Sleep Induction Mechanisms and Circadian Control

Homeostatic Control

• Homeostatic control dictates that increased brain usage during the day results in a greater need for slow-wave sleep afterward.

• This process is regulated by adenosine, a chemical that accumulates with energy expenditure in the brain.

• Adenosine accumulation promotes sleepiness and increases the likelihood and duration of slow-wave sleep.

• Caffeine blocks adenosine receptors, preventing adenosine from inducing sleepiness.

• Tolerance to caffeine develops as the brain produces more adenosine receptors to compensate for the blockage.

• Medications causing tiredness don't necessarily affect adenosine clearance; they can interfere with the sleep-wake flip-flop by:

  • Reducing the effectiveness of arousal systems.

  • Increasing the effectiveness of sleep-promoting systems.

• The length of the sleep cycle varies among individuals due to genetic and experiential differences.

Adenosine's Role and Slow-Wave Sleep

• Adenosine deaminase is an enzyme that breaks down adenosine during slow-wave sleep; variations in its activity influence sleep duration.

• Boosting adenosine deaminase function to reduce sleep need is not feasible because:

  • Adenosine is merely a signal to initiate slow-wave sleep, not the sleep itself.

  • Slow-wave sleep is essential for clearing toxic metabolites that accumulate in the brain during active functioning.

• During slow-wave sleep, the space between neurons increases, facilitating metabolite clearance, a process incompatible with active brain function.

• Adenosine triggers slow-wave sleep by inhibiting cells that inhibit the ventrolateral preoptic area (VLPO).

• Removing adenosine doesn't eliminate the need for slow-wave sleep; it only eliminates the signal.

• Brain temperature and exercise studies show a link between increased brain metabolism and subsequent slow-wave sleep.

Brain Recovery Theory

• Increased brain activity leads to more slow-wave sleep, regulated by adenosine.

• Adenosine buildup results from increased activity and triggers the brain to enter the slow-wave sleep state, which clears metabolites such as amyloid-beta.

Dreaming and REM Sleep

• Dreaming predominantly occurs in REM sleep, with minimal dreaming in slow-wave sleep.

• Muscle paralysis is exclusive to REM sleep, distinguishing it from the relaxed state of slow-wave sleep.

• Waking up briefly during a dream and falling back asleep allows resumption of the dream because the brain remains in a similar state to REM sleep.

• However, engaging in activities before returning to sleep disrupts the continuity of the dream.

Sleep Disorders

• Valproate regulates sleep in the brain.

• REM sleep behavior disorder involves acting out dreams due to the absence of muscle paralysis, while other aspects of REM sleep remain intact.

• The magnocellular nucleus is responsible for muscle paralysis during REM sleep.

Allostatic Control

• Allostatic control refers to the influence of threats to survival on the sleep-wake cycle, primarily driven by:

  • Hunger

  • The stress response

Hunger

• Leptin, produced by fat cells, signals energy availability and inhibits hypocretin neurons, favoring sleep.

  • Leptin uparrow, Sleep uparrow

• Ghrelin, produced by an empty stomach, stimulates hypocretin neurons, promoting wakefulness.

  • Ghrelin uparrow, Wakefulness uparrow

• Hypocretin, also known as orexin, was initially believed to signal hunger but primarily functions to prevent sleep in order to find food.

• A heightened Orexin level leads to prevented sleep, which allows one to seek food.

Stress

• Stress activates the medial prefrontal cortex and central extended amygdala, which stimulate hypocretin and noradrenergic neurons, promoting wakefulness.

  • Stress uparrow, Wakefulness uparrow

• The stress response prepares the body to deal with threats by:

  • Increasing heart rate

  • Raising blood pressure

  • Promoting wakefulness

Circadian Control

• Circadian control governs the rhythmic nature of sleep, making it easier to fall asleep at night than during the day.

• This rhythm persists even without external cues, indicating an endogenous biological clock.

• The circadian rhythm is approximately 24 hours long, slightly longer for most people.

• Exposure to light and dark synchronizes the internal clock with the external world.

Suprachiasmatic Nucleus (SCN)

• The suprachiasmatic nucleus (SCN) in the hypothalamus serves as the primary biological clock.

• Endogenous refers to processes internal to an organism.

• The SCN is located near the optic chiasm, where optic nerves cross.

• All vertebrates possess an SCN.

• Damage to the SCN disrupts the organization of the sleep-wake cycle, resulting in ultradian sleep-wake cycles.

• The homeostatic control is still present.

• During the day, the SCN exhibits high action potential activity, while it is quiet during the night.

• SCN cells maintain a 24-hour rhythm even when isolated in a dish, indicating intrinsic rhythm generation.

• Individual SCN cells have slightly varying rhythms but communicate to synchronize.

• Hamsters with a 20-hour circadian rhythm have SCN cells that also exhibit a 20-hour cycle.

• Transplanting SCN cells from a hamster with a normal (24-hour) circadian rhythm to a hamster with a damaged SCN restores the circadian cycle.

• Transplanting SCN cells from a 20-hour hamster into a normal hamster causes the recipient to adopt a 20-hour rhythm.

Molecular Mechanisms of the SCN Clock

• The core components of the SCN clock involve genes and proteins: period 1, 2, and 3 (Per1, Per2, Per3), cryptochrome 1 and 2 (Cry1, Cry2), clock, and BMAL1.

• Clock and BMAL1 proteins form a complex that stimulates the transcription of Per and Cry genes into messenger RNA (mRNA) in the nucleus.

• mRNA exits the nucleus and is translated into Per and Cry proteins in the cytoplasm.

• Per and Cry proteins form complexes that re-enter the nucleus.

• Cryptochrome-period one complexes suppress the function of Clock and BMAL1, reducing transcription of Per and Cry genes. This creates a negative feedback loop.

• The process from transcription to suppression takes approximately 12 hours, with a full cycle lasting about 24 hours.

• Enzymes clear the proteins, and the cycle restarts when protein concentrations are low enough.

• The concentration of cryptochrome and period proteins rises until production stops, followed by clearing, and the cycle restarts, maintaining a 24-hour rhythm.

• Period two stimulates the transcription of BMAL1, leading to BML1 protein.

• As cryptochrome and period proteins increase and suppress the transcription of cryptochrome and period genes, BMAL1 transcription is stimulated.

• It creates two cycles operating in anti-phase: one stimulates the production of period and cryptochrome, while the other inhibits their production.

• RNA levels of period and cryptochrome fluctuate during the day, with protein levels peaking about six hours later. BMAL1 RNA peaks about 12 hours after period and cryptochrome RNA.

• The speed of production and clearing sets a rhythm close to 24 hours, maintaining rhythm in SCN neurons.