The Science of Sleep

• Sleep stands out as the most prevalent human "behavior".

Sleep Overview

• Topics include sleep, biorhythms, physiology of sleep, drugs that affect sleep, and sleep disorders
• Approaches to studying sleep include examining its phases, dreams, interpretation, and functions
• It addresses evolutionary perspectives, the effects of sleep deprivation, REM sleep functions, sleep's role in memory, and recuperation

Approaches to Studying Sleep

• Scientists use electroencephalography (EEG) to measure electrical activity in the brain
• Electrooculography (EOG) tracks eye movement during sleep
• Electromyography (EMG) monitors muscle tone.

Brain Waves and Sleep Stages

• Beta waves are >12 Hz and are associated with alert wakefulness
• Beta and Alpha waves range from 8-12 Hz and occur just before sleep
• Theta waves range from 3-8 Hz and are present in stage 1 sleep
• Delta waves range from 1-2 Hz and are found in stage 3 sleep

Sleep Stages

• Initial Stage 1 is the beginning phase of the sleep cycle
• Emergent Stage 1 is characterized by rapid eye movement (REM measured by EOG) and no core muscle tone (EMG)

Sleep Stages Nomenclature

• REM sleep involves rapid eye movements and occurs in emergent stage 1
• REM is characterized by loss of body core muscle tone, increased cerebral activity resembling waking levels, and autonomic nervous system activation
• Autonomic activation is measured with blood pressure, pulse, and respiration
• Sexual arousal and complex dreams often occur
• NREM sleep includes initial stages 1, 2, and 3
• Slow wave sleep is stage 3 sleep with a low frequency EEG

REM vs NREM Dreams

• REM dreams are complex, emotionally charged, and have a narrative component
• People can recall dreams better if woken from REM sleep compared to NREM
• NREM dreams tend to be single experiences, like a feeling of falling
• Sleepwalking and sleep talking are more common during NREM
• NREM dreams can be vivid
• Antidepressants can reduce REM sleep, sometimes without affecting dreaming
• Cortical lesions can abolish dreaming but don't affect REM sleep

Theories of Dreams

• Theories of why we dream include: psychoanalytic, Hobson’s Activation-Synthesis Hypothesis, Revonsuo’s Evolutionary Theory of Dreams, and Hobson’s Protoconsciousness Hypothesis

Psychoanalytic Theories of Dreaming

• Freud (1913) theorized that dreams come from unacceptable repressed wishes where latent desires go through an unconscious censor to become manifest dreams
• Jung (1934) proposed that dreams offer insight into an individual's future and act as a compensatory mechanism for the psyche/ego

Hobson's Activation-Synthesis Hypothesis (1989) of Dreaming

• During REM sleep, the cerebral cortex is bombarded by random neural signals
• Dreams are the cortex's attempt to make sense of the random signals

Revonsuo's Evolutionary Theory of Dreams (2000)

• Dreams have a biological function
• Dreams simulate life’s threatening events and allow people to simulate responses

Hobson's Updated Protoconsciousness Hypothesis (2009)

• Activation-Synthesis Hypothesis indicates that during REM sleep the cerebral cortex is bombarded by random signals which it tries to make sense of
• Dreams provide evolutionary advantage by simulating positive and negative experiences
• During development, dreams mature sensory input systems
• Throughout life, dreams help foresee how events will unfold, acting as a "training mechanism"

Functions of Sleep

• There are two theories of why we sleep: recuperation and adaptation (circadian)
• Recuperation theories suggest sleep helps restore energy levels and clear toxins like beta-amyloid
• Adaptation theories suggest sleep helps conserve energy and avoid trouble

Comparative Analysis of Sleep

• Most animal species sleep in some way
• Sleep in mammals and birds is similar to humans, including EEG changes
• Sleep is important, but sleep duration depends on predation pressure and energetic/metabolic needs

Sleep Deprivation Theories

• Recuperation theories: sleep deprivation disrupts homeostasis and lost sleep should be regained
• Circadian theories: sleep deprivation leads to "skipping" a night and normal sleep the following night

