Transcript PAIN - University of Alabama at Birmingham

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
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
main features of rhythms
 self-sustained
 i.e., free-running
 cycle = 24 hrs
 entrained by
external cues
 e.g., light
wake-sleep
general organization
photoreceptor
circadian
pacemaker
Clock
entrainment
pathways
output
pathways
overt
rhythms
where is the clock?
 anterior hypothalamus
 above the optic chiasm
 each ~ 10,000 neurons
SCN is necessary……
rest-activity
SCN ablation:

 results in a
loss of
circadian
rhythms
…and sufficient
fast-running mutant SCN transplant
http://www.hhmi.org/biointeractive/clocks/index.html
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
What drives the rhythmic firing?
gene cycling
 e.g. per
(mRNA)
activation-repression loops
(Herzog 2007)
animation
QuickTime™ and a
H.264 decompressor
are needed to see this picture.
http://www.hhmi.org/biointeractive/clocks/animations.html
clock genes drive oscillations
rhythmic electrical
activity is driven by
the molecular clock
clock gene knockout
(Herzog et al., 1998)
electrical oscillation is only output
gene cycling drives electrical rhythm
(Welsh et al., 1995)
BK channels…..
….are the key regulators of firing rate
(Meredith et al., 2006)
entrainment
RHT - retinohypothalamic
IGL - intergeniculate leaflet
 associated with LGN
 driven by Raphe (5HT)
SCN output mechanisms….
examples….
 temperature regulation
 autonomic function
 arousal - sleep
sleep characteristics
behavioral criteria
 reduced motor activity
 decreased response to stimulation
 stereotypic posture (lying down/eyes closed)
 relatively easily reversible (c.f. coma)
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
what makes us sleep?
prior sleep history = best predictor of sleep
 C: circadian rhythm (SCN)
 S: homeostatic property:
 accumulation of sleeppromoting substance (?)
 sleep pressure:
 vertical distance between
the S and C curves
Sleep & Death
record amount of deprivation
in animals……
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
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
sleep stages
 EEG (Electroencephalogram) wave form is
different in each stage
REM state: paradoxical sleep
awake
EEG
EMG
EOG
REM
EEG
EMG
EOG
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
thalamocortical activity
non-REM sleep
no sensory input
 synchronized
activity disrupts
signaling
REM sleep (awake)
no motor output
 descending brain
stem glycinergic
inhibition of motor
neurons
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
dreams
unknown - cognitive / memory (?)
both REM and non-REM sleep
lifetime
Circadian (expanded)
photoreceptor
RHT
circadian
pacemaker
“slave”
oscillators
REMNREM
SCN
Clock
entrainment
pathways
output
pathways
overt
rhythms