These are my notes from one of the lectures in the series called Secrets of Sleep Science: From Dreams to Disorders, which is a recording of a class on sleep taught at Stanford University by Professor H. Craig Heller, PhD, and available from The Great Courses series. I have also posted notes for other lectures in this series including:
The Neurophysiology of Sleep.
Narcolepsy
More Sleep Notes
Some background stories:
In the experiments of Moruzzi and Magoun, in which it was found that electrical stimulation of a particular deep brain region always woke a sleeping cat, and additional experiments by Walter Hess found that electrical stimulation of another deep brain region always put a cat to sleep. These experiments demonstrate that certain parts of the brain act as "switches", turning sleep on and off. Early in the 20th Century, there was an epidemic of something at the time called The Sleepy Sickness, in which a person is partially conscious and aware of her surroundings, but unable to fully wake up to move or interact (there is a book about this disease, called "Asleep: the Forgotten Epidemic That Remains One of Medicine's Greatest Mysteries" by Molly Caldwell Crosby, whose grandmother was a survivor of the illness) This disease was also called Von Economo's Flu, or Encephalitis Lethargica.
The first cases of this disease were identified just prior to the great pandemic flu of 1918. Von Economo was a neurologist, who noticed that a subset of the patients with pandemic flu had a specific set of symptoms, that began with sore throat and mild fever, and progressed to extreme sleepiness. Many of these patients could be woken up, but could not stay awake. The sleepiness got progressively worse, until many patients went into a coma and died. Of those who survived, many developed Parkinson's Disease or Parkinson's like symptoms later in life, such as being frozen and unable to move out of particular poses, an expressionless face, and they frequently exhibited OCD behaviors (the movie Awakenings is a dramatization about people with this disease). Von Economo did post-mortem studies of the brains of people who had died of The Sleepy Sickness, and found lesions and inflammation just above the region of the brain that Moruzzi and Magoun had found put cats to sleep. No pathogen has ever been identified that caused this disease. Other epidemics, that appear similar, have occurred at various times in history.
There is another disease that is a very rare genetic disease and is essentially the opposite of Encephalitis Lethargica, called Fatal Familial Insomnia. This is a prion disease. Prions are small, mutant proteins that can self-replicate and accumulate in the brain (if prions sound familiar, you may have heard of them in regards to Mad Cow Disease). In this disease, a person begins to experience insomnia that gets progressively worse until they are unable to sleep at all, in the process exhibiting severe mental health symptoms, weight loss, and dementia. The person usually dies within 18 months of onset. Post mortem studies show that these people have damage to the part of the brain that Hess found put cats to sleep when electrically stimulated.
About brain structure relating to sleep...
A group of neurons that release the same neurotransmitters, and which are involved in the same functions, is called a "nucleus". Information is carried between the body and brain by axons, which are nerve cells that pass through the brain stem. All axons transmit an electric pulse, which is the same for any information, whether it be light or a touch or a taste. The meaning of the electrical impulses is only determined by where the cells connect, where they fire in the brain. There are some nuclei in the brain stem that are called "neuromodulators", because they project neurons into many parts of the brain, so they have a wide effect when they release their neurotransmitters. Some of these nuclei release excitatory neurotransmitters, and project widely to the cortex, which puts the brain into an awake state, which explains why electrical stimulation of these brain regions always arouses sleeping cats. These modulators include norepinephrine (the same neurotransmitter that leads to fight or flight in the sympathetic nervous system), in the brain this neurotransmitter is released by neurons in the Locus Coeruleus, in the brain stem. The Raphe nuclei are also in the brain stem and they release serotonin, which increases the sensitivity of the cortex. There are also a number of cholinergic nuclei that release the neurotransmitter acetylcholine (the nicotinic receptor, that is activated by nicotine, is an acetylcholine receptor). Near the hypothalamus is the Tuberomamillary Nucleus, whose neurons use histamine as their neurotransmitter. This nucleus projects all around the cortex and releases histamine that promotes arousal. Neurons in the Substantia Nigra produce and release dopamine, the neurotransmitter of motivation and reward, but also one of arousal and stimulation. These brain nuclei all work to excite and arouse the cortex and promote wakefulness. In Encephalitis Lethargica, damage to the connections between these brain nuclei and the cortex made it very difficult for people to stay awake.
What turns these wakefulness-promoting brain regions on and off?
There is another cluster of neurons in the hypothalamus that release a neurotransmitter called Hypocretin (Hypocretin is deeply involved in narcolepsy). These hypocretin-producing neurons project to all the wakefulness-promoting areas of the brain discussed above, and when they turn on, they coordinate arousal. Von Economo, the doctor who worked with people with The Sleepy Sickness, proposed that there is a region in the hypothalamus that shuts off the wakefulness-promoting regions of the brain and allows us to sleep. In the 1990s, a region was found in the anterior hypothalamus of neurons that release GABA, and which project to all of the wakefulness-promoting regions. These neurons become MORE active just before sleep (the opposite of most neurons) because they release GABA to turn OFF the wakefulness-promoting regions. The hypothalamus is also the region of the brain where the circadian clock, the regulation of the brain that coordinates our biorhythms with input about time, is located (specifically, the region is called the Suprachiasmatic Nucleus, which is part of the hypothalamus). Harvard researchers who discovered the GABA-producing neurons in the anterior hypothalamus have proposed the model of the sleep/wake system as a "flip/flop" switch, which in electrical terms is a switch between two states that mutually inhibit each other. When the system is in one state, it is actively inhibiting the other state. Outside input must be introduced in order to cause the state to change.
In Fatal Familial Insomnia, it has been found that a region in the thalamus (which is just above the hypothalamus and is also the brain region that Hess stimulated to produce sleep in cats) called the Reticulated Nucleus is involved. The thalamus relays sensory and other information to the cortex, which promotes wakefulness. The Reticulated Nucleus projects GABA producing neurons to all the other regions of the thalamus, effectively "shutting it down" to allow sleep. In Fatal Familial Insomnia, the Reticulated Nucleus is destroyed, and sleep becomes impossible.
During sleep, the cholinergic neurons actually "turn on" the cortex, which is active during REM sleep. Inputs and outputs to and from the cortex remain inhibited, which is what allows someone to stay asleep while the cortex is activated. REM sleep is an awake cortex in a sleeping body.