Sleep Deprivation Experiments

• Moderate deprivation (3-4 hours/night, 1-2 days) causes sleepiness, mood disturbances, and impairs vigilance
• Severe deprivation (continuous, 3-4 days) results in microsleeps, poor vigilance, quick exhaustion, and impairs executive functions
• In experiments with lab animals, experimental rats' EEG is monitored and a platform rotates to prevent sleep

Recuperation vs. Circadian Theories

• Recuperation and circadian theories both explain sleep

REM Sleep

• A REM rebound after deprivation implies it is regulated independently from NREM sleep and is important

Memory Consolidation and REM Sleep

• Necessary for memory processing and consolidation
• Dreams may be involved in memory processing or consolidation
• Tricyclic antidepressants disrupt REM sleep but don't seem to impair explicit memory

Default Theory of REM Sleep

• NREM sleep is difficult to maintain, but REM is the brain switching to a default "awake" state and is similar to wakefulness and easy to maintain
• It is adaptive when wakefulness is not needed
• Nykamp (1998) suggested wakefulness can be substituted for REM, thus during sleep there is no REM rebound

Sleep and Memory

• Juvenile songbirds "replay” tutor songs during sleep, improving song quality and memory consolidation
• Sleep is critical for song plasticity and improved learning during the waking phase
• Hippocampal place cells activate during slow-wave (NREM) sleep corresponding to locations in a maze
• Place cell activity occurs even for unexplored parts of the maze
• REM sleep reactivates and replays memory traces formed during the day
• NREM sleep refines memory traces by reducing unused connections

Sleep and Recuperation

• During sleep, the lymphatic system drains toxins from the extracellular fluid
• Reduced toxin removal is linked to brain disorders like Alzheimer's

Circadian Sleep Cycles

• Tuned to the planet's light-dark cycle
• They regulate physiological, biochemical, and behavioral processes
• Diurnal: active during the day, sleeping at night (e.g., humans)
• Nocturnal: active at night, sleeping during the day (e.g., mice, rats, bats)
• Crepuscular/Vespertine: active at twilight and dawn

Regulation of Circadian Sleep Cycles

• Cycles present even without external cues are free running rhythm cycles
• Internal clock: typical free running circadian sleep cycle is about 25 hours
• Zeitgebers: environmental cues that acts as “time givers" such as social interactions, meals, and exercise

Shift Work and Health Problems.

• Shift work can cause circadian rhythm disruptions, mental health issues, brain effects, cardiovascular, gastrointestinal, and reproductive disorders and increased cancer risk

Circadian Clock

• The circadian clock is an endogenous timing mechanism located in the suprachiasmatic nucleus (SCN) of the medial hypothalamus

Suprachiasmatic Nucleus (SCN)

• In vitro, neurons are more active during the day than at night
• Lesions disrupt the sleep/wake cycle, not total sleep
• Light/dark entrainment occurs, but not food/water entrainment
• SCN transplant studies from mutant hamsters (20h light cycle) to normal hamsters (25h light cycle) has an effect

Genetics of Circadian Rhythms

• Jeffrey C. Hall, Michael Rosbash, and Michael W. Young won the 2017 Nobel Prize in Physiology or Medicine for discovering molecular mechanisms controlling the circadian rhythm

Genes Regulating Circadian Rhythms

• Several highly conserved genes (e.g. clock, tau, Per1, Per2, Per3, Sleepy 1, 2)
• Exhibits cyclic transcriptional activity and expressed in many cells in the body
• Not self-regulating, but entrained by SCN
• PER (period) gene: protein accumulates during the night and degrades during the day

Period (PER) Gene Regulation

• A transcription/translation cycle that approximately takes 24 hours long and is entrained by light
• Genes involved are Timeless (TIM), Doubletime (DBT), Clock (CLK), Cycle (CYK)
• Clock and Cycle (CLK and CYK) are transcription factors that activate the Period (PER) gene
• PER mRNA is translated into PER protein in the cytosol
• Doubletime (DBT) degrades PER protein to delay PER negative feedback
• Timeless (TIM) binds PER protein and allows it to enter the nucleus
• Negative feedback of PER inhibits further transcription of the PER gene.

