Glymphatic System: Why We Sleep

Part Of: Demystifying Consciousness sequence
Content Summary: 1000 words, 10 min read

Introduction

At some point tonight, your movements will become lethargic, your eyes droop, and you will lose consciousness for eight hours.

This won’t be a one-time thing. You’ll spend twenty years of your life in this zombie state.

Together with reproduction and feeding, sleep appears to be one of the fundamental requirements of all vertebrates.

Why? Let’s find out!

Three Modes of Existence

An EEG takes electrical recordings of the scalp. If you use an EEG during sleep, you can distinguish different kinds of sleep:

sleep-eeg-recording-simplified

There seem to be three modes of existence: wakeful consciousness, REM sleep, non-REM (NREM) sleep. These modes switch back and forth abruptly during a typical night’s sleep. Consider the following, a sleep architecture diagram:

sleep-stages-across-night-3

Chronobiological Influences

The rotation of the earth has profound implications on biological life. The temporal distribution of bodily functions is highly structured. Chronobiology studies biological rhythms.

Circadian rhythms are those that reset every 24 hours. The suprachiasmatic nucleus (SCN) drives your circadian clock. It is also a central hub of the hypothalamus, passing information to DMH to distribute to systems of feeding, stress, thermoregulation, and sleep:

sleep-hypothalamic-circadian-pathway-1

The pineal gland exists in nearly all vertebrates. It originally evolved with a third eye, which measured light intensity. However, mammals have long since lost their third eye, and instead splice retinal signals from the optic nerve to the hypothalamus, delivering light intensity data.

As long as there is light, the pineal gland is inert. However, with the onset of darkness, it produces melatonin. Melatonin thereby synchronizes the hypothalamus to the day-night cycle.

Ultradian rhythms are biological rhythms that reset more frequently than every 24 hours. Of these, the basic rest-activity cycle (BRAC) is most important. BRAC duration varies across species:

Cats exhibit a 20-minute rhythm in rate of responding. Likewise, it is been found that if one unobtrusively observes humans, they tend to show invigorated periods of facial grooming (eg touching the face, including nose picking) approximately every 90 minutes.

90 minute cycles have also been observed in heart rate, urine flow, eating, vigilance tasks, and tests for verbal and spatial intelligence. Importantly, these cycles need not start at the same time. Your peak time for verbal intelligence does not necessarily correspond with heightened face touching, but both will reset every ninety minutes.

Sleep is driven by the ventrolateral preoptic area (VLPO) of the hypothalamus. The VLPO incorporates the following systems:

  1. circadian rhythms (sleep tends to occur at regular intervals);
  2. ultradian rhythms (the REM-NREM cycle is 90min); and
  3. melatonin production (sleep tends to be facilitated by darkness).

The Purpose of Sleep

Cellular metabolism uses adenosine triphosphate (ATP) to produce energy, which yields protein waste (metabolites) that float around outside of cells (interstitial space).

In the body, the lymphatic system is responsible for removing this waste. But in the brain, the blood-brain barrier (BBB) removes access to the lymphatic system. So, how does the brain remove metabolites?

Your brain does not rest against the base of your skull (that would destroy brain tissue). Instead, it is immersed in a fluid bath. This fluid is called cerebrospinal fluid (CSF)

In addition to surrounding the skull and inhabiting your ventricles, CSF also participates in the blood brain barrier. Specifically, CSF inhabits paravascular space (outside the blood vessel, but inside the astrocyte processes).

Neuroendocrine- BBB

The cerebrospinal fluid flows between arteries & veins, creating a current that sweeps away metabolic waste. This is the glymphatic system:

glyphatic_system
In vein diameter, we see a tradeoff between metabolism (which uses blood, and produces waste) and glymphatics (which uses CSF, and removes waste). 

During sleep, the brain consumes about 40% less energy. This means smaller vascular diameter, which in turn expands the paravascular channel. Therefore, we would predict that sleep would be favorable to glymphatic processes. And in 2013, it was confirmed that the glymphatic system is indeed 60% more effective during sleep.

Let me say that again. In 2013, we discovered why we sleep: to remove neural metabolites.

This discovery unifies two previously separate theories of sleep:

  1. That sleep is metabolic (more difficult to catch food at night)
  2. That sleep is restorative (that something is replenished by the act of sleep)

Homeostatic Influences

As we have seen, sleep urge involves more than simple neural oscillators. If a predator keeps an animal awake all night, that animal will feel an increased need to sleep.  Excess metabolites induce a stronger urge to sleep.

A central organizing feature of the human body is the homeostatic setpoint, which regulates some quantity. For example, the brains of warm-blooded organisms represent and maintain blood temperature at a fixed value (in humans, 98.6 degrees Fahrenheit).

In this way, the part of the brain that regulates the body – the “hot loop” – can be conceived as a fairly elaborate kind of thermostat. And one such knob on this thermostat is sleep debt. But how does the brain represent sleep debt?

Adenosine is an inhibitory neuromodulator, ubiquitous in the vertebrate brain. Concentrations in the basal forebrain seem to represent sleep debt. Sleep deprived individuals have unusually high levels of adenosine, which is restored to normal levels only after a recovery sleep.

Along with biological oscillators, adenosine seems to induce sleep urgency. This is why caffeine works: it is an adenosine antagonist.

Importantly, adenosine is a metabolite. As adenosine triphosphate (ATP) is converted into cellular energy, adenosine (a byproduct of the reaction) is ejected from the cell into the interstitial space.  

Adenosine not only measures time spent awake, but also directly represents the levels of toxins within your skull. Adenosine concentration is reduced during sleep because the glymphatic system removes it, along with other metabolites.

Adenosine thus provides another glimpse at the deep relationship between sleep and metabolism.

Takeaways

  • Mammals inhabit three modes of existence: wakeful consciousness, REM sleep, and non-REM sleep
  • Sleep is a consequence of metabolism: the brain uses sleep to remove metabolic waste via the glymphatic system.
  • Sleep is heavily influenced by circadian rhythms (reset every 24hr), ultradian rhythms (reset every 90min) and melatonin production.
  • Sleep is also influenced by adenosine, which is a more direct representation of ambient metabolites (and also, of course, sleep debt).

References

  • Saper et al (2005). Hypothalamic regulation of sleep and circadian rhythms
  • Kleitman (1982). Basic Rest-Activity Cycle-22 Years Later  
  • Xie et al (2014). Sleep Drives Metabolite Clearance from the Adult Brain
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