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 sleepREM versus non-REM

mechanisms

self-sustained pacemakers

a master clock enables the organism to regulate a variety of behaviors at appropriate times during the daye.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

Clock entrainment

pathwaysoutput

pathways

photoreceptorcircadian pacemaker

overtrhythms

where is the clock?

anterior hypothalamus

above the optic chiasm

each ~ 10,000 neurons

SCN is necessary……

SCN ablation: results in a

loss of circadian rhythms

rest-activity

…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 cyclinge.g. per

(mRNA)

activation-repression loops

(Herzog 2007)

animation

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

QuickTime™ and aH.264 decompressor

are needed to see this picture.

(Herzog et al., 1998)

clock genes drive oscillations

rhythmic electrical activity is driven by the molecular clock

clock gene knockout

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 leafletassociated with LGN driven by Raphe (5HT)

SCN output mechanisms….

examples…. temperature regulationautonomic functionarousal - sleep

sleep characteristics

behavioral criteria reduced motor activitydecreased 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 ponsmidbrain -> 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 sleep-

promoting 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 activitynon-REM sleep REM sleep (awake)

no sensory input synchronized

activity disrupts signaling

no motor outputdescending 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)

RHT

“slave” oscillators

REM-NREM

Clock entrainment

pathways output pathways

photoreceptorcircadian pacemaker

overtrhythms

SCN