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Unlocking the Mysteries of Sleep: A Comprehensive Guide to Your Body's Natural Process

Delve into the intricate world of sleep with this comprehensive guide by James M. Robertson. Explore the stages of sleep, the impact of orexin, and the complexities of narcolepsy. Unravel the science behind your body's need for rest and discover how sleep affects your overall well-being. From REM sleep to narcolepsy, this guide will shed light on the mysteries of the sleep cycle and its vital role in maintaining optimal health.

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Unlocking the Mysteries of Sleep: A Comprehensive Guide to Your Body's Natural Process

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  1. Zzzz zzzz zzzz… … … • Zzzz….. • Zzzz… • Zzzzz…. • Zzzz…. • Huh? Wha? Oh… right…

  2. Who Needs Sleep? Mammals, birds, reptiles, amphibians, fish, insects, nematodes, barenaked ladies Likely a universal phenomenon for animal kingdom By James M. Robertson

  3. Repeat. SLEEP 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

  4. How much should you sleep? • From recent recommendations of National Sleep Foundation

  5. Your Biological Clock • Humans have variable sleep “chronotypes” • Two hours either side of average

  6. Sleep is a cyclical process

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Narcolepsy and Cataplexy Sakurai 2011 • Concomitant disorders • Cataplexy • Triggered by emotional stimuli • i.e. scaring the cute little goats • Unlike narcolepsy, consciousness is kept

  14. 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

  15. Orexin and Narcolepsy Sakurai 2011 • Narcolepsy is two things: • Difficulty staying awake • Abrupt transitions from wakefulness to NREM • Mouse studies suggest deficiencies in Orx-2 signalling • Orx-2: Anxiolytic/Antidepressive • 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)

  16. 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

  17. Orexin and sleep function Sakurai 2011 • Feedback loop important for Orx regulation • GABA • Other hormones, peptides • Metabolic cues

  18. 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 Orexin and sleep function Sakurai 2011

  19. 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? ?

  20. Suzuki 2013Methods • C57 BL/6 Mice • 6 hours sleep deprivation – two methods: • Gentle handling • Cage changing • Evokes emotional, behavioral, physical arousal • “Frequent Flyer Program” – Gitmo • 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 I would prefer this one

  21. Suzuki 2013 Methods

  22. 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

  23. Suzuki 2013 • Biochemical markers • Dynamin 1 • Formation of new vesicles • Shows directed cellular growth • Reflect biochemical changes associated with arousal and sleep need

  24. Suzuki 2013 • Biochemical markers • NDRG2 • Astrocyte protein • Role in neurite outgrowth • Shows directed cellular growth • Reflect biochemical changes associated with arousal and sleep need

  25. Suzuki 2013

  26. Suzuki 2013Take-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?

  27. 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

  28. Matsuki 2015 • GABAB receptor • Knockout led to severe fragmentation of vigilance states • GABAA receptor • Poorly characterized • SD upregulates on: • Basal forebrain cholinergic neurons • Perifornical Hypothalamus • GABAAreceptor likely plays a role in homeostatic regulation of sleep • How does it act on Orx?

  29. Whole cell patch clamp Matsuki 2015Methods • 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

  30. Matsuki 2015 • GABAA R alpha 1 • Enhanced in Orx neurons following SD • HAP1/NLGN2 • Molecules in Orx neurons • GABA trafficking and inhibitory synapse specialization

  31. Matsuki 2015 • GABAA R agonist muscimol • Increased amplitude in Orx neurons following SD • Orx neurons enhanced sensitivity to GABA post-SD

  32. Matsuki 2015 • SD increased freq., amplitude of IPSC in Orx neurons

  33. 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

  34. 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

  35. Would Cage Change result in different IPSP?

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