neurobiology SLEEP

Sleep Dr. Katie Dabrowski, PT, DPT

The need for sleep • The importance for sleep is best illustrated by the overpowering effects of

total sleep deprivation in humans - it is recognized as a form of torture!

• The longest documented voluntary total sleep deprivation lasted for 11 days

• During complete sleep deprivation, cognition and mood become rapidly impaired

• Endocrine and thermoregulatory changes may occur • Hallucinations are common

• These effects are all rapidly reversed by sleep, but rebound sleep after deprivation is not equal in terms of amount of sleep lost

• In rats, sleep deprivation is lethal after 2-3 weeks

The day-night cycle

• Plays a fundamental role in the evolutionary development of sleep homeostatic mechanisms

• Most physiological functions are shown to be under control of the circadian timing system

• Sleep differs from rest during wakefulness because there is reduced responsiveness to stimulation

• During sleep, a large number of physiological processes return to sustainable levels in preparation for a new day

Neurobiology of sleep

Sleep states and sleep cycles

• Sleep consists of two distinct states: REM and non-REM sleep.

• REM sleep: High levels of desynchronized cortical EEG activity, absence of muscle tone, irregular heart rate and respiratory patterns, and episodic bursts of phasic eye movements

• Non-REM sleep: Low-frequency, high-voltage EEG activity, low muscle tone, and absence of eye movements.

Sleep states and sleep cycles

• Non-REM sleep: Further divided into 4 stages:

• Stage 1: Occurs at transitions of sleep and wakefulness

• Stage 2: Frequent bursts of EEG activity (sleep spindles) and high- voltage slow spikes (K complexes)

• Stage 3 and 4: Slow-wave sleep

• At night, non-REM and REM sleep alternate in periods of 90 minutes

Homeostatic and Circadian regulation of sleep and wakefulness

• The need to sleep and feeling of sleepiness increases the longer you are awake, and is highest at night when it is dark

• This results in the overlapping of the circadian sleep process and the homeostatic sleep process

• These two processes are thought to interact in order to optimize sleep at night and wakefulness during the day

Circadian regulation of sleep

Circadian regulation of sleep

• Circadian rhythms can be produced and sustained by a single mammalian cell, in the absence of any external stimuli

• These rhythms result from coordinated daily oscillations of several clock genes – and this process takes 24 hours (circadian period) – this is the core mechanism behind the circadian time- keeping mechanism

• They persist even in the absence of external cues

Circadian regulation of sleep

• The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the master circadian oscillator in the brain – it coordinates all rhythms across the entire body

Molecular regulation of the Circadian clock • The central pacemaker is entrained each day by the

environmental light-dark cycle

• Positive and negative regulation of a set of core clock genes forms a rhythmic feedback loop with a time constraint of 24 hours per cycle

Central Circadian clock

• Entrained by light

• Light input to the retina is transmitted to the SCN to activate SCN neurons

• The effect of light input to the SCN depends on time of exposure – if light is received at the beginning of one’s habitual dark period, it will result in a phase delay (leading to the person being more tired, later)

• If light is received at the end of the dark period, it will result in a phase advance (leading to the person being more tired, earlier)

Peripheral clocks

• Autonomous and synchronized by signals from the SCN

• The SCN signals to many peripheral tissues – the heart, vasculature, adrenal glands, liver, pancreas, and adipose tissues

• These signals are sent via ANS connections and the release of hormones, like glucocorticoids

• Other factors like body temperature, rest/activity, and feeding also affect peripheral clocks

Circuitry and molecular aspects of sleep

Wakefulness and cortical activation

• Wakefulness is regulated by many neurochemical systems in the upper brainstem, hypothalamus, and forebrain

