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Zzzz zzzz zzzz… … … Zzzz….. Zzzz… Zzzzz…. Zzzz…. Huh? Wha? Oh… right… Who Needs Sleep? • Mammals, birds, reptiles, amphibians, fish, insects, nematodes, barenaked ladies • Likely a universal phenomenon for animal kingdom By James M. Robertson SLEEP Repeat. Sleep features: Altered consciousness Inhibited sensory activity Inhibition of voluntary muscles Decreased ability to react to stimuli Less so than being awake More so than hibernation, comatose Heightened anabolic state Anabolism = Building Up Anabolism/Catabolism How much should you sleep? From recent recommendations of National Sleep Foundation Your Biological Clock Humans have variable sleep “chronotypes” Two hours either side of average Sleep is a cyclical process Sleep Stages: NREM Non-rapid Eye Movement Sleep EEG Neural Oscillations = Engine Noise Lower arousal threshold: Stage 1 – Between sleep wakefulness Muscles active & eyes slowly rolling Low voltage / mixed freq. Stage 2 – Wave activity Strong oscillatory EEG rhythms EEG Sleep Stages: NREM Higher arousal threshold: Stage 3 – Slow Wave Sleep (SWS) 20-50% Delta Waves EEG Delta wave = high amplitude brain wave 0-4 hz Stage 4 – “Deep Sleep” >50% Delta Waves EEG Sleep Stages: REM Rapid Eye Movement Sleep Low Muscle Tone Difficult to arouse Rapid/low voltage EEG ↑ Brain Arousal ↑ Brain Oxygen Consumption Similar EEG pattern to waking 20 – 25% Total Sleep 1.5 – 2 hours per night in humans Lack of REM impairs learning ability Orexin and sleep function Sakurai 2011 Sakurai is an O.G. His lab discovered Orexin Reverse pharmacology methods Two orphan GPCR receptors Orx A, Orx B Molecular cloning techniques reveal prepro-orexin De Lecea id’d mRNA for prepro-orexin around same time Orx neurons localized to hypothalamus 3000 neurons - rats 70,000 neurons - humans Possibly wanksta Orexin and sleep function Sakurai 2011 Loss of Orexin Neurons implicated in: Narcolepsy Excessive daytime sleepiness Sleep Attacks REM Sleep Disorder Cataplexy Episodic loss of muscle function Ranges from weakness to complete collapse Observed in narcoleptic patients Narcolepsy Sakurai 2011 Affects ~ 1 / 2000 in United States Notably reduced latency for REM sleep Sleep-Onset REM (immediately preceded by waking) Sleep Attack = REM sleep intrusion Nocturnal sleep highly disturbed Vivid dreaming Hallucinations Sleep Paralysis Narcolepsy and Cataplexy Sakurai 2011 Concomitant disorders Cataplexy Triggered by emotional stimuli i.e. scaring the cute little goats Unlike narcolepsy, consciousness is kept Orexin and Narcolepsy Sakurai 2011 Orx involved in narcolepsy (-)Orx mice, dogs show similar phenotypes to human condition Behavioral arrests similar to cataplexy REM sleep attacks Human narcoleptic postmortem No detectable Orx in cortex or pons (normally present) 80-100% reduction in neurons containing prepre-orexin mRNA Hypothesized to result from selective immune response Degeneration of Orx neurons Tribbles homolog 2 (Trib2) antigen possible culprit Orexin and Narcolepsy Sakurai 2011 Narcolepsy is two things: 1. Difficulty staying awake Abrupt transitions from wakefulness to NREM Mouse studies suggest deficiencies in Orx-2 signalling Orx-2: Anxiolytic/Antidepressive 2. Intrusion of REM sleep Cataplexy, hallucinations, sleep paralysis Treated with SSRIs – abnormal monoaminergic neurotransmission Lack of signaling in both receptors associated with cataplexy Orx2 in Limbic System = emotional valence Orx1 in PPT = ↓ REM atonia (sleep paralysis) Orexin and sleep function Sakurai 2011 Preoptic area – VLPO Region of Hypothalamus NREM initiation and maintenance Inhibitory GABA to: LC TMN DR Orx neurons innervated by GABA cells in VLPO Turns off Orx during sleep Disruption of GABAB receptor results in fragmented sleep-wake cycles Orx and inhibitory feedback = feedback loop Orexin and sleep function Sakurai 2011 Feedback loop important for Orx regulation GABA Other hormones, peptides Metabolic cues Orexin and sleep function Sakurai 2011 Orx-2 KO and prepro-Orx