Entrainment of the Biological Clock

• Involves external cues that entrain the internal biological clock
• Light/dark cycles and other zeitgebers (e.g., meals, social interaction, physical activity) have an effect

Light/Dark Entrainment of the SCN

• The wake/sleep cycle is entrained by the light/dark cycle involving retinohypothalamic tracts
• Melanopsin is a photopigment in specialized cells in the retina for light entrainment and responds to variations in background light

The Food-Entrained Circadian Clock

• Dorsomedial hypothalamic nucleus (DHN) acts as the food-entrained circadian clock
• Food entrainment occurs in SCN-lesioned mice (Mieda et al, 2006)
• Mice with a small DHN had reduced prepradial (pre-meal) anticipation
• Food entrained mice had higher DHN activity and lesions to DHN had no effects on total intake, but was no longer food entrained

Neurobiology of Sleep

• Sleep is not a state of neural quiescence
• Sleep-promoting circuits can lead to sleep via stimulation or impaired sleep via lesions
• The various correlates of sleep are dissociable
• Different mechanisms/brain areas are involved in different aspects of sleep

Brain Regions Regulating Sleep

• Reticular formation: various nuclei control different aspects of sleep
• Anterior and posterior hypothalamus
• Basal forebrain
• Biological clocks (circadian rhythms) in suprachiasmatic nucleus (SCN) of the medial hypothalamus and dorsomedial hypothalamic nucleus

Early Studies of the Neurobiology of Sleep

• Bremer developed a passive sensory theory of sleep
• Cerveau isolé involves transection between the superior and inferior colliculi resulting in continuous slow-wave sleep
• Strong visual/olfactory stimuli can induce desynchronized EEG
• Sleep occurs when there is minimal or no sensory input to the forebrain

Reticular Formation

• Composed of 100+ different nuclei that occupy the central core of the brain stem
• Reticulum is the latin word for little net

Key Studies of Neurobiology of Sleep

• A transection between the superior and inferior colliculi is called Cerveau isolé
• Reticular formation lesions and reticular formation stimulation also have an effect Encéphale isolé occurs in this area
• Sleep is actively regulated by an arousal mechanism in the reticular formation and the reticular activating system
• Low levels of activity produce sleep and high levels produce wakefulness

Caudal Reticular Formation

• Regulates various aspects of REM sleep involving the nucleus basalis magnocellularis

REM Sleep Muscle Paralysis

• Muscle paralysis results from increased inhibition or decreased excitation of motoneurons or a balance between increased motoneuron inhibition and reduced motoneuron excitation
• Increased inhibition involves activation of metabotropic GABAB and ionotropic GABAA/glycine receptors
• Decreased excitation results in a reduction in glutamate, noradrenaline, dopamine and hypocretin release

Anterior and Posterior Hypothalamus

• Posterior lesions: excessive sleep (von Economo encephalitis lethargica) or increased wakefulness
• Anterior lesions reduce sleep or promote it

Basal Forebrain

• Cholinergic neurons (ACh) promote wakefulness and REM sleep
• Acetylcholine is present in the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis
• Adenosine is an inhibitory neurotransmitter that starts low, accumulates throughout the day, and enhances deep, slow-wave sleep
• Caffeine is an adenosine receptor antagonist to promotes wakefulness and delays sleep

Drugs that Affect Sleep

• Antihypnotic drugs such as stimulants (e.g., cocaine, amphetamine) and tricyclic antidepressants (which increase norepinephrine, epinephrine, dopamine) reduce sleep
• Tricyclic antidepressants affect REM sleep
• Hypnotic drugs induce sleep with benzodiazepines, barbiturates, imidazopyridines, and 5-hydroxytryptophan (5-HTP)
• Melatonin influences the circadian rhythmicity of sleep

