Lect 11-20-23-Sleep.pdf

Neurobiology of Sleep Ketema Paul, Ph.D. Professor Topics covered in today’s lecture • What is sleep (the two process model)? • Neural basis of the sleep-wake cycle • Sleep diagnostics • Circadian regulation of the sleep-wake cycle What is sleep? Sleep: Reversible behavioral state of perceptu...

Neurobiology of Sleep Ketema Paul, Ph.D. Professor Topics covered in today’s lecture • What is sleep (the two process model)? • Neural basis of the sleep-wake cycle • Sleep diagnostics • Circadian regulation of the sleep-wake cycle What is sleep? Sleep: Reversible behavioral state of perceptual disengagement from, and unresponsiveness to the environment Principles and Practice of Sleep Medicine, 4th Edition Two process model Ø Proposed by Alexander Borbely in 1982 Ø Circadian and homeostatic regulation of sleep are driven by separate and independent mechanisms Ø These mechanisms interact to consolidate sleep and wakefulness Why Do We Feel Sleepy? The 2-Process Model Ø2 processes combined determine sleep propensity and the duration of sleep ØCircadian rhythm: ØProcess driven by biological clock (time of day) ØCyclical—periods of sleepiness occur at roughly the same times each day ØHomeostatic sleep drive: ØProcess driven by amount of time awake ØLinear and cumulative—one gets progressively more tired with each passing hour (“sleep load” increases) Borbely AA. Hum Neurobiol. 1982. Circadian rhythms are driven by molecular clocks Circadian clocks exist throughout the body What is homeostasis? The active defense of a set point. Homeostatic drive for sleep Ø Homeostasis: the coordinated physiological processes which maintain most of the steady states in the organism Ø Sleep drive is proportional to the duration of prior wakefulness Ø Sleep drive is expressed as EEG delta power during nonREM sleep Ø Neurobiological substrates for sleep drive are unknown Processes that regulate the sleep-wake cycle: 1) Homeostatic process determined by prior sleep and waking. 2) Circadian process independent of sleep and waking. 3) Ultradian process involving the alternation of nonREM and REM sleep. Sleep Stages ØWake: Low arousal and response thresholds Behaviorally active ØRapid Eye Movement Sleep (REM): Rapid eye movements Lack of muscle tone Dreaming ØNon-REM (NREM): No eye movements Sustained muscle tone No Dreaming Sleep Stages • Stage1 transition • Stage 2 disengage • Stage 3/4 slow wave sleep, delta waves, NREM • REM paradoxically active brain state The Human Sleep Cycle • Sleep cycle length is ~ 90-110 minutes • Each cycle is repeated 3 to 6 times per night • Two stages of sleep • Non-REM sleep • REM sleep • Hypnogram – a recording of the sleep cycle Neural basis of the sleep-wake cycle Constantin Von Economo Ø Discovered Encephalitis lethargica (1917) Ø Three types: Ø Somnolentophthalmoplegic Ø Hyperkinetic Ø Amyostatic-akinetic (parkinsonism) Wake-promoting mechanisms Saper et al., 2005, Nature 437:1257-1263 Reticular Activating System § Maintains the conscious, alert state that makes perception possible § § § § brainstem reticular formation ascending projection system non-specific thalamic nuclei non-specific thalamocortical projections (diffuse) § Activated by sensory information being relayed to the cerebrum Reticular Activating System § Anatomic components § brainstem reticular formation § ascending projection system (thalamus & hypothalamus) § non-specific thalamic nuclei § non-specific thalamocortical projections (mostly glutamatergic; diffuse cortical areas) § Role of specific thalamic nuclei: attention to a specific sensory modality during consciousness Orexin activates arousal regions ( ) REM-on neurons Sleep-promoting mechanisms Saper et al., 2005, Nature 437:1257-1263 Mechanisms of non-REM sleep Mechanisms of REM sleep See Saper lab Nature 2006 Circadian control of sleep Activity of state-regulatory nuclei Wake Amines (locus coeruleus, dorsal raphe, tuberomammillary nucleus) Acetylcholine (LDT/PPT, basal forebr.) Orexin/Hypocretin GABA (ventrolateral preoptic nucleus) é é Non-REM REM é O é é O é é O O O é é Wake-on, REM-off arousal systems: Norepinephrine: Primarily from locus coeruleus (LC). LC neurons exhibit regular discharge during waking, reduced discharge during NREM sleep, and near-complete cessation of discharge during REM sleep. Serotonin (5-HT): Found in the dorsal and median raphe. Large diversity of receptor supbtypes. Arousal promoting effects are receptor specific. Histamine (HA): Discreetly localized in the tuberomammillary nucleus (TMN). Transient activation of the TMN region results in increased NREM sleep. HA neurons exhibit regular discharge during waking, greatly reduced discharge during NREM sleeo, and cessation of discharge during REM sleep. Wake-on, REM-on arousal systems: Acetylcholine: