Week 4 - Chronobiology Flashcards
what does a normal sleep cycle consist of? how long is it?
Light sleep: Stage 1 = 6%, 2 = 49%
Deep sleep: Stage 3/4 = 23%
Dream sleep: REM = 22%
cycles are 90 minutes, that go from wake –> 1 –> 2 –> 3 –> 4 –> 3 –> 2 –> REM –> 2…
-there may be brief arousals from stage 1 that are not remembered
what happens to the REM and stage 4 amount throughout the night?
REM increases as stage 4 lessens
what is an EEG?
electroencephalogram; measures cyclic predictable pattern
what is seen during wakefulness on an EEG, for both alert and “drowsy”
alert: low-voltage, fast, random activity with high frequency beta waves
drowsy/relaxed: low voltage, fast, random activity with alpha waves
what does the EEG show for the 4 stages of non-REM (NREM) sleep/
1: lightest sleep, high frequency, low voltage with theta waves
2: light sleep with sleep spindles and K complexes
3: deep/slow wave sleep, synchronous delta waves
4: deepest sleep, delta waves >50%
what happens during stage 4 NREM?
deepest sleep, parasympathetic control, lowered vital signs, restorative sleep
what happens during in REM sleep? what does the EEG look like?
desynchronized, paradoxical, activated
- low voltage, high frequency, random, fast sawtooth waves
- EEG appears awake
- paralysis and dreams occur
- eyes move and erections occur
- sympathetic tone dominates
how many hours of sleep has the soonest mortality?
short sleepers: 8 hours
how does sleep length change as we age?
III/IV (deep sleep) decreases while I/II (light sleep) increases
what does melatonin do for sleep chemistry? what receptors does it stimulate?
made in the pineal gland at night due to a loss of light-induced neuronal firing in retinohypothalamic tract
- stimulates MT1: lower brain activation/arousal (turns off midbrain and suppresses sympathetic)
- stimulates MT2: facilitates 24 hr circadian clock
what does cortisol do for sleep chemistry?
peaks in the morning (4-5 AM) linking the HPA (hypothalamic-pituitary axis) to the circadian system
what is the reticular formation (ascending reticular activating system)?
runs through core of brainstem from medulla to midbrain to posterior hypothalamus
- “monolithic” system that incorporates systematic input from many entities that cause arousal
- -ACh, glutamate, monoamines (NE, DOPA, SE, His)
- -these act directly on certain brain areas and modulate other transmitters’ effects, and allow amplification of arousal signals
what are the 6 nt that make up the RAS?
ACh, glutamate, and the monoamines (norepinephrine, dopamine, serotonin, histamine)
how is ACh involved in waking? what makes it? when is it active? what does it do?
made in basal forebrain, and active during wakefulness and REM
- in pons, the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT)
- from these, project to sub-cortical regions like thalamus, lateral hypothalamus, then back to basal forebrain
how is it that the basal forebrain can promote wakefulness and lower sleepiness?
ACh is active during wakefulness (most robustly via projection to thalamus) and REM
GABA inhibits inhibitory neurons in sleep promoting centers, meaning that sleep drive is diminished
how is NE involved in waking?
made by locus coeruleus under 4th ventricle
- neurons fire during wakefulness, less during NREM and none during REM
- optimizes attention and task performance while awake
how is NE involved in insomnia/anxiety? what is it inhibited by?
excessive firing causes insomnia and anxiety at night (anxious and worried at bed time)
inhibited by alpha-1/2 receptors in a feedback loop
-use BP medications to lessen nightmares and anxiety
how is histamine involved in waking? what receptors does it bind to?
made in tuberomammilary nucleus in posterior hypothalamus
- increased firing when awake > NREM > REM
- H1 receptors –> wakefulness
- H3 autoreceptors –> inhibit histamine activity
- -blocking/antagonizing H3 receptors promote wakefulness
how is serotonin involved in waking? which receptors increase wakefulness? which blocking drugs promote NREM or promote/correct circadian rhythms?
there are 15 different receptors, so sometimes will wake or sleep
- serotonin supply is the dorsal raphe
- generally promotes wakefulness and inhibits REM (stimulate 5HT1a,1b,2,3)
- drugs that block 5HT2 promote NREM
- drugs that block 5HT1D and 5HT7 promote/correct circadian rhythms
how is dopamine involved in waking?
made in substantia nigra (promotes movement) and ventral tegmental area (reward)
- ventral periaqueductal gray in pons fires durign wakefulness
- provides motivational arousal as opposed to task oriented alertness
how is orexin/hypocretin involved in waking? what happens if you don’t have it?
NOT part of RAS, but rather innervates and controls all other wakefulness areas
- excitatory neuropeptides orexin A/B made in lateral hypothalamus as wakefulness regulators
- fire only when awake, not in NREM or REM
- sustain wakefulness when other systems falter
- if missing this, will go to sleep randomly
how is the thalamus involved in waking?
all of RAS is coordinated/gated via thalamic relay tracts/systems
-brain stem arousal center info must go thru thalamus to arouse cortex to wakefulness
what do glutamatergic VS GABAergic neurons do?
glutamatergic neurons - facilitate cortical arousal
GABAergic neurons - dampen ascending arousal pathways when sleep is needed
how is the thalamus involved in sleep? how is this related to ACh?
sleep spindles originate in thalamus, signifying that during NREM thalamic neurons are hyperpolarized and decrese responsiveness to external stimuli and synchronous SWS/delta occurs
-during wakefulness and REM, ACh input depolarizes the same neurons, increasing arousal and awareness causing desynchronous firing
how does the reticular activating system act as a dimmer?
operates by incrementally increasing NE, DA, SR, ACh
- may go from 0 to 150%
- can manipulate faltering system with stimulants, TCAs, SNRIs, NRI, NDRIs
how does the TMN (histamine) and VLPO (sleep center) act as simple switches?
operates in bipolar, all-or-none fashion by facilitating histamine or GABA/galanin
- may be either 0 or 100%
- is a slave to the SCN (suprachiasmatic nucleus) master switch
- can manipulate faltering system with modafinil, armodafinil
what is a “faltering system” for wakefulness?
fatigue, sleepiness, inattention, executive dysfunction
how does the orexin/hypocretin system act as a backup generator?
operates by incrementally increasing orexin
- may go from 0 to 100%
- innervates dimmer (reticular activating system) and the switch (TMN and VLPO)
- manipulate faltering system with modafinil, armodafinil (like TMN/VLPO)
what is needed in order to sleep?
ventrolateral and median preoptic areas (VLPO/MNPO) of lateral hypothalamus are “off” switch and NREM promoting center of CNS
- causes sleep via increased GABA and galanin activity
- turns off histamine-based TMN wakefulness half of the switch
- IOW: VLPO/MNPO are silent during wakefulness, but fire rigorously during NREM
when do MNPO VS VLPO fire? what do they contain?
MNPO fires as one drifts to sleep, while VLPO fires while asleep (to maintain it)
-both have GABA and galanin inhibitory transmitters with fibers projecting to arousal centers
how is REM sleep controlled?
by laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT) ACh firing
- allows desynchronized firing similar to wakefulness
- provides atonia by stimulating neurons in medulla that release GABA and glycine into spinal motor neuron tracts
how does 5HT, NE, DA, and ACh interact during NREM? during REM?
NREM: they all fire to some degree, suppressing ACh to allow process of sleep staging 1–>4 throughout the night
REM: ACh peaks and feedback inhibits the others
how can you wake up without the alarm?
RAS has woken us up
what does adenosine homeostasis have to do with sleeping?
increases while awake during metabolism (ATP breakdown)
- adenosine buildup is governed by astrocytes and yields inhibitory feedback to wakefulness centers, and stimulates VLPO sleep center so sleep occurs
- once concentrated enough, we fall asleep, and recover ATP
what are somnogens and how do they work?
cytokines IL-1B, TNF-alpha from brain parenchyma and promote sleep
- all increase in the evening, inhibiting arousal centers
- prostaglandin D2 is made in the meninges and promotes NREM
what is the circadian clock?
lack of light via eyes/optic nerve signals suprachiasmatic nuclei of hypothalamus to allow melatonin release
- can suppress melatonin with 24 hour light
- melatonin can drive circadian 24 hour rhythm as well
what controls the circadian clock? how do they fluctuate? what can affect these?
genes and proteins (CRY, CLOCK, BMAL1, PER1/2/3
- these genes make clock go faster/slower or be synchronized
- some fluctuate on a 24-hour basis
- -based on the time it takes for the genes to turn on, make enough PRO to trigger the next cascade
- -time it takes to transcribe and translate creates the 24 hour clock
- can be affected by light and temperature
how are BMAL1 and PER1/2/3 related? what do PER2 and CRY do?