Benzodiazepines

• Valium (diazepam) are effective anxiolytics
• Long-term use leads to tolerance, addiction, and withdrawal
• This distorts normal sleep patterns, increases NREM2 and decreases short wave and REM Sleep
• leads to next day drowsiness and is associated with shorter life expectancy

Imidazopyridines

• Ambien (zolpidem) act on Benzodiazepine (BDZ) binding site faster than Benzodiazepines and have shorter half-life
• Not truly safer since there is next day drowsiness and there are sex differences in dosage

5-hydroxytryptophan (5-HTP)

• Tryptophan lead to Serotonin which in raphe nuclei may help sleep
• Serotonin does not cross the BBB easily, but its precursor 5-HTP does reverse insomnia induced in cats and rats by 5-HT agonist PCPA and is more limited (if any) effects in humans

Melatonin

• Suprachiasmatic nucleus promotes this via pineal gland which causes an increase in serotonin
• Biorhythms in fishes, amphibians, reptiles, and birds are circadian and seasonal
• The day-night cycle is high at night
• It may be effective for the blind since it has a limited light entrainment
• Jet lag helps retrain cycle
• It is used to shifting cycle (chronobiotic) rather than promoting sleep (soporific/hypnotic)

Sleep Disorders

• Include insomnia, hypersomnia, and REM sleep dysfunction

Insomnia

• Can be caused by doctors through excessive prescription of benzodiazepines and imidazopyridines
• Other conditions are sleep apnea (obstructive or central), periodic limb movement disorder (multiple awakenings due to twitching of the body especially legs) and restless legs (tension in legs)
• Treatment depends on the cause and may include sleep restriction therapy

Hypersomnia

• A type of daytime sleepiness that includes narcolepsy
• Caused by insufficient sleep, circadian rhythm disruption/disorders (shift work, jet lag), and psychiatric disorders such as depression
• Can be substance-induced or come from a another medical condition (chronic fatigue syndrome, Parkinson’s, multiple sclerosis)

Narcolepsy

• Affects approximately 1 in 2000 individuals or ~80 per 100 000 in the US, 3-10 per 100 000 in Canada
• Core behavioral symptoms are excessive daytime sleepiness, cataplexy (loss of muscle tone while awake), sleep paralysis (inability to move when falling asleep or waking up), hypnagogic hallucinations (dreamlike experiences during wakefulness), and fragmented sleep
• It is genetic, 25% in identical twins
• During cataplexy, the nucleus magnocellularis is active
• Is caused by spontaneous mutation in the gene for orexin (hypocretin) in dogs and can also be caused by an autoimmune disease that results in loss of orexin neurons/functionality

Narcolepsy Treatment

• Can be treated by administration of Old-fashioned stimulants (e.g., amphetamines, methylphenidate), novel stimulants (e.g., modafinil), antidepressants for the cataplexic symptoms (tricyclic antidepressants, SSRIs/SNRIs)
• Sodium oxybate (GHB/Xyrem) – GABAB agonist (not currently approved for use in Canada)

REM Sleep Dysfunction

• Consists of narcolepsy (REM sleep in initial stage 1), lack of REM sleep (very rare, no major effects), REM sleep disorder (lack of REM sleep atonia (loss of muscle tone)
• Sleep paralysis is adaptive which and stops patient from acting out dreams and Lesions in nucleus magnocellularis
• Is common in people with Parkinson's disease
• Includes sleep paralysis (person lacks muscle tone while awake)

Sleep Paralysis and Bedroom Intruder

• Dissociation or "cortical decoupling" - mistaking one's own presence in the room as an intruder causing aberrant activity in:
• Pedunculopontine nucleus (PPT) and laterodorsal tegmental nucleus (LDT): REM-promoting ACh projections which causes sensory gating
• Mirror neurons (confusion of self-other boundaries) and right superior parietal cortex/temporal parietal cortex (self/body image)
• Is highly correlated with stress
• Jalal & Ramachandran, 2017; Smith & Terhune, 2023