Sleep Regulation and Circadian Rhythms

Homeostatic Control of Sleep:

Homeostatic control dictates that increased brain use during the day leads to a greater need for slow-wave sleep afterward.
Adenosine is the chemical mediator of this process; it accumulates with increased brain energy usage.
Adenosine promotes sleepiness and slow-wave sleep.
Caffeine blocks adenosine receptors, thus preventing adenosine from inducing sleepiness.
Building tolerance to caffeine can occur as the brain produces more adenosine receptors to compensate for the blockage.
Medications causing tiredness can interfere with the sleep-wake "flip-flop" by: Reducing arousal system effectiveness or increasing sleep system effectiveness.
Individual differences exist in sleep cycle length due to genetic and experiential factors.
Adenosine deaminase, the enzyme that breaks down adenosine, varies in speed among individuals, affecting sleep needs. Slower enzyme variants necessitate more sleep.

Role of Slow Wave Sleep:

Adenosine is a signal indicating the need for slow-wave sleep but doesn't cause the recovery itself.
Slow-wave sleep is critical for clearing toxic brain metabolites that accumulate during wakefulness and cannot be cleared in an active brain.
During slow-wave sleep (or a drug-induced state mimicking it), the space between brain cells expands, facilitating metabolite clearance in mice.
Adenosine inhibits cells that inhibit the ventrolateral preoptic area (VLPA).
The need for slow-wave sleep will persist even if adenosine is artificially removed.
Warming up a person's brain with a hairdryer or Disney World stimulation lead to having more slow wave sleep afterwards.
The more you use your brain, the more slow wave sleep you'll have the night after.
Adenosine links brain activity to slow-wave sleep by signaling the need for metabolite clearance, including amyloid-beta.

Dreams and REM Sleep

Dreaming predominantly occurs in REM sleep, with minimal dreaming in slow-wave sleep.
Muscle paralysis is exclusive to REM sleep.
It can be possible to wake up and go back to sleep and back into the dream because the brain never completely left that state.
Wake state of the brain and the REM sleep state are very similar.

REM Sleep Behavior Disorder

In REM sleep behavior disorder, individuals act out their dreams due to the absence of muscle paralysis.
The magnocellular nucleus is responsible for the paralysis aspect of REM sleep.

Allostatic Control of Sleep

Allostatic control is related to threats to survival, such as starvation and predation.
Hunger and stress interact with the sleep-wake flip-flop.

Leptin:

Leptin, produced by fat cells, signals the body's energy state.
More fat = more leptin = inhibits hypocretin neurons.
Leptin biases the sleep-wake flip-flop towards sleep as it signals that the body's energy is in a good state.

Ghrelin:

Ghrelin, reflecting stomach fullness, stimulates hypocretin neurons.
Empty stomach = more ghrelin = stimulates hypocretin neurons and biases the sleep-wake flip flop to the wake side.
Full stomach = low ghrelin = less stimulation of hypocretin neurons.
Hypocretin is also called orexin because it was discovered by people studying appetite regulation and hunger
Orexin was higher when people were hungry.
Orexin controls not falling asleep so that you can go out and find food.

Stress response:

Hypocretin and noradrenergic neurons are stimulated by external and internal stimuli.
Medial prefrontal cortex and central extended amygdala activate the stress response.
Stress response activates the wake side of the sleep-wake flip-flop.
Different outputs of the stress system include waking up, increased heart rate and increased blood pressure.

Circadian Control of Sleep

Sleep occurs rhythmically, influenced by circadian control.
Endogenous rhythms persist even without external cues but may drift.
Suprachiasmatic nucleus (SCN) in the hypothalamus functions as the biological clock.

Suprachiasmatic Nucleus (SCN):

Endogenous means internal.
Located above the optic chiasm (crossing point of optic nerves).
Present in all vertebrates.
Damage to the SCN results in ultradian sleep-wake cycles (disorganized sleep).
SCN neurons exhibit a 24-hour rhythm of action potentials.
Every individual cell has its own rhythm.
SCN cells maintain rhythmicity even when isolated in a dish.
SCN transplants can restore circadian rhythms in lesioned animals.
Hamster studies were used to understand circadian rhythms.

Molecular Mechanisms of the Circadian Clock

Clock "cogs" are proteins derived from genes.
Key genes: period (PER1, PER2, PER3), cryptochrome (CRY1, CRY2), clock, and BMAL1.

Process:

Clock and BMAL1 form a complex that stimulates transcription of PER and CRY genes in the nucleus.
Messenger RNA (mRNA) for PER and CRY exits the nucleus and is translated into proteins.
PER and CRY proteins form complexes (e.g., CRY with PER1, CRY with PER2) in the cytoplasm.
These complexes re-enter the nucleus, where CRY-PER1 suppresses the Clock-BMAL1 complex, inhibiting further transcription of PER and CRY genes.
The cryptochrome period one complexes suppress the function of clock and BMI mol one.
The time period from starting to make race to the next time it starts making RNAs again takes about 24 hours.
This negative feedback loop takes approximately 24 hours, creating a self-perpetuating cycle.
Clearing process is from enzymes that continuously clear these.
PER2 stimulates transcription of the BMAL1 gene.
The concentration of female one and therefore of female one clock complexes will be highest when these are at their lowest and lowest when these are at their highest.
BMAL1 protein then forms complexes with Clock, influencing the cycle. Two cycles going in opposition to each other: one producing proteins that stimulate the production of period and cryptochrome, one that produces proteins that inhibit the production of proteins of the RNA appeared in cryptochrome.
This is a self-perpetuating system.
RNA levels of PER and CRY vary during the day, with protein levels following (peak about six hours later).
BMAL1 RNA peaks approximately 12 hours after PER and CRY RNA peaks, resulting in anti-phase relationships.