BMAL1 and PERs are in counterphase
PER2 positively enhances BMAL1 system
CRY negatively enhances PER and CRY loops
what are Zeitgebers?
exogenous melatonin, caffeine, alcohol, light, food, exercise/activity, and social interaction
-they all can modify or override our clock
what are the components of sleep drive, versus circadian alerting signal?
sleep drive: adenosine, clock genes, GABA, galanin
circadian alerting signal: NE, DOPA, SR, orexin, histamine
what is insomnia? how is it treated?
difficulty initiating or maintaining sleep, early morning awakening, or non-restorative sleep for one month
- next day consequences
- no organic, psychologic, substance etiology
- treat with sleeping pills (block anti-histamine) or sleep hygiene
what causes something to be a disorder?
only a disorder if it messes with one’s life
what happens to brain activity with sleep deprivation?
obvious decrease in brain activity, particularly in frontal cortex
what is hypersomnia? how is it treated?
excessive daytime sleepiness or inability to maintain wakefulness
- next day consequences
- no organic, psychological, substance etiology
- treat with stimulants and wakefulness hygiene
what is narcolepsy? what does cataplexy and hyponogic mean? how is it treated?
daily sleep attacks over 3 months
- cataplexy/hypnopompic (muscle weakness) upon awakening
- hyponogogic hallucinations (upon sleeping)
- no organic, psychological, or substance etiology
- almost no REM latency (goes into instant REM)
- sleep paralysis is common
- treat with stimulants and a 20 minute nap every 2 hours
what are breathing related sleeping disorders, and how are they treated?
central and obstructive apnea, that yield insomnia or hypersomnia
- treat by avoiding sedatives, use CPAP mask, dental devices, or surgery (ineffective)
- NEVER give GABA or alcohol, b/c would decrease breathing
why is snoring a protective factor?
snoring will startle you to wake you up so you can breathe
what is circadian rhythm sleep disorder? what is the difference between the advanced or delayed type? how to treat it?
yields insomnia or hypersomnia due to sleep-wake cycle mismatch, shift, or synchrony
- advanced: in elderly; fall asleep too early at night, wake up too early in the morning
- delayed: jet lag, shift work; fall asleep too late, and wake up too late
- treat with sleep scheduling, benzodiazepines, melatonin, exercise, stimulants, or light therapy
what are examples of dyssomnia NOS (not otherwise specified)? how are they usually treated?
- nocturnal myoclonus - unconscious leg movements (periodic limb movement)
- restless leg syndrome - creeping sensnations, conscious movement occurs
- often treated with dopamine (D2) receptor agonists
what is nightmare disorder? when does it occur? how is it treated?
mostly in kids; long, frightening dreams
- awake, alert, and oriented afterwards
- remember the dream
- occurs during REM
- self-limiting, no treatment
what is sleep terror disorder? when does it occur? how is it treated?
mostly in kids; awake but disoriented, non consolable (scream and flail around, but not really “awake”)
- no memory of it
- happens in the first 1/3rd of the night during NREM stage 3/4
- self-limiting, no treatment
what is sleepwalking disorder? how is it treated? when does it happen?
somnambulism (can be caused by sleeping pills)
- happens in first 1/3 of night during NREM 3/4
- no memory, may awake confused but orients easily
- self limiting
what is sleep related bruxism? when does it happen? how is it treated?
teeth grinding during stage 2
-treat with mouth guard/bite plate
what is REM sleep behavior disorder? how is it treated?
loss of atonia during REM, which usually doesn’t happen
- men typically act out dreams, often violently (can hurt people sleeping next to them)
- treat with D2 agonists (like for restless leg syndrome)
what is sleeptalking? when does it occur?
somniloquy
- happens in all stages of sleep
- self limiting
what is sleep paralysis?
inability to move just prior to fallign asleep or awakening
-self limiting
