SLEEP + CIRCADIAN RHYTHMS

Question 1

What is sleep?

Answer 1

Sleep is a natural periodic state that involves reduced responses to environmental stimuli and decreased mobility -> It is a behaviour observed in all humans across cultures and numerous other species, even in unicellular organisms – humans spend a third of their lives sleeping -> Sleep is a type of behaviour that always fascinated people, especially because it involves dreaming (mythology, Sigmund Freud etc) -> In the last few years there has been a renewed interest in the scientific study of sleep.

Question 2

Sleep is controlled by two main processes

Answer 2

Homeostasis (S) -> if we do not sleep, we accumulate sleep debt -> Circadian(C) -> sleep tends to happen at a particular time during the 24-hour cycle. Sleep differs from states such as coma (extended period of unconsciousness), vegetative state or brain death (no sign of brain activity and no response to stimuli).

Question 3

Polysomnography?

Answer 3

The ‘gold’ standard of sleep research -> discovered by Hans Berger 1929 -> used initially in cats but now it is used for research and for clinical purposes -> involves recordings of electrical activity from multiple sources – ‘poly’ somnography.

Question 4

EEG recordings

Answer 4

electroencephalogram -> recordings of activity of populations of neurons in the brain underneath the skull.

Question 5

EOG recordings?

Answer 5

electrooculogram -> recordings of activity of the muscles around the eyes to decipher eye movements

Question 6

EMG recordings

Answer 6

electromyogram -> recordings of the activity of the muscles in the body -> These recordings can be combined with others such as heart rate, temperature, breathing (O2) etc.

Question 7

What are beta waves?

Answer 7

Beta waves consist of irregular activity of 13–30 Hz -> Beta activity takes place when the brain is processing information -> The person is alert and attentive to events in the environment or engaging in cognitive processes.

Question 8

What are alpha waves?

Answer 8

Alpha waves consist of activity of 8–12 Hz -> Occur when a person is resting quietly, not particularly aroused or excited and not engaged in strenuous mental activity.

Question 9

Stage 1 of sleep

Answer 9

(3.5–7.5 Hz): presence of theta activity - it is a transition between sleep and wakefulness

Question 10

Stage 2 of sleep

Answer 10

Sleep begins – characterized by irregular activity and also sleep spindles (12-14Hz) although these occur in other stages of sleep and K complexes which are only found during stage 2.

Question 11

Stage 3 sleep

Answer 11

High-amplitude and low-frequency delta activity (less than 3.5 Hz) -> Synchronized, regular waves, reflecting synchrony and coordination in the activity of neurons in underlying brain areas. -> There is a slowing down of brain activity as well as other bodily functions, such as heart rate, breathing, temperature, kidney function, etc -> Sometimes referred to as slow-wave sleep (SWS), or deep sleep.

Question 12

what is REM sleep?

Answer 12

A sleep phase characterized by increased brain activity and asynchrony in brain waves accompanied by muscle atonia. Aserinsky and Kleitman,1953: Sleep characterized by rapid eye movements - Rapid Eye Movement sleep (REM). -> Michel Juvet, 1959: deep sleep, in terms of muscle activity but light sleep, in terms of brain activity - Paradoxical sleep. Facial twitches, erections, vaginal secretions and dreaming occur during this stage.

Question 13

Brain activity during sleep

Answer 13

Sleep recordings revealed four distinct patterns of activity, three stages of sleep (NREM), 1, 2, 3 and an additional REM sleep episode -> We cycle through each stage and back, with each cycle lasting approximately 90 minutes. *Used to consider 4 stages of NREM and then REM.

Question 14

What are dreams?

Answer 14

Discovered by Dement and Kleitman, 1957 when participants were awakened from REM sleep. They tended to report vivid dreams. Considered important in psychoanalysis -> Freud thought of dreams as the ‘royal route to the unconscious’ and an opportunity to realize our secret wishes -> Jung viewed dreams as a glimpse into the collective unconscious -> Most dreams are related to events that happen in a person’s life -> Calvin Hall et al (1982): analyzed 10,000 dreams of healthy people and found that more than 64% are associated with sadness, anxiety or anger whereas 18% are happy dreams and only 1% involved sexual content

Question 15

What is the activation synthesis hypothesis

Answer 15

bottom-up view on dreams. The brainstem is activated during REM and sends signals to the cortex which creates images with actions and emotions from memory -> The frontal cortex is less activated during dreaming so there is no logic in the timing or the sequence of events, although the person tries to organize the content into a logical story when awake -> There is no meaning in dreaming although dreams are based on each person’s experiences.