KO mice = both have sleep attacks (NREM) Orx-2 KO have less disrupted wakefulness Only mildly affected by cataplexy, direct REM transitions Suzuki 2013 Sleep is regulated by homeostatic mechanisms Limited by circadian and environmental arousal What is the link between them? ? Sleep need is correlated with delta wave power (NREM) Correlated with prior wakefulness time Conversely, level of arousal ↑ latency to sleep Latency varies inversely with delta power How does arousal level relate to sleep need? Suzuki 2013 Methods C57 BL/6 Mice 6 hours sleep deprivation – two methods: Gentle handling Cage changing Evokes emotional, behavioral, physical arousal “Frequent Flyer Program” – Gitmo I would prefer this one MSLT – Multiple Sleep Latency Test Had their cages jiggled ((every 30 min – 5min) x6) Assessed: Sleep latency Sleep need (via delta power – NREM) Biochemical correlates w/arousal, sleep need Suzuki 2013 Methods Suzuki 2013 Most results seen in first 3 MSLT trials GH saw decreased latency to sleep, increased sleep time comparatively CC increased latency to sleep, decreased time Similar to control except in Delta power (sleep need), gene expression ↑mRNA transcripts known from brains of SD rodents Sleep latency ≠ duration of wakefulness Suzuki 2013 Biochemical markers Dynamin 1 Formation of new vesicles Shows directed cellular growth Reflect biochemical changes associated with arousal and sleep need Suzuki 2013 Biochemical markers NDRG2 Astrocyte protein Role in neurite outgrowth Shows directed cellular growth Reflect biochemical changes associated with arousal and sleep need Suzuki 2013 Suzuki 2013 Take-homes Sleep homeostatic response not influenced by means of SD Not affected by level of arousal Rather, means of SD affected subsequent arousal CC reduced latency to sleep to control levels Delta power similar to GH SD DNM1-mediated regulation of presynaptic endocytosis and the level of arousal NDRG2 increase = involvement of glial cells Arousal > Sleep need Mice with histamine deficiency ≠ prolonged sleep latency Histamine subserves Orx-induced arousal How does Orx support arousal? Matsuki 2015 What is the mechanism that inhibits sleep during arousal? How does prolonged waking influence Orx neurons? GABA Primary (and most abundant) inhibitory neurotransmitter Sleep-active GABA Neurons from around the hypothalamus innervate Orx neurons GABA ↑ in LH during NREM sleep GABAB receptor Knockout led to severe fragmentation of vigilance states GABAA receptor Poorly characterized SD upregulates on: Basal forebrain cholinergic neurons Perifornical Hypothalamus GABAA receptor likely plays a role in homeostatic regulation of sleep How does it act on Orx? Matsuki 2015 Whole cell patch clamp Matsuki 2015 Methods Orexin-enhanced GFP transgenic mice SD with GH for 6 hours Tested for immunohistochemistry Stained with antibodies for GABAA receptor subunits Luminescence observed, intensity measured Electrophysiology Cells emerged in bath Muscimol (GABAA agonist) squirted in Response measured Matsuki 2015 GABAA R alpha 1 Enhanced in Orx neurons following SD HAP1/NLGN2 Molecules in Orx neurons GABA trafficking and inhibitory synapse specialization Matsuki 2015 GABAA R agonist muscimol Increased amplitude in Orx neurons following SD Orx neurons enhanced sensitivity to GABA post-SD Matsuki 2015 SD increased freq., amplitude of IPSC in Orx neurons Take Home Messages Arousal > Sleep need??? Thanks Orexin… Prolonged wakefulness affects Orx through changes in GABAA receptors GABAA receptor subunits upregulated following SD Enhanced inhibitory affect Post Synaptic Current Changes in Orx neurons Altered synapse number, sensitivity to GABA Take Home Messages Change in synaptic plasticity following prolonged wakefulness Previous Studies: Orx neurons maintain activity via excitatory post-synaptic plasticity changes Adapt to homeostatic sleep pressure SD alters sensitivity of Orx neurons to inhibitory input Modulated by GABA release Prepares for sleep onset Under GH SD Would Cage Change result in different IPSP?