A Primer on Sleep

If you aren’t asleep when the clock strikes three in the early morning, your eyelids get heavy and your brain feels like mush. You still have that paper to finish writing and you want to stay awake but staying awake is a struggle, a fight against our own brain. We have all been there (especially during finals week). With today’s post, lets look at how our brain regulates sleep and why we spend our days alternating between sleep and wakefulness?

Identifying a sleep regulating brain region


The identification of brain regions involved in specific function often occurs by studying patients with injury or viral-induced brain lesions resulting in impairments in function. This is the case for learning and memory, personality as well as sleep. In the early 1900s, Professor Constantin von Economo treated a number of patients with a disorder aptly named encephalitis lethargica or Sleepy Sickness (note: this is different from the Sleeping Sickness associated with the Tse Tse fly). Patients presented symptoms such as insomnia, lethargy, a reversal of sleep-wake times as well as a dissociation of mental and physical awakeness (patients would be awake but sit motionless)1.

By studying the brain regions affected in these patients, von Economo was able to identify brain regions involved in sleep and awake-states. Interestingly, he found that there are distinct brain regions involved in sleep and wakefulness. Since we are talking about sleep today, lets just focus on the brain regions underlying sleep. Von Economo found that lesions to the hypothalamus resulted in patients being unable to fall asleep despite being tired. Later studies in animals revealed that a specific group of cells known as the ventrolateral preoptic nucleus (VLPO) is involved in promoting sleep. In these animal models, lesions of the VLPO reduced sleep by over 50%2.

So now that we know where sleep is regulated in the brain, how does it work? Why do we cycle between sleep and awake? The answer (based on research so far): our brains are wired to switch between sleep and wake states, like the way we can switch our lights on and off. This switch is known as the flip-flop switch.

The flip-flop switch

As mentioned earlier, there are distinct brain regions involved in sleep and wakefulness. These two distinct regions exist in a state where they mutually inhibit each other. This is what allows us to either be awake or be asleep. For example, when we are asleep the VLPO, our sleep region releases GABA, an inhibitory neurotransmitter that suppresses neuronal activity in the brain regions associated with our awake state. The opposite occurs when we are awake. This is what scientists call the flip-flop model. This model also explains why we either fall asleep or wake up almost instantaneously (very little time is spent in a transitional state – this does not include the time we spend being lazy in bed). You may now be wondering, what influences these states? What changes flip to flop? There are at least two factors that can control these flip-flop states: sleep homeostasis and circadian regulation.

The homeostatic regulation of sleep

Sleep is known to be beneficial to the brain and the body. It is even believed to be important in memory consolidation. When you pull that all-nighter, you usually compensate by sleeping a certain amount of hours. You need to sleep. Therefore, it is believed that sleep is homeostatically regulated. One possible mechanism underlying this homeostasis is that there is a build up of some compound while you are awake that would at some point drive the flip-flop switch towards its sleep state. Adenosine is believed to be one such molecule. While you are awake, the body produces adenosine. The VLPO has receptors for adenosine. The activation of these adenosine receptors leads to the activation of VLPO neurons that then lead to sleep.

This is where caffeine may come in: Caffeine is an antagonist of these adenosine receptors. This means that the caffeine can block the ability of adenosine to bind these receptors and activate the VLPO. This may be one explanation as to how that cup of coffee can help you stay awake.

The circadian regulation of sleep

A second regulator of the flip-flop switch also explains why we cycle between sleep and wake on an approximately 24 hour cycle. This regulation involves a new brain region known as the suprachiasmatic nucleus (SCN). The SCN fires in a 24-hour cycle and is regulated by light inputs. The SCN indirectly projects to and influences the activity of the VLPO, which then regulates the light-dark dependence of our sleep cycle. This light-dark dependence of circadian regulation explains why it is harder for night shift workers to stay awake or why daylight savings time changes can take some getting used to.


Sleep is something that comes so naturally. We probably don’t even realize how tightly regulated it is until we try to stay awake past our bedtime. There is still so much we do not understand about the mechanisms regulating sleep and also how sleep itself exerts its beneficial on the brain and body. So here’s something to think about as you try to go to sleep tonight!


  1. Von Economo, C. Sleep as a problem of localization (1930) The journal of nervous and mental disease Vol. 71
  2. Lu, J., Greco, M.A., Shiromani, P., Saper C.B. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep (2000) Journal of Neuroscience 20
  3. Saper, C.B., Scammell, T.E., Lu, J. Hypothalamic regulation of sleep and circadian rhythms (2005) Nature Vol 437
  4. Schwartz J.R.L., Roth, T. Neurophysiology of sleep and wakefulness: basic science and clinical implications (2008) Current Neuropharmacol. 6(4):367-378
  5. http://www.howsleepworks.com/how_twoprocess.html

Featured image: Sleeping Girl by Domenico Fetti, 1622