OE

Week 10 ELM 20: Rhythms and Sleep

Biological Rhythms

  • Organisms adapt to 24-hour environmental changes by developing biological rhythms.
  • Examples across species:
    • Cyanobacteria (Synechococcus): gene activity
    • Plants (Bean): leaf movement
    • Fungi (Neurospora): conidiation
    • Insects (Drosophila): eclosion
    • Mammals (hamster): activity

Importance of Biological Clocks

  • The clock and its component genes have a wide-ranging impact on physiology:

    • Sleep/wake cycles
    • Body temperature
    • Cardiac output
    • Memory
    • Energy metabolism
    • Eating behaviour
    • Immune response
    • Detoxification
    • Cell cycle progression
    • DNA damage repair
    • Cellular energy metabolism
    • Neuronal excitability

  • Association with diseases:

    • Affective disorders (bipolar depression)
    • Sleep disorders
    • Neurodegenerative diseases (e.g., Alzheimer's)
    • Obesity/metabolic syndrome
    • Inflammation (asthma, COPD)
    • Cancer

  • Modern lifestyles often conflict with natural rhythms:

    • Chronic shift work (approximately 15 million people in the EU)
    • Sleep deprivation
    • Altered eating habits
    • Jet lag

Consequences of Clock Alterations

  • Clock alterations lead to:
    • Jet lag
    • Shift work-related problems
    • Social jet lag
    • Road accidents
    • Industrial accidents
    • Health problems

Shift Work and Its Effects

  • Shift work consequences:
    • Mental health issues: stress, anxiety, depression, neuroticism, reduced vigilance, burnout syndrome
    • Circadian rhythm disruptions: body temperature, respiratory rate, hormonal production, menstrual cycle, urinary excretion, cell division
    • Brain effects: sleep loss, REM sleep reduction, Stage 2 sleep reduction, fatigue, reduced brain volume
    • Cardiovascular disorders: 40% increased risk for angina pectoris, hypertension, myocardial infarction
    • Gastrointestinal disorders: dyspepsia, heartburn, abdominal pains, flatulence
    • Reproductive effects: spontaneous abortion, low birth weight, prematurity
    • Increased cancer risk: breast cancer, colorectal cancer

Types of Biological Rhythms

  • Ultradian: Period (T) less than 20 hours (e.g., seconds, minutes, hours)
  • Circadian: Period (T) between 20-28 hours (approximately daily)
  • Infradian: Period (T) greater than 28 hours
    • Circalunar: Monthly rhythms
    • Circannual: Annual/seasonal rhythms

The Mammalian Circadian System

  • Self-sustained oscillator with a period of approximately 24 hours.
  • Entrained by the environment, particularly light.
  • Drives rhythmical outputs.

The Suprachiasmatic Nucleus (SCN)

  • The master circadian pacemaker located in the hypothalamus.
  • Receives light information via the retinohypothalamic tract (RHT) from melanopsin-expressing retinal ganglion cells.
  • Sends outputs to various brain areas, including:
    • VLPO (sleep regulation)
    • SPZ, PVN, DMH, LH (wakefulness and feeding)
    • Periphery (kidney, liver, lungs)
  • Influences melatonin and corticosteroid secretion.

SCN Organization

  • Core (ventrolateral SCN): Receives input from the eyes (RHT).
  • Shell (dorsomedial SCN): Sends output to other brain areas.
  • Neuropeptides involved:
    • VIP (vasointestinal polypeptide)
    • AVP (arginine vasopressin)

The Molecular Clock

  • Clock genