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 Clock circadian pacemaker photoreceptor overt rhythms entrainment pathways output pathways

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

SCN is necessary…… SCN ablation: 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 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 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 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

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

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) Clock “slave” oscillators circadian pacemaker RHT “slave” oscillators REM- NREM Clock entrainment pathways output photoreceptor circadian pacemaker overt rhythms SCN