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 Clock circadian pacemaker photoreceptor 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…… SCN ablation:
rest-activity
SCN ablation:
results in a loss of circadian rhythms

8. …and sufficient fast-running mutant SCN transplant

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

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

26. pharmacology of sleep GABA interneurons in thalamus
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. Circadian (expanded) Clock “slave” oscillators circadian pacemaker
RHT
“slave”
oscillators
REM-
NREM
Clock
entrainment
pathways
output
photoreceptor
circadian
pacemaker
overt
rhythms
SCN