Question 16

What is the coping hypothesis?

Answer 16

Valli and Revonsuo (2009) – argued that dreams are biologically adaptive and they lead to enhanced coping strategies -> Coping Hypothesis (also known as Clinico-Anatomical Hypothesis) (top-down view on dreams) -> People dream about events that they find threatening in their lives -> Support for this hypothesis is the evidence that problem solving occurs during sleep (“sleep on it”).

Question 17

The neural basis of sleep

Answer 17

Idea of a sleep-inducing substance perhaps due to the fact that many natural substances cause sleep i.e. morphine -> Neurochemicals and hormones produce sleep-wake cycles -> Melatonin secreted by the pineal gland during the dark promotes sleepiness, but it is not the only one.

Question 18

What is adenosine?

Answer 18

Adenosine -> accumulates during the day, after prolonged wakefulness and promotes sleep -> caffeine antagonizes the effects of adenosine and decreases sleepiness.

Question 19

Observations and Discovery in sleep

Answer 19

Constantine von Economo early 20th century observed patients with encephalitis -> Most had continuous sleepiness and would wake up only to eat and drink and these had damage in the base of the brain -> Fewer patients displayed insomnia and they had damage in an area of the anterior hypothalamus.
This area of the anterior hypothalamus was later identified as the ventro-lateral preoptic area (vlPOA) which contains inhibitory neurotransmitters such as GABA -> Damage to this area causes insomnia in rats and they eventually die -> Electrical stimulation of this area causes sleepiness and sleep.

Question 20

Brain Areas involved in wakefulness and arousal

Answer 20

Moruzzi and Mogoun (1949) discovered these regions accidentally -> While recording from anaesthetized cats they stimulated the cat’s brainstem and noticed that the delta waves were replaced by beta waves -> Stimulating the brainstem in a sleeping cat resulted in waking the animal

Question 21

The reticular formation (reticular activating system-RAS)

Answer 21

is comprised by several nuclei in the brainstem that extend to the forebrain to promote arousal -> Locus coeruleus (LC - NE/NA) -> Raphé nucleus (RN – 5HT) -> Tuberomammillary nucleus (TMN-Histamine) * antihistamines -> Nucleus basalis of Maynert (NBM-Ach) * also high during REM sleep.

Question 22

The flip-flop switch (inhibited)

Answer 22

Inhibited -> sleep-promoting region in vIPOA (ventrolateral pre-optic area) -> brain stem and forebrain arousal systems -> releasing Ach NE, 5-ht, Histamine (alert waking state). Flip is ‘on’.

Question 23

The flip-flop switch (on)

Answer 23

Activated -> sleep-promoting region in vlPOA -> mutual inhibition -> brain and forebrain arousal systems -> slow release of Ach, NE, 5-HT, Histamine (Slow-wave sleep) – flip-flop is ‘off’.

Question 24

Orexin (or hypocretin)

Answer 24

It is a peptide released from the lateral hypothalamus (LH) -> highly responsible for the maintenance of wakefulness -> implicated in narcolepsy -> Orexinergic neurons in the lateral hypothalamus -> motivation to remain awake, activation holds flip-flop ‘on’.

Question 25

What is the circadian rhythms?

Answer 25

Circadian ‘circa’ and ‘died’ – rhythms or regular patterns of activity associated with a 24h cycle such as day and night. Endogenous cycles (‘generated from within’) our brain and body spontaneously generate their own rhythms based on the earth’s rotation -> endogenous rhythms can also be annual (migration) or seasonal (breeding) in animals. Humans are diurnal (vs nocturnal) -> this 24h rhythms not only controls sleep and wakefulness but also other important functions such as body temperature, secretion of hormones, urination, etc.

Question 26

Early discoveries of circadian rhythms. 1

Answer 26

Biorhythms are not unique to humans and animals -> flowers may open during the day and close during the night -> 1729: French geologist, Jean Jacque d’Ortous de Mairan experimented with the mimosa plant -> Even if isolated from light, dark or temperature cues the leaves continued their rhythmic behavior.

