The phase response curve describes how light affects the circadian rhythm at different times of the cycle. The mechanism of light's influence can clarify this phenomenon.
The curve is a description based on experiments with hamsters, where light exposure at different circadian times results in shifts in their circadian rhythm.
Light information must reach the biological clock to change it.
In mammals, the retina is the primary light-detecting organ that communicates with the SCN (suprachiasmatic nucleus).
Birds and reptiles have light-detecting cells inside the brain, near the pineal gland.
The photoreceptors responsible for this are retinal ganglion cells, not rods and cones, which are used for image formation.
Retinal ganglion cells are neurons with cell bodies in the retina and synapses in the brain (thalamus).
A subset of these cells contains melanopsin, a photopigment discovered relatively recently.
Melanopsin-containing retinal ganglion cells synchronize the biological clock to the external environment.
The ability of blind individuals to synchronize their clocks depends on the cause of blindness.
If rods and cones are absent but melanopsin-containing cells are intact, light response is still possible.
Cortical blindness does not affect this synchronization.
Degeneration of the retina or absence of eyes prevents light-based synchronization.
Melatonin can help synchronize the biological clock in individuals who cannot use light.
Melanopsin-containing retinal ganglion cells directly synapse onto SCN neurons.
These ganglion cells also synapse on the lateral geniculate nucleus (LGN), part of the visual pathway.
Axons from these cells have branches that synapse on the SCN, located near the optic chiasm.
This provides a direct signal indicating the presence of light.
These retinal ganglion cells detect light, generate action potentials, and release glutamate onto SCN neurons.
While the LGN also feeds back to the SCN, the primary route is the direct connection from the retina.
Other cues like meal times and sounds may work through the thalamus, but light is the main synchronizer.
Axons form the retina to the SCN are called the retinohypothalamic tract.
Retinohypothalamic tract axons synapse onto SCN neurons, releasing glutamate.
Glutamate binds to NMDA receptors on SCN neurons. NMDA receptors are ligand-gated calcium channels.
Calcium influx into SCN neurons influences the transcription of clock genes, specifically upregulating Period (PER) and Cryptochrome (CRY) genes.
Mechanism recap:
Light activates melanopsin in retinal ganglion cells, leading to action potentials.
Glutamate is released onto SCN neurons.
NMDA receptors open, allowing calcium influx.
Calcium increases, upregulating PER and CRY mRNA levels.
Normal Cycle: PER and CRY mRNA levels increase from the end of the subjective night through the subjective day, peaking in the middle to the end of the subjective day, then decreasing.
Light During Subjective Day: Has little effect as mRNA levels are already increasing.
Light During Subjective Night: Increases mRNA levels when they would naturally be low, altering the cycle.
Light pulse at the end of the subjective night:
Increases RNA levels, causing protein production to start earlier.
This shortens the low concentration phase, shifting the entire cycle earlier by approximately 4-5 hours.
The activity cycle is shortened for a few cycles before stabilizing.
Light pulse at other times:
Always cause calcium to come into transcription and increase.
If this the peak of gene transcription is already at full capacity, there will be no difference.
If it happens in the night when there is little transcription, transcription is increased when not expected. i.e., shifts everything.
Light early in subjective night:
Lengthens the cycle, causing a delay.
The next cycle will start later.
Light late in subjective night:
Shortens the cycle, causing an advance.
The next cycle will start sooner.
Remember:
An increase in mRNA earlier than expected or keeping the peak longer affects everything.
Melanopsin is most responsive to blue light.
Blue light is most effective at resetting the clock.
Sunlight is helpful due to its blue light content, while many artificial lights lack sufficient blue light to be effective.
To minimize clock resetting, use yellowish light.
Voltage-gated calcium channels change the calcium concentration inside the cell, but not the membrane potential.
This does not cause action potentials, but changes transcription.
It may be impossible to evolve a perfectly matched system.
The Earth's rotation rate may change over long periods.
A system that can adjust to external information is more robust than a perfectly matched but inflexible one.
The pineal gland, located on top of the thalamus, releases melatonin.
Melatonin secretion is influenced by the SCN and, in turn, feeds back to the SCN.
The SCN, active during the subjective day, inhibits the sympathetic superior cervical ganglion.
This ganglion innervates the pineal gland and stimulates melatonin release.
During the subjective day, melatonin release is actively inhibited.
During the subjective night, the sympathetic superior cervical ganglion becomes active and releases noradrenaline onto the pineal gland.
This triggers melatonin production and release into the bloodstream.
Melatonin release is determined by the subjective night, not simply darkness.
Melatonin synchronizes circadian rhythms throughout the body because most cells have an internal clock.
Melatonin travels through the bloodstream and binds to receptors in the SCN, inhibiting SCN firing.
Administering melatonin during the subjective day can halt SCN activity and adjust the internal cycle.
Melatonin signals the dark phase, opposite of light's signal.
Light and melatonin work together to maintain synchrony.
SCN firing inhibits melatonin release; melatonin inhibits SCN firing.
Melatonin also plays a role in seasonal rhythms, released longer during long nights and shorter during short nights.
The SCN is the biological clock, influencing the sleep-wake cycle.
The clock can be reset by light because it has a slightly longer than 24-hour cycle.
Daily light exposure synchronizes the clock.
This synchronization allows adjustment to new time zones during travel.
Humans, as migrating species, need to synchronize to local rhythms.
Sleep induction (circadian control).
Homeostatic control (adenosine accumulation).
Allostatic control (hunger & stress).
The SCN influences the flip-flop switch that controls sleep and wakefulness.
Red means inhibiting.
Black means exciting.
Green Just means control.
Conditions where sleep does not function properly.
Difficulty falling asleep.
Less common then we think, people overestimate it.
May be caused by stress or factors biasing the flip-flop switch.
Sleeping pills (benzodiazepines) can lead to tolerance and worsen insomnia in the long run.
Sleep apnea, where breathing stops during sleep, disrupts sleep.
Individual differences exist in sleep needs.
Sudden, unexpected transitions between wake and sleep.
Often linked to problems with hypocretin neurons in the lateral hypothalamus.
Genetic forms may involve issues with hypocretin receptors.
In humans, it may be due to degradation of these receptors.
Varieties:
Sudden sleep attacks.
Cataplexy: REM sleep paralysis without loss of consciousness.
Sleep paralysis: Paralysis during the transition from wakefulness to sleep.
Hypnagogic hallucinations: Dreams intrude into waking awareness.
Hypocretin neurons stimulate the REM-off side of the REM flip-flop switch.
Dysfunction causes REM-on to occur without slow-wave sleep or while fully awake.
Lack of paralysis during REM sleep.
Often due to damage to the magnus cellular nucleus.
Individuals act out their dreams, which can be dangerous to themselves or others.
Distinct from sleepwalking, which occurs during slow-wave sleep and is more coordinated.
Bedwetting (enuresis): More common in children.
Sleepwalking: Also more common in children.
Night terrors.
Sleep-related eating disorders: Eating while asleep.
A problem arising from travel across time zones.
Causes misalignment between the internal clock and the new time zone.
Symptoms include difficulty waking up or falling asleep.
All physiological response are affected (hunger).
Resetting the clock requires exposure to light at appropriate times.
Adjust around one hour per day.
Easier to adjust when traveling west.
Melatonin can help signal the subjective night in the new time zone.
Internal Clocks thinks its night but its still light outside, that is when you should expose yourself to light.
Morning = expecting light, not doing anything for period/cryptochromes because they are already high.
Circadian Rhythms, Light Entrainment, and Sleep Disorders