• These systems send ascending projections to the entire cortex and thalamus

• This system is called the ascending arousal system

Transitions between wakefulness and sleep • Animals and humans are vulnerable during sleep, so we need

to be able to wake up quickly and completely when in danger

• Neurons that trigger wakefulness or sleep mutually inhibit each other

Regulation of REM sleep

• Mostly occurs at the brainstem, with input from the hypothalamus

• The non-REM/REM regulating system also has a mutually inhibitory set-up

• During REM sleep, neurons in the sublaterodorsal nucleus (SLD) are active, and they activate neurons in the hippocampus and cortex (which can explain dreaming)

Current theories on why we sleep

Sleep decreases energy consumption

• Sleep is associated with reduced brain energy expenditure

• Sleep may have been selected to reduce energy expenditure at times when food is difficult to access, since the human brain accounts for upwards of 30% of energy expenditure!)

• Sleep may also allow for reallocation of energy to the immune system

Sleep is involved in information processing and synaptic plasticity • Cognition, attention, and memory are rapidly affected by sleep

deprivation

• A major function of sleep is to scale down synapses that have accumulating during learning, which can free up space and energy in the brain

Sleep disorders

Sleep disorders

• Affect 10% of the population

• Prevalence increases with age

I. Circadian rhythm sleep disorders

• Misalignment of the internal circadian clock in a sleep-wake schedule

• For example – if the phase of body temperature is misaligned with the expected sleep-wake cycle, individuals may be trying to go to sleep when body temperature is rising, making sleep impossible

a. Advanced sleep phase syndromes

• “Extreme early birds”

• Have sleep times that are much earlier than what would be suitable for a normal light-dark cycle

• Rare

b. Delayed sleep phase syndrome

• ”Extreme night owls”

• Have sleep times much later

• Unable to go to bed until 3 or 4am, but then sleep until noon

• Improves with age

c. Shift work

• Individuals are forced to sleep during normal waking period

• This cases impaired sleep consolidation and shortened sleep duration

• Even worse with rotating night and day shifts (no ability to adapt)

• Chronically, this results in reduced productivity and increased risk of accidents

• Creates hormonal imbalances and results in increased metabolic and cardiovascular risk of shift workers

c. Shift work

• Shift work sleep disorder = insomnia and/or excessive sleepiness associated with working and sleeping at non- standard times

• Increased risk for heart disease, diabetes, depression, GI problems, and cancer

d. Jet lag

• Caused by rapid changes in environmental time from travel across time zones

• Sleep and wakefulness often occur at abnormal biological times

• A few days with the new schedule results in adaptations and normalcy, but complete resynchrony can take multiple weeks

e. Free-running circadian disorder

• Occurs when the circadian clock completely fails to entrain to the normal 24 hour light-dark cycle

• Sleep and wakefulness progressively delay or advance from day to day

• Most common in completely blind invidiuals with no light perception

II. Narcolepsy

• Disorder of wakefulness and REM sleep

• Severe, irresistible daytime sleepiness, cataplexy (sudden muscle weakness that causes collapse), dissociated REM sleep events, disturbed nocturnal sleep, and abnormally rapid transitions into REM sleep

Narcolepsy with cataplexy

• Caused by orexin deficiency

• Orexin neurons function to sustain wakefulness and suppress REM sleep

• These neurons also project to the spinal cord and may regulate muscle tone

• Orexin neurons also affect functions of feeding, cardiovascular regulation, pain, locomotion, stress, and addiction

• Loss of orexin neurons in narcolepsy = believed to be an autoimmune function

III. Kleine-Levin Syndrome

• KLS affects adolescents

• Characterized by recurrent episodes of severe hypersomnia, cognitive impairment, apathy, derealization, and psychiatric/behavioral disturbances

• Episodes last days-weeks, and recur every 1-12 months for a median of 14 years

• Between episodes, individuals are completely normal

• Pathophysiology = completely unknown

IV. Restless Leg Syndrome

• RLS is a sensorimotor disorder where patients suffer from an urge to move their legs, affecting patients at night (midnight- 2am)

• Likely linked to dysfunctional dopamine neurotransmission and iron deficiency