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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