Wednesday, April 11, 2012 CC-BY-NC
Circadian and Homeostatic Regulation of Sleep

Maintainer: admin

1Sleep criteria

  • Behavioural critera:
    • behavioural quiescence: not moving
    • elevated arousal threshold: harder to become active
    • homeostatically regulated : less sleep --> more sleepy.
  • Eletrical Criteria (EEG) : different among sleep stages in a cycle (~4.5hr)
    • Awake: low amp high freq
    • non-REM:
      • stage 1: low amp high freq. can be easily woken up.
      • stage 2: hard to be awaken. high amp. EEG has sleep spindle
      • slow wave sleep (SWS):
        • (Delta wave (1~4Hx), learning, memroy, synaptic equilibrium. growth hormone secretion)
        • (regulation: homeostasis)
        • Stage 3: high amp and lower freq.
        • stage 4: very high amp and lowe freq.
    • REM sleep: EEG looks like that of awake stage.
      • (Theta wave (4~8Hz). rapid eye movement, muscle atonia.)
      • (CNS maturation, synaptogenesis, memory consolidation. dreams.)
      • (regulation: circadian rhythm. meaning that we have more REM at certain time of day.)
      • every cycle has longer REM stage than the previous sleep cycle.
  • Pharmacological Criteria
    • sleep states
    • hormones level
  • molecular criteria: changes in gene expression

2Why do we sleep

  • sleep must be important because
    • many animals sleep....
    • since we are defenseless when sleeping, evolutionary advantages of sleeping somehow outweights disadvatages
    • severe adverse effects
  • functions (mostly hypotheses):
    • brain restoration
    • energy conservation (replenishment of brain glycogen levels)
    • synaptic homeostasis: resetting/remodeling synapses made during the day
    • memory consolidation

3Sleep Regulation

  • lesion in some area of ant. hypothalamus cause insomnia
  • lesion in between brain stem and hypothalamus cause narcolepsy : sudden and fragmented sleep.
  • asending arusal system --> cortical activation
    • LH: locus coeruleus (noradrenaline)
    • raphe (5-HT/serotonin)
    • TMN: Tuberomammilary nucleus (histamine) : more posterior hypothalamus
    • brain stem nuclei that project to thalamus which than projecto t:
      • PPT (Ach), LDT (ACh)
    • lateral hypothalamus/perifornical region (LHA/PeF): hypocretins
      • not just project to cortex
      • also activate LC, raphe, TMN, LDT/PPT
      • so they reenforce functions of those nucelei above.
    • lesion in boundary between brain stem and forebrain, that interrup pathway that go directly to cortex or through thypothalamus cause extreme sleepiness
  • ventral lateral pre-optic nucleus:
    • GABA-nergic neurons, inhibit neuclei in the ascending arousal system and thereby promotes sleep
      • inhibit LC, Raphe, TMN, Hcrt, LDT/PPT
    • lesion in this causes insomnia
    • strong firing during nonREM and REM. but very little firing during awake state.
  • Two processes model of sleep control#
    • hormeostatic process: sleep pressure increases with time awake
    • circadian process: clcok controls timing of sleep and wakefulness
    • so if you stay up late you'd feel sleepy, but feel last sleepy when the sun comes up.
      • but then the following night, addtive effects of circadian rhythm and homeostatic process make you fall asleep quickly.
  • SCN (superchiastmatic) output sot sleep regulatory system
    • few/little projections to VLPO (which induces sleep)
    • dense projections to DMH (dorsal medial hypothalamus : center of command). projectios to
      • wake promoting neurons (during the day
        • LHA(hypocretin, aka orexins), PVH
      • VLPO


  • aka Orexins
  • strongly expressed in a distrete set of neurons in the lateral hypothalamus.
  • two types:
    • both matured from preprohypocretin
    • hypocretin 1 and 2 (Hcrt1/2)
    • same C terminal but different N terminal
  • ligand for GPCR (G-protein coupled receptor)
    • hcrtR1: preferentially bind hcrt1
    • hcrtR2: bind both
    • receptors location correspond to where hypocretin neurons project
      • some reasons have both or just one type of receptor
    • hypocretin neurons project to wake-promoting neclei and cortex.
    • however, during sleep, hypocretin neurons activity is smaller
  • injection of hypocretins in the brain stimulates arousal and food intake (may due to reward pathway, may be indirect).
  • narcolepsy is associated with very low hypocretin levels in CSF.
    • excessive daytime sleepiness, cataplexy (sudden loss of muscle tone, resemble characteristics of REM sleep), sleep paralysis, hypnagogic hallucinations
    • maybe due to degeneration of hypocretin-producing neurons
    • dogs and mouse narcolepsy models show mutant receptor
    • mice with degenerated hcrt neurons
    • mice KO for hcrt or receptor
      • sleep is much more fragmented
      • could go from wake to REM directly (similar to cataplexy)

5Flip Flop model of sleep states

  • awake: orexin stimulate wake-promoting neurons, which promote wakefullness and suppress VLPO
  • sleep: VLPO suppress orexin neurons and wake-promoting neurons
    • orexin neurons continue to promote wakefullness
    • since VLPO need to suppress orexin to promote sleep, orexin is like a buffer so you don't fall asleep quickly.
      • lack of orexins lead to nacrolepsy.

6Hormeostatic control of sleep

  • sleep mechanisms are quite conserved across organisms.
    Questions we ask:
  • what's the molecular and cellular basis for the homeostatic drive for sleep.
  • what accumulates during wakefullness that makes us feel the need to sleep?
    • homer Ia, adenosine...


  • increases during waking and sleep deprivation
  • sleep-inducing
  • binds to A2AR (adenosine receptor), so A2AR KO mice : less sleep and less response to sleep deprivation
    • caffeine is an antagonist
  • involvement of glial cell
    • glutamate release from presynpatic termianl binds on mGluR of a nearly astrocytic process.
    • which cause astrocytes to release vesicles containing ATP
    • ATP is converted into adenosine by extracellular enzyme.

6.2Homer 1a

  • regulates glutamate receptors (signaling and internalization of those receptors)
  • expression of mRNA goes up during sleep deprivation and waking
    • RNA level goes down after sleep
  • genetic locus co-segregates with level of EEG slow waves
    • slow wave sleep is known to be higher when sleep pressure is higher.
  • known to be involved in synaptic plasticity