Circadian Rhythms, Light Entrainment, and Sleep Disorders

Phase Response Curve

• 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.

How Light Influences the Biological Clock

• 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.

Neural Pathway of Light Signals

• 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.

Mechanism of Light-Induced Clock Resetting

• 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.

Impact on Period and Cryptochrome Genes

• 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.

Phase Shifts and Light Pulses

• 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.

Wavelength Sensitivity of Melanopsin

• 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.

Calcium Channels and Synaptic Transmission

• 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.

Evolutionary Benefit of a Circadian Cycle Longer Than 24 Hours

• 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.

Pineal Gland and Melatonin

• 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.

Summary of SCN

• 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 Influencers

• 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.

Sleep Disorders

• Conditions where sleep does not function properly.

Insomnia

• 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.

Narcolepsy

• 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.

REM Sleep Behavior Disorder

• 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.

Slow Wave Sleep Disorders

• Bedwetting (enuresis): More common in children.
• Sleepwalking: Also more common in children.
• Night terrors.
• Sleep-related eating disorders: Eating while asleep.

Jet Lag

• 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.

Determining how to counteract jetlag:

• 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.