Question 27

Early discoveries of circadian rhythm 2

Answer 27

-> Humans were placed in an underground bunker where no external cues -> Allowed to select their light-dark cycle and turn the lights on and off at will -> The participants continued to show daily sleep-activity rhythms, even though they drifted to >24hrs -> Concluded that humans have an endogenous biological clock which governs sleep-wake behaviour.

Question 28

What are zeitgebers and entrained?

Answer 28

External cues that serve serve to set our biological clock are called Zeitgebers (“time givers”) -> The most potent zeitgeber for humans is light although there are others (meals, activity, temperature, etc) -> When a zeitgeber resets a biorhythm, that rhythm is said to be entrained.

Question 29

Jet lag in disruption of sleep

Answer 29

Jet lag -> a disruption of the circadian rhythms due to crossing time zones -> stems from a mismatch of the internal circadian clock and external time. Sleepiness during the day, sleeplessness at night, and impaired concentration. Traveling west ‘phase-delays’ our circadian rhythms whereas traveling ‘phase-advances’ our circadian rhythms – people find it more difficult.

Question 30

Variability in our circadian rhythms

Answer 30

May differ between people and can lead to different patterns of wakefulness and alertness – chronotypes. Morning people “larks” and evening people “owls” -> Rhythms have a genetic basis, but they also change as a function of age and other external factors (lifestyle, social factors etc).

Question 31

Chronotypes across lifespans

Answer 31

We all start off (infancy and childhood) and finish off (adulthood and old age) as morning people “larks” -> During adolescence there is an increasing shift towards “eveningness” – teenagers become “owls”, which is particularly difficult given that school starts early in the morning - Some schools in the US have changed their curriculum to a later start in order to accommodate teenagers (A. Carskadon) -> Differences in chronotype may result in “social jet lag” -> Morning people report to be happier than evening people.

Question 32

supporting existence of biological clock

Answer 32

Curt Paul Richter, Prof. of Psychobiology at Johns Hopkins (1927): Introduced the concept that the brain generates its own rhythms, so it must have a biological clock which he attempted to locate in the brain of wild rats -> He performed electrical lesions in various parts of their brain in order to locate the biological clock -> The rats lost their rhythmic behaviour after damage to the hypothalamus -> In his book “Biological Clocks in Medicine and Psychiatry” (1965) he hypothesized that many disorders may result from disruption of the biological clock.

Question 33

The suprachiasmatic nucleus is the clock

Answer 33

1972, independent discovery by researchers in two different laboratories. Moore & Eichler and Stephan & Zucker. The primary biological clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus -> Lesions of this nucleus disrupted circadian rhythms of wheel running, drinking, and hormonal secretion, and was thus named “the master clock”.

Question 34

The Suprachiasmatic nucleus (SCN)

Answer 34

Recording electrodes in the SCN confirm that neurons are more active during the light period than during the dark period -> A single cell extracted from the SCN and raised in tissue culture continues to function in a rhythmic pattern -> Transplantation of an SCN into a donor organism results in the recipient following the donor’s rhythm. The SCN receives information about light through the retinohypothalamic tract, formed by a special population of ganglion cells (photosensitive retinal ganglion cells-PRGCs which make up 1-3% of ganglion cells.

Question 35

What are Photosensitive retinal ganglion cells (PRGCs)

Answer 35

These PRGCs have their own photopigment called melanopsin and can respond directly to light, especially blue light (Provencio et al 2000). They do not rely on rods and cones which explains the fact that blind people remain entrained -> Experiments where rods and cones were inactivated had no effect on circadian rhythms -> Part of this tract terminates in the midbrain to control the size of the pupil in response to light.

Question 36

The Retino-hypothalamic tract

Answer 36

SCN which is in the (Hypothalamus) circadian oscillator (biological clock) -> retinal ganglion cell containing melanopsin.

Question 37

What is the ‘per’ gene?

Answer 37

Jeffrey Hall & Michael Rosbash (Brandeis Univ, Mass) -> Studied the SCN in Drosophila (fruit flies) ->1984: Discovered the “per” gene and the “PER” protein (period)

Question 38

What is the TIM protein?

