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circadian rhythms

circadian rhythms. Basic Neuroscience NBL 120 (2008). biological clocks & sleep. self-sustained biological oscillators importance? where is the clock? how does the clock work? how is the clock adjusted? patterns of sleep REM versus non-REM mechanisms. self-sustained pacemakers.

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circadian rhythms

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  1. circadian rhythms Basic Neuroscience NBL 120 (2008)

  2. biological clocks & sleep • self-sustained biological oscillators • importance? • where is the clock? • how does the clock work? • how is the clock adjusted? • patterns of sleep • REM versus non-REM • mechanisms

  3. self-sustained pacemakers • a master clock enables the organism to regulate a variety of behaviors at appropriate times during the day • e.g., upregulation of metabolic pathways before meals

  4. main features of rhythms • self-sustained • i.e., free-running • cycle = 24 hrs • entrained by external cues • e.g., light wake-sleep

  5. general organization circadian pacemaker photoreceptor Clock overt rhythms entrainment pathways output pathways

  6. where is the clock? • anterior hypothalamus • above the optic chiasm • each ~ 10,000 neurons

  7. SCN is necessary…… rest-activity • SCN ablation: • results in a loss of circadian rhythms

  8. …and sufficient • fast-running mutant SCN transplant http://www.hhmi.org/biointeractive/clocks/index.html

  9. SCN neurons are oscillators • Individual SCN neurons: • circadian oscillators (out of phase with each other) • day ≈ 8 Hz • night ≈ 2.5 Hz • coupled to generate a uniform rhythm of electrical firing • GABA acts as a primary synchronizing signal • gap junctions may also play a role in synchronization

  10. What drives the rhythmic firing? • gene cycling • e.g. per (mRNA)

  11. activation-repression loops (Herzog 2007)

  12. animation http://www.hhmi.org/biointeractive/clocks/animations.html

  13. clock genes drive oscillations • rhythmic electrical activity is driven by the molecular clock • clock gene knockout (Herzog et al., 1998)

  14. electrical oscillation is only output • gene cycling drives electrical rhythm (Welsh et al., 1995)

  15. BK channels….. • ….are the key regulators of firing rate (Meredith et al., 2006)

  16. entrainment • RHT - retinohypothalamic • IGL - intergeniculate leaflet • associated with LGN • driven by Raphe (5HT)

  17. SCN output mechanisms…. • examples…. • temperature regulation • autonomic function • arousal - sleep

  18. sleep characteristics • behavioral criteria • reduced motor activity • decreased response to stimulation • stereotypic posture (lying down/eyes closed) • relatively easily reversible (c.f. coma)

  19. anatomy of sleep-wake cycles • SCN only regulates timing of sleep • brainstem - reticular formations either side of pons • midbrain -> wake • damage = comatose state / reduction in waking • medulla -> sleep • transect above medulla = awake most of time

  20. what makes us sleep? • prior sleep history = best predictor of sleep • C: circadian rhythm (SCN) • S: homeostatic property: • accumulation of sleep-promoting substance (?) • sleep pressure: • vertical distance between the S and C curves

  21. Sleep & Death • record amount of deprivation • in animals……

  22. sleep • a critical behavioral state • purpose? physical versus cognitive rest • an active brain process • electrical activity in the brain changes but does not cease during sleep • multiple cycles of two states

  23. sleep cycles • REM (rapid eye movement) and NREM (non-REM) • states alternate in each cycle • one sleep cycle is about 90 minutes • each successive cycle has longer REM state

  24. sleep stages • EEG (Electroencephalogram) wave form is different in each stage

  25. awake EEG EMG EOG REM EEG EMG EOG REM state: paradoxical sleep

  26. pharmacology of sleep reciprocal interactions • NREM sleep: low ACh, high 5HT & NE • REM sleep: low 5HT or NE, high Ach (pontine tegmentum) • GABA interneurons in thalamus

  27. thalamocortical activity non-REM sleep REM sleep (awake) • no sensory input • synchronized activity disrupts signaling • no motor output • descending brain stem glycinergic inhibition of motor neurons

  28. clinical relevance (too much / little) • Narcolepsy • intrusion of sleep into wakefulness • cataplexy • atonia - loss of muscle tone • abnormal brainstem descending control of motor neuron • Sleep apnea • compromised breathing • decreased skeletal muscle tone • brief sleep arousals to restore tone • REM behavior disorder • violent dream enactment

  29. dreams • unknown - cognitive / memory (?) • both REM and non-REM sleep

  30. lifetime

  31. “slave” oscillators circadian pacemaker photoreceptor REM- NREM SCN RHT Clock overt rhythms entrainment pathways output pathways Circadian (expanded)

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