disorders such as Ehlers-Danlos Syndrome?).
REM Sleep Behavioral Disorder is when a person acts out their dreams, it is a temporary loss of the muscle atonia that normally occurs during REM sleep. The person may be coherent and can injure themselves or others. Talking and yelling in one's sleep can precede the acting out by years. This disorder can make someone more likely to develop Parkinson's or Alzheimer's later.
Sleep paralysis usually occurs upon waking, and is when the person is partially awake but still has muscle atonia and may have parts of their dreams still mixed in with their perceptions. It usually passes in a matter of minutes.
Sleep and the test of the body
Many physiological systems are seriously adversely affected by sleep deprivation, and are restored by sleep. In rats kept awake, they eventually died after 16-21 days without sleep. Every physiological system was negatively affected- there were immune system changes, hormonal changes, sores developed on their skin, their fur became oily and matted, they lost weight even as they ate more, and their digestive systems were damaged. It was like accelerated aging or multi-system failure. The most striking results in mice studied were their increase in food intake, loss of body mass (especially fat tissue), and even a fall in body temperature.
Human studies have demonstrated large changes in glucose metabolism after 6 days of restricted sleep, enough to give them score of glucose clearance from the blood to put them at risk of type 2 diabetes. After the subjects were rested, their scores returned to healthy levels. Epidemiological studies have also found a correlation between short sleep and the development of type 2 diabetes. Other studies suggest that short sleep is strongly correlated with the development of obesity. Another research study found that after 6 days of restricted sleep, subjects had a significant decrease in a hormone (leptin) that suppresses appetite, and a significant increase in ghrelin, a hormone that increases appetite. the subjects reported an increase in appetite, especially for carbohydrates. Sleep loss impairs how the body handles glucose and regulates appetite, and these changes can have lasting effects on metabolism and body mass.
When we get sick, some of the cells in our immune systems release cytokines that induce sleep. Even low levels of sleep loss lead to an increased production of pro-inflammatory cytokines. There is experimental evidence that restricted sleep leads to significantly less antibody formation by the immune system. In another study, after only one night of limited sleep (limited to 4 hours) subjects' level of natural killer cells in the blood was reduced by 73% (NKC target virus-infected cells and tumor cells).
In experiments with rats, it was found that sleep deprivation led to significant loss of bone density. This study also found a significant change in the composition of bone marrow. All bone marrow cells originate from stem cells. In sleep deprived rats, there was a skewing of the new cells to form blood cells and not to form bone and fat cells. This increase in blood cells is an inflammatory process. The amount of each type of white blood cell in the blood is closely regulated. Diseases of the bone marrow can be treated with a bone marrow transplant. In a study it was found that bone marrow that was donated form a (mouse) subject (to another mouse) was only half as successful if the donor was sleep deprived the night before the transplant. Further study showed this to be due to reduced ability of the stem cells in sleep deprived subjects to migrate between the blood and the bone marrow. Restorative sleep returned the cells' ability to migrate effectively. It was found that this change was the result of the expression of a single gene that is under the control of growth hormone, a hormone that is released during sleep and suppressed during wakefulness (could this be one cause or contributing factor to Mast Cell Disease, which involves changes in the stem cell production of blood cells?)..
OTC sleeping medications almost always have diphenhydramine (benadryl) in them, because histamine is wakefulness promoting. Melatonin can help to reset the circadian rhythm, if taken at night before attempting to sleep.
Barbiturates and other sedatives act through the GABA receptor. This receptor is an ion channel that lets chloride ions into the neuron when it opens. This makes the membrane potentials of the neurons more negative, and less likely to fire in response to incoming stimuli. Barbiturates increase the length of time that these ion channels stay open when acted on by GABA, increasing the action of GABA. They also affect other neurotransmitter receptors as well, in ways that are not well understood and complex. All benzodiazepines work by binding to a particular site on the GABA receptor. and increase the efficacy of GABA on that receptor. The benzos are more selective than the barbiturates. Long-term use of these drugs results in tolerance. Different benzos act on the GABA receptors differently. Another newer class of drugs, called the Z-drugs because their names begin with the letter Z, act exactly the same way as benzos but are chemically different. Doxepin works by blocking the wake-promoting effects of histamine, it is a tricyclic antidepressant. It works better for early morning insomnia.
PTSD results in terrifying nightmares. It involves over activity in the hippocampus, amygdala, and frontal cortex. It can be thought of as super consolidation of the memory. His opinion is that PTSD is a REM sleep disorder, that the nightmares are a major factor in it's development and persistence, and we should be able to treat it through sleep. His hypothesis is that the nightmares in PTSD are so arousing that the person wakes up, and replays the dream, which allows it to be remembered. There is a natural amnesia of dreams that often occurs, which he suspects is an adaption to allow us to distinguish between dreams and reality. People with PTSD have high levels of circulating norepinephrine.