Answer 38

Michael Young (Rockefeller Univ) ->1994: Discovered the gene “tim” that produces the “TIM” protein (timeless) -> When TIM meets PER they combine and shut the period gene down -> 2017 Nobel prize in physiology and medicine

Question 39

Transcription-translation-inhibition feedback loop

Answer 39

A few genes and their protein products are involved in this clock -> Transcription from DNA to mRNA, to translation into proteins which form dimers ->These dimers enter the nucleus in order to inhibit transcription and then they decay -> The cycle begins again in a daily rhythm.

Question 40

Suprachiasmatic nucleus on the effects on pituitary gland and pineal gland

Answer 40

The SCN regulates waking and sleeping by controlling activity levels in other areas and secretory glands such as the pituitary and the pineal gland.
SCN -> pituitary gland (glucocorticoid release) ‘light phase’ arousal activities -> pineal gland (melatonin release) ‘dark phase’, reset activities.

Question 41

Other effects of the SCN

Answer 41

Breeding of animals is controlled by the SCN via the pineal gland -> During winter, the increased melatonin produced at night inhibits the gonads which shrink -> During spring, there is less melatonin produced which allows the gonads to enlarge, to produce testosterone and support mating behaviours -> The time of day affects performance in humans on a wide range of cognitive tasks measuring attention, executive functions and memory -> Treatment of disease can be influenced by circadian rhythms i.e. surgery outcome or pharmacotherapy -> Toxicity of a drug varies from 20-80% depending on the time of day (not necessarily considered in drug studies) -> Risk for illness also changes depending on the time of day, i.e. there is a higher likelihood of a stroke or heart attack in the morning. The SCN drives a number of slave oscillators, each responsible for the timing of a different type of behaviour, i.e., drinking, sleeping body temperature, activity etc.

Question 42

Sleep deprivation in rats

Answer 42

Rechtschaffen et al 1983 -> sleep-deprived rats -> the animals looked sick, they stopped grooming, became weak and lost their ability to thermoregulate -> they were losing weight although they were eating more and eventually, died. In human studies there are restrictions due to ethical reasons, but sleep deprivation is associated with increases in body weight.

Question 43

Sleep is adaptive

Answer 43

The original function of sleep was probably to conserve energy -> Decrease in body temperature of about 1-2 degrees Celsius in mammals -> Decrease in muscle activity -> Increase in sleep time when there is scarcity of food -> Normally our brain spends ~20% of our energy even though it is very small (2%) compared to our body weight -> This is true especially for NREM sleep, particularly SWS where metabolic rate and blood flow to the brain decrease, but not for REM sleep.

Question 44

Sleep is restorative

Answer 44

Sleep takes place at night, at the end of a busy day and helps us to feel refreshed and energized the next day -> activity during wakefulness results in the accumulation of free radicals (oxidative stress) and potentially toxic waste (such as amyloid beta) -> During sleep, restorative mechanisms take place to remove the free radicals and toxic waste.

Question 45

Sleep promotes development

Answer 45

The first clue that perhaps sleep has a role in brain development comes from the fact that infants sleep a lot more than adults -> REM sleep in adults accounts for about 20-25% of total sleep whereas in infants it takes up about 50% of total sleep time -> During stage 3 sleep (SWS), Growth Hormone (GH) release is at its peak which is important for growth such as neurogenesis.

Question 46

Sleep facilitates cognition

Answer 46

Sleep enhances learning and memory -> Performance on a newly learned task is often better the next day if adequate sleep is achieved during the night whereas deficits are evident following sleep-deprivation -> During sleep, neurons replay the previous experience to retain the information (Wilson and McNaughton, 1994) -> Evidence that possibly different types of learning may be supported by the different stages of sleep (SWS vs REM and declarative vs non-declarative). Problem solving and creativity -> During sleep, the brain continues to process material and enables the solution to problems, as evidenced by the “aha” phenomenon upon waking.

Question 47

Consolidation and Systems Consolidation

Answer 47

Müller and Pilzecker 1900: consolidation helps to establish memories in our brains for future use -> It involves the synthesis of new proteins and the formation of new synapses -> The memory traces themselves are not stored in the hippocampus forever. Instead, they are transferred to areas of the cortex, known as systems consolidation-> Memory traces that are thought to be unnecessary are removed Synaptic homeostasis hypothesis (Tononi & Cirelli 2014) -> synaptic pruning during sleep helps to reinstate the brain so that it can be able to function and learn more the next day.