Circadian Rhythms and Sleep

Endogenous, Exogenous changes

Endogenous biological clocks (i.e., that are internal to the individual) influence biological rhythms.

• last about a day, sleepier at night and more alert in the day even without sleep.Higer cortisol in the day, higher melatonin at night, higher body temp during day.

Exogenous: Changes in the environment, external to an individual influencing biological rhythms.

Endogenous circannual vs circadian rhythms

Endogenous biological clocks (i.e., that are internal to the individual) influence biological rhythms

• Circannual: Year-long (migration, internal, self-regulated rhythm)

• Circadian: 24-hour rhythms → Sleepier at night and more alert in the day, even without sleep.Higher cortisol in the day, higher melatonin at night, higher body temp during the day.

Exogenous rhythm 

Changes in the environment (i.e., those that are external to the individual) influence biological rhythms.

• Light–dark cycle (most important)

• Temperature

Internal changes occurring in the circadian cycle

• Cortisol (stress hormone) circadian response: Peaks right what you wake up and diminishes through the day and drops and replenishes in sleep

• Melatonin circadian response: released by the pineal gland - builds though the day, fluctuates high in sleep, drops right before you wake up

• Body temp: Drops at high and rises through the day → rising body temp tells you to wake up

Chronotypes

There are individual differences in this called chronotypes → morning person vs night

• Early chronotypes: Wake up energized and get tired as the day goes on

• Late chronotypes: Wake up tired and get more energy as the day goes on

This often changes with age: as a kid you are an early chronotype and then you become late and then go back towards early

• Should we push school hours to better align with adolesent sleep patterns? - reduces absense (13-16) and better school performance (14-16)

Free running rhythms 

Shift in sleep time without external cues - sun coming up is not resetting clock 

So when you don’t have external signals, you would see sleep time would start to shift later and later → too much light would = the opposite 

• (when we don’t have the circadian cues, our internal clock isn’t actually 24 hours, its longer)

Blindness and circadian rhythm 

Unexposed to the sun → insomnia and daytime sleepiness

• Your clock isn’t resetting (typically more significant in people who are completely blind (destroyed optic tract or retina)  

• Can experience a free-running tract 

Zeitgebers

Anything in the environment that helps reset the clock and circadian rhythem - Most powerful one is light (resetting SCN)

Others:

• Melatonin: sleep onset 

• Exercise: high intensity in evening can delay next days cercadian cycle

• External temp, exercise

• Mealtime routines 

• Social influence 

Jet lag

Disruption of circadian rhythms due to time zone changes.

• Stress elevates cortisol, which damages the hippocampus; adjusting to circadian rhythms damages hippocampus.

Canadian example - phase delay and phase advance 

Toronto → Vancouver (west): you lanmd 10pm but 7am vancouver time = phase delay (stay up later) - easier to do 

Vancouver → Toronto (east): you land 7pm but 10pm toronto time = phase advance moving the clock forward (harder to do so you stay up late and wake up toronto time tired) 

• If your going for a short period of time you should try and stay on the time your coming from → better than taking meletonin

Suprachiasmatic Nucleus location, what does it do

DOESNT RELY ON ANYTHING ELSE

located in the hypothalamus above the optic chiasm

Main driver of sleep and body temp rhythms

• Generates circadian rhythms automatically, even if in cell culture isolated from the rest of the body.

Three major visual pathways (RGR)

There are three different pathways collecting info from the retina 

1. Retinal-collicular pathway: retina to the superior colliculus - primary visual cortex (NON-IMAGE FORMING)

2. Geniculostriate pathway: lateral geniculate nucleus, not going to the primary visual cortex; synapse with different cells around it (IMAGE FORMING)

3. Retinohypothalamic Tract: some axons coming from ganglion cells in the retina go off early just above the optic chiasm and activate in SCN involved in regulating circadian rhythms allowing it to act as a zeitgeber

• Located near nose and see towards the periphery, respond to the overall amount of light.

• Respond mostly to short wavelength or blue light.

ipRGCs

Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs)

How the Retinohypothalamic Tract Gets Information 

• Ganglion cells that have opsins able to transduce light energy into ion formation 

• Contain the pigment melanopsin and respond directly to light. Light resets the SCN via these ganglion cells 

Circadian rhythm genes

Two key circadian clock genes that produce PER and TIM proteins.

• Proteins rise and fall over 24 hours, helping regulate the body’s sleep–wake cycle.

• High PER/TIM levels promote sleepiness, and their daily oscillation keeps the internal clock running.

PER = period → affects the length of the daily cycle.

TIM = timeless → without it, the body has no timekeeping signal.

PER and TIM feedback loop

Cells functioning as an internal clock:

1. Genes are transcribed into proteins inside the SCN (from per & tim mRNA to per and tim proteins - slow at first) - DNA → MRNA → Proteins 

2. When PER and TIM proteins accumulate (after a lag) they inhibit the transcription of per and tim genes that create the mRNA molecules.

3. Fewer proteins are produced = less inhibition on the genes which makes them start to produce more (mRNA has declined leading to PER and TIM protein levels decline again.)

During the day, PER and TIM mRNA increase concentration which delays the increase PER and TIM protein concentrations.

During the night PER and TIM protein concentrations remain high to promote sleep and by the next morning, mRNA has declined leading to PER and TIM protein levels decline again.

How does light effect TIM protein

Light helps facilitate breaking down the tim protein to speed up this reset process (starting to produce the MRNA again faster) 

Different types of Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs)

• M1: Non-image-forming → axons done help us make an image they send axons to SCN and convey how much light is coming in (not ab shapes or objects) → THIS IS WHAT RESETS THE SCN 

• M3: Not sure what they do

• M2, M3, M4: Image forming: gives info about light contrasts → some going to the superior colliculus

What would happen to SCN if it was taken out of the brain

They would still be able to keep time

Process of melatonin entering the blood stream 

1. Starting at the Suprachiasmatic Nucleus → sends axons to the paraventricular nucleus both in the hypothalamus

2. Axons move from para down to the intermediolateral nucleus of the spinal cord 

3. Connects to superior cervical ganglion 

4. This triggers the SCN, which activates the pineal gland, secreting melatonin (hormone) 2-3 hours before sleep 

Feedback effect on the SCN through MT1 and MT2 receptors

How do melatonin supplements work

They trick the system into thinking the pineal gland has been activated secreting melatonin 

What kind of gland is the pineal gland

Endocrine gland releasing melatonin

Pedunculopontine nuclei & Laterodorsal tegmental nuclei

2 nuclei responsible for regulation of arousal

• Secreting Acetylcholine

Locus Coeruleus 

In the basal forebrain 

• Secretes adrenaline (norepinephrine)

Dorsal and medial raphe nuclei

Secretes serotonin (5HT)

Tuberomammillary nucleus of hypothalamus

Secretes histamines in the hypothalamus → if you have allergy symptoms, you have a lot of histamine activation

• Antihistamines = make you drowsy because it stops the excretion of histamine which is excitatory 

Lateral Hypothalamus

• Releases orexin - alerts the system to keep the other areas active (excitatory) → lack or orexin = narcolepsy

• Releases melanin-concentrating hormone more active during sleep (can be inhibatory more in REM) 

Ventral Periaqueductal Grey

Releases dopamine (excitatory)

Basal Forebrain

Releases Acetylcholine (excitatory) and GABA (can have inhibitory effects in REM)

Ventrolateral preoptic nucleus

Primarily active during sleep

• Contains inhibitory neurotransmitters galanin and GABA

It is connected to and inhibits all the excitatory neurons 

Flip-fop switch

• When the arousal system is active → it inhibits the VLPO → you stay awake.

• When the VLPO is active → it inhibits the arousal system → you fall asleep.

Inhibitory area (VLPO) shuts off when the arousal system is activated on when the arousal system is inactive

• Changes your state in a rapid period of time (unconscious to conscious) 

• One is inhibited and one isn’t 

Sleep pressure

Buildup of adenosine, which is inhibitory 

• Ultimately, there is enough; it inhibits the excitatory area, meaning it cant inhibit LPVO

• If you inhibit the excitatory area, it can’t inhibit the VLPO

What makes the flip switch

In the daytime, the suprachiasmatic nucleus inhibits the VLPO and excites the excitatory areas

At night, it stops sending excitatory and inhibitory signals, allowing inhibitory signals to take over, and because excitatory isnt getting a boost from the SCN it’s inhibited

• Another elements driving flip if the switch – adenosine build up 

• SCN is no longer tipping the scales towards excitatory area and sleep pressure had built up inhibiting sleep 

Alpha waves 

relaxation 

Coma

Extended unconsciousness with low brain activity

Polysomnography

How do we record sleep stages  - a combo of EEG and eye-movement records

Stage 1 of sleep

Stage 1: sleep has just begun showing low-voltage, irregular, lagged alpha waves (brain activity is beginning to decline) - eyes are generally stable

K-complex

Sharp wave inhibiting neuronal firing temporarily

Stage 2 of sleep

Two EEG patterns emerge

• Sleep steadiness: Sleep spindles 12- to 14-Hz waves showing a burst that lasts at least half a second

• K-complex: a sharp, LARGE-amplitude negative wave followed by a smaller, slower positive wave → might be related to external stimuli (noises) 
  
  Related to the consolidation of memory 

Sleep spindle

Burst of 12-14 Hz waves, improves memory.

