An Independent Project by Monika Nemcova ’19
Part 2 of 9
My first week of studying the mechanisms behind sleep revolved mainly around how different neurotransmitters create and affect the three basic states of the brain: wakefulness, REM sleep, and NREM sleep. But firstly, we should define what exactly these states mean. Neuroscientists recognize three standard, easy-to-measure characteristics that are used to define the brain states: EEG in the cortex, eye movement, and muscle tone. They are in the picture below. All of them measure electrical activity in certain areas. The first line, EEG, shows the activity of the brain. It is easy to spot the strange similarity between wakefulness and REM sleep in that first line: both have low voltage (seen as shorter marks on the graph) and high-frequency (the marks are close to each other) discharge patterns. It makes sense: dreaming, which happens during REM, often resembles our waking hours, so similar circuits are used to process it . However, there is one interesting exception – our prefrontal cortex, active during wakefulness, is turned-off in the REM phase. The prefrontal cortex is the part of the brain that is responsible for decision making and behavior modulation. So, as it turns off during REM, in dreams we often do things that we would never, ever do awake .
The second characteristic used to distinguish between the three brain states are the eye movements, noted as EOG in the picture. Eyes move the most when we are awake (even when we do not change their position conscientiously) and are still during NREM. During REM (which stands for rapid eye movement), they occasionally twitch under eyelids – that could be seen as irregularity on the otherwise flat graph .
The third line stands for muscle tone – how much does the body move; the less it moves, the lower the muscle tone. Quite obviously, the biggest is during wakefulness. After that, we are the most active in NREM – that is the phase when we move in the bed. Or, in the case of the less popular individuals for bed-sharing (such as myself), the phase when we steal all the pillows and kick any unfortunate person sleeping nearby. During REM, muscle activity is actively inhibited – probably as a preventive measure so that we could not act on our dreams .
While these three characteristics are useful in classifying the state the brain is in, it does not tell us what caused it to be so. As in many other cases in the body, the regulation of the sleep-wake cycle depends upon releasing site-specific chemicals, which, in turn, promote or inhibit the release of other chemicals. In the context of the brain, they are called neurotransmitters. Many neurotransmitters fulfill also other roles than only regulating sleep, so an average student has at least heard the name of many of them – serotonin, norepinephrine (also called noradrenaline), dopamine, acetylcholine, etc. When the electrical signal within a neuron is strong enough, it prompts the release of neurotransmitter – each neuron can do that only with one. So if the neuron releases serotonin, it is called serotonergic; if acetylcholine, cholinergic. The neurotransmitter then acts as a messenger between two neurons – the second neuron can fire more or less rapidly as the result of the chemical. It is important to note that naturally, the neurotransmitters occur only in the small space between two neurons.
That allows them to be site-specific. For example, one neurotransmitter called GABA is normally the chief promoter of NREM sleep. However, if it is released in a specific region of the brainstem called the pontine reticular formation, it inhibits REM and promotes wakefulness. When we take sleep medications (or any other drugs affecting the central neural system), our whole brain suddenly bathes in the neurotransmitters. That can account for some counter-intuitive results of some sleep medication. Most of the sleep drugs as well as the drugs used to induce general anesthesia work by promoting the effects of the beforementioned GABA. It works very well in most of the cases. However, in some patients, the drugs can promote GABA activity in the pontine reticular formation, which eliminates sleep. That is extremely unfortunate especially in children when instead of calming down before an operation, the stressed offspring becomes even more agitated .
The chemical cocktail of the brain is complicated but fairly well-understood. Studying sleep has the imminent advantage that it is an all-animal phenomenon, so a lot of studies could be accurately done using animal models. To simplify it, the three categories of brain states correspond with increased levels of certain neurotransmitters. The state of wakefulness is associated with high amounts of released monoamines – a group of chemical compounds where belong also serotonin and norepinephrine. They play a permissive role in sleep occurrence – it basically means that sleep can begin when their levels are low. Some anti-depressants, which work on the basis of increasing serotonin levels, can thus cause insomnia as a side effect . Another important neurotransmitter is called acetylcholine. It occurs in the brain in high concentrations during both wakefulness and REM sleep. In fact, from the chemical point of view, the main difference between the REM sleep and wakefulness is the ratio of monoamines to acetylcholine. When we are awake, their levels are roughly similar. During REM sleep, the monoamines level plummet but the acetylcholine levels stay consistent . I am saying levels – again, do not imagine brain bathing in acetylcholine; the neurotransmitters are released between two neurons and immediately recycled. The fact that the brain uses acetylcholine (and, therefore, the same circuits) in both wakefulness and REM sleep, again provides some rational basis why dreams resemble our waking reality so much.
As for the NREM phase – the traditional, if not a bit boring, sleep in which we spend the majority of our sleeping time, the main neurotransmitter there is the beforementioned GABA. However, I would like to talk mainly about another neurotransmitter associated with NREM sleep, adenosine. Adenosine, as in adenosine triphosphate, is the breakdown product of the famous energy-storing molecule ATP. It is relevant to us because caffeine acts by blocking the receptors for this sleep-promoting neurotransmitter. As we are awake, increasing amounts of adenosine are released. It effectively determines the length of time we can be alert – as adenosine builds up, we become to feel tired. When we go to sleep, the adenosine levels gradually decrease – the more we sleep, the bigger the decrease. That is the biological basis why we feel more rested and alert after a night full of sleep. Caffeine blocks the adenosine receptors and thus keeps us awake [5, 1]. That is maybe something to think about – caffeine does not make us less tired, it just blocks our ability to recognize how tired we are.
So that is all from me about the neurobiology of learning. Next time, I would like to focus on circadian rhythms and something important for all students: the biological basis of learning and how is that affected by sleep.
 Brown, R. E., Basheer, R., McKenna, J. T., Strecker, R. E., & McCarley, R. W. (2012). Control of Sleep and Wakefulness. Physiological Review, 92(3), 1087-1187. https://doi.org/10.1152/physrev.00032.2011
 Baghdoyan, H. A. (n.d.). Historical Overview: Brainstem & Forebrain [Video file]. Retrieved from https://www.coursera.org/learn/sleep/lecture/hRTfO/02-03-historical-overview-brainstem-forebrain
 Baghdoyan, H. A. (n.d.). Wake & REM: GABA [Video file]. Retrieved from https://www.coursera.org/learn/sleep/lecture/bBMkF/02-06-wake-rem-gaba
 Baghdoyan, H. A. (n.d.). Wake & REM: Monoamines [Video file]. Retrieved from https://www.coursera.org/learn/sleep/lecture/Vuu3a/02-04-wake-rem-monoamines
 Baghdoyan, H. A. (n.d.). NREM: Adenosine [Video file]. Retrieved from https://www.coursera.org/learn/sleep/lecture/I0u9B/02-09-nrem-adenosine
Vazque, J., Lydic, R., & Baghdoyan, H. A. (2002). The Nitric Oxide Synthase InhibitorNG-Nitro-l-Arginine Increases Basal Forebrain Acetylcholine Release during Sleep and Wakefulness. Journal of Neuroscience, 22(13), 5597-5605. https://doi.org/10.1523/JNEUROSCI.22-13-05597.2002