Localized in two regions: LDT & PPT. Neurons in both groups exhibit higher rates of discharge during waking and REM sleep. Dopamine: Primarily located in the substantia nigra. The degeneration of nigrostriatal DA system is the primary neuropathologic basis of Parkinson’s disease and excessive daytime sleepiness is one manifestation of it. Glutamate: Glu neurons are found throughout the brain, including in the core of the pontine and midbrain RF. Other sleep-promoting agents: Adenosine: Inhibitory neurotransmitter. Arousal promoting effects of caffeine arouse from being an antagonist of adenosine A1 receptors. Proinflammatory cytokines: Sleep deprivation increases cytokine levels and peripheral infections increase sleep amount. Prostaglandin D2: Stimulates sleep at the VLPO. Growth Hormone Releasing Hormone: Synthesized in and secreted from the arcuate nucleus of the hypothalamus. Sleep diagnostics Clinical analysis of sleep and wakefulness • Subjective measures: • • • •  Pittsburgh sleep quality index Epworth sleepiness scale Berlin questionnaire Horne-Ostberg Questionnaire for Morningness-Eveningness Objective measures: – Polysomnography – Wrist actigraphy – Cell phone apps (accelerometry) Objective measures of the sleep-wake cycle Sleep Staging Variables ØElectroencephalogram (EEG) - acquired by surface electrodes on the scalp at standardized locations (10-20 system) ØElectrooculogram (EOG) - acquired by surface electrodes placed at the outer canthus of each eye ØElectromyogram (EMG) - acquired by surface electrodes placed on the chin muscle (sub-mental) Characterization of the EEG §Amplitude: 2 - 400 µV §Frequency: 0.5 - 50 Hz § delta (D): 0.5 - 4 Hz, 20 - 400 µV § theta (q): 5 - 7 Hz, 5 - 100 µV § alpha (a): 8 - 13 Hz, 5 - 100 µV § beta (b): 14 - 50 Hz, 2 - 20 µV Patterns often superimposed Origin of the EEG frequencies § Alpha frequency - driven by neurons in the thalamic relay nuclei (LGN, MGN, VPL) projecting to specific cortical areas § Delta frequency - intrinsic rhythm seen in the absence of thalamic inputs § Beta frequency - arousal driven by nonspecific (intralaminar) thalamic nuclei § Theta frequency - ? transition from intrinsic delta to thalamic-driven alpha Origin of the EEG – Cortical surface brain potentials §EPSPs and IPSPs on apical dendrites of cortical pyramidal cells §other cortical and subcortical components (minor contributions) Generation of very small electrical fields by synaptic currents in pyramidal neurons Cross-section of cortex: Afferents release glutamate Open cation channels at pyramidal cell dendrites Only if thousands of neurons contribute their small voltage is the signal large enough to see at the scalp electrode - forest for the trees Generation of large EEG signals by synchronous activity Two mechanisms of synchronous rhythms Top: Cues from a central clock or pacemaker Bottom: Distribute timing function among members by mutual excitation and inhibition of each other Cortical rhythms depend on both mechanisms, via thalamic maker input, and collective cooperative interactions among cortical neurons themselves. Thalamic cells have a particular set of voltage-gated ion channels to allow each cell to generate rhythmic, self-sustaining discharge patterns even in the absence of external input to the cell. To cortex via thalamocortical axons Rhythms in thalamus driving rhythms in cerebral cortex Cortical rhythms: general purpose 1. Sleep - brain’s way of disconnecting the cortex from sensory input 2. Awake brain often generates bursts of synchronous neural activity that elicit frequencies around 30-80 Hz (sometimes called gamma rhythms) 3. Momentary fast rhythms, different parts of brain & cortex, binds several components into a common construction - percept, complex act, etc Explain the synaptic homeostasis theory of consolidation…. Synaptic Homeostasis- idea that information encoding during wakefulness leads to an increase in synaptic strength in the brain. Sleep downscales synaptic strength to a sustainable level in energy and tissue volume demands that allows reuse of synapses for future encoding. Figure 2: Encoding information during waking, synapses become widely potentiated (large yellow nerve ending), resulting in an increase in synaptic strength. (W= strength). Small nerve ending represents a new synapse and the unfilled ending is not activated, thus does not increase in weight. Slow oscillations during SWS serve to downscale synaptic strength. Weak connections are reduced, where the relative strength of the remaining connections is preserved. The transitions between up and down states in cortical neurons have been hypothesized to underlie changes in synaptic plasticity, or synaptic strength, during sleep, and to contribute to sleep-dependent changes in learning and memory.