• Result from oscillating interactions between cells in the thalamus and cortex, increase after new learning and improve memory.

Paradoxical sleep

REM sleep

• Called paradoxical sleep bc even through  brain activity looks like its more active, your postural muscles are completely inhibited - brain more active

• The cornea creates a bulge that makes an indentation on the eyelids

• Light sleep

Electrooculogram

Tracks the movement of eyes in REM sleep Measures the electrical activity of the eye muscles

• EEG shows irregular voltage signals, indicating neural activity has increased relative to stage 4

Stage 3-4 of sleep

Slow-wave sleep (deepest sleep):

• EEG recording of slow, large amplitude waves

• Slowing of HR, breathing rate, & brain activity

• Highly synchronized neuronal activity

• Periods of rapid eye movement sleep (REM); aka paradoxical sleep

• EEG waves are irregular, low-voltage & fast indicating ↑ neuronal activity (light sleep)

• Postural muscles of the body are more relaxed than other stages (deep sleep)

• Eyes move back and forth

Why do the waves become larger amplitude in stage 3 & 4

neural activity is synchronizing

What would an average sleep cycle look like

Repeating every 90 mins

• Typically goes through stages 1,2,3,4

• Going up to REM and going back down to deep sleep over and over

• With some random wake up periods

• Low wave is earlier in the night → stages aren’t equally distributed (if you woke up at hour 4 you would miss out on a lot of REM sleep but have a lot of slow wave sleep)

PGO wakes

High-amplitude electrical potentials in pons, lateral geniculate, occipital cortex.

Hypnogram - what are common things to see 

Measures the time spent in various stages of sleep during a single night

• Slow sleep waves = earlier in sleep period

• Cycles repeat roughly every 90 mins 

• REM increases later in the sleep period

Sleep differences among the lifespan

• You sleep mostly as a baby, mostly in REM (16 hours)

• Old: More waking moments, less deep sleep, less REM sleep (overall worse)

You sleep less over time and less REM sleep - there are always individual differences

• adenosine cannot be cleared, and your adenosine load increases

What happens if you don’t get enough sleep 

adenosine cannot be cleared, and your adenosine load increases

What are the main functions of sleep 

• Upregulation of growth hormones, especially in children 

• Cell restoration and replication go up - won’t be as efficient in cell rep without it 

• Clearance of byproducts built up from the day 

How do biproducts clear (study on rat) 

• During the day, the beta-amyloid builds up and needs to be removed (very little movement in the day) 

• Space between the cells is bigger in sleep, allowing for more movement of the fluid between the cells

• Movement of substances through the interstitial space (space between cells in the brain) was more efficient while the rat was asleep than when it was awake (tracked by a tracer) - adenosine is also moved out
  
  Beta Amyloid build up can cause alzhimers’s  

Memory consolidation and sleep

If given a task, you can become faster and make fewer errors after sleep 

• While you're asleep your brain is consolidating the learning and benefiting first thing in the morning – training gets better with time – leads to durable learning (consolidation stays)

• If you engage in some learning before bed and then sleep, you will do better

Longer stage 2 non-REM sleep, more benefit obtained

• Just before you go to sleep, go over notes, key: RETREVAL things are easier to remember

How does dreaming work - activation synthesis model

Mess of emotions, memories, etc, with no filter - won’t even realize it’s weird until after 

Deactivated:

• When you're asleep, the prefrontal cortex is deactivated, reducing insight, reasoning, and volition (typically suppresses things) 

• Processing of incoming stimulation is reduced

• Motor system is deactivated (so you don’t act on what is happening in the dream) 

Activated:

• Amygdala and hippocampus are activated, triggering emotions and memories 

• Visual association areas are activated, leading to visual imagery 

• Brainstem arousal neurons activate various areas in the brain 

EMG vs EOG

• EMG = Electromyogram → tracks muscle tension/tone

• EOG = Electrooculogram → tracks eye movements

Lucid Dreaming

Sharing characteristics of wakefulness and dreaming (its not either, it’s a hybrid) - your aware that your dreaming

How can people become better lucid dreamers

Sleep studies done using EEG, EOG, EMG

• Awake with eyes closed → practice specific eye movement pattern tracked by EOG (lots of activity seen in the prefrontal cortex

• Then when they are sleeping there are irregular eye movements (lower prefrontal cortex activity) 

• But when you tell them before sleep “when you notice something strange in you sleep notice it but stay asleep” signal to us that your in this state by moving your eyes in the original pattern they trigger a level of awareness and do the pattern (muscle activity is still inhibited, prefrontal is in hybrid state not as active as awake not as inactive as normal sleep) 

What is narcolepsy

Sleep disorder with a dysregulation of sleep and normal waking times - Loss of orexin-producing neurons in the lateral hypothalamus, which normally activate other areas promoting wakefulness.

• Sleep attacks → unexpected moments of sleepiness during normal waking hours 

• Cataplexy → Unexpected moments of muscle weakness 

• Sleep Paralysis → Inability to move during transitions between waking and sleep (conscious but can’t move) 

• Hallucinations → might occur with paralysis

Might not have all 

Cause of narcolepsy

Caused by a loss of hypothalamic cells that release orexin (for staying awake), often caused by an autoimmune reaction where the immune system attacked those cells

• Low orexin levels can diagnose.

• Flip-flop switch not controlled.

• Treating with stimulant drugs that enhance dopamine and norepinephrine activity

  • Orexin itself cannot cross the blood-brain barrier.

Hypnagogic vs Hypnopompic

Hypnagogic (while falling asleep)

Hypnopompic (while waking up)

Physiology of cataplexy

orexin loss - associated with strong positive emotions

• Activate amygdala and arousal areas (hypothalamus) releasing orexin 

• But with orexin loss that part doesnt get activated - the amygdala activation reduces activity in brain regions that inhibit REM sleep and therefore REM sleep is premoted (in the brainstem/nuclei) 

• This inhibits muscle movement like would happen in REM = weakness in muscles

OSAS

Obstructive Sleep Apnea Syndrome

Airway in your neck and back of mouth collapses, restricting air flow → all of a sudden stop breathing, triggering gasping for air - back to bed, gasp back again 

• They don’t realize it, don’t feel rested 

Treated with a Continuous Positive Airway Pressure Machine → forces air down the airway

What are risk factors for sleep apnoea

• Older age

• Male sex

• Obesity (especially upper-body obesity)

• Upper airway narrowing from craniofacial or soft-tissue abnormalities

• Genetic predisposition (family history)

• Smoking

• Nasal congestion

• Genetically smaller airways

• Menopause or post-menopause

• Medical conditions: hypertension, diabetes, Marfan syndrome, acromegaly, hypothyroidism, end-stage renal disease, congestive heart failure, COPD, neurological disorders, pregnancy

• Medications/substances: alcohol, benzodiazepines, narcotics

NREM Insomnias

Unusual behavioral experiences during sleep

• Confusion Arousal: Aroused momentarily during sleep (gets confused and disoriented and then goes back to sleep - not fully awake) 

• Sleep Terrors: Sudden arousal state, waking up terrified maybe run around, screaming, etc - almost impossible to consol, when episode has ended they will go back to sleep and not remember in the morning

• Somnambulism - asleep but engaging in some movement

Different kinds of somnambulism

Sometimes purposful

• Sleep walking 

• Sexsomnia

• Sleep-related eating disorder

• Sleep texting

REM Parasomnias

REM Behavior Disorder

• Dream-enactment behavior can occur when muscles become disinhibited during REM sleep.

• Can involve movements of limbs and even getting out of bed

• Mucles inhibition isn’t strong enough

Onset vs Maintenance Insomnia

More common than parasomnias

• Onset: difficulty getting asleep - Phase delay (body temp had trouble going down)

• Maintence: staying asleep - phase advance (body temp says its time to wake up)

Can be caised my a cercadian shift (phase delay or phase advance

Triggers of insomnia

• Stress

• Too much light at bedtime (serving as zygabers)

• High temperatures at bedtime (serving as zygabers)

• Late night exercise 

• Late night eating

• Drugs (caffeine & alcohol)

• Irregular bedtimes: -you need a stable circadian rhythm - theres an aspect of sleep that’s contextually learned (routines signal to you that you need to start lowering body temp, etc) aka you can classically condition yourself

• Late night media use: Studying on the bed is bad because your signaling your body to sleep (being in bed when your not sleeping will make it harder to sleep later)

Why does alcohol make it hard to sleep

To some extent it does help because it’s a neural inhibitor

• but then it is seen as the body and a toxin, and it will raise the body temperature and you will get waken up later because the body is hot

Unresponsive wakefulness syndrome

Higher than coma, alternates between sleep and arousal

Minimally concious state

Higher than UWS, brief purposeful actions, limited speech comprehension.

Brain Death

No brain activity ot response to stimuli

Polysomnograoh

Records EEG and eye movements to measure sleep stages.

Thalamic neuron hyperpolarization

Reduces response to stimuli during sleep, neurons firing less than usual rate is caused by inhibition to keep us asleep (GABA release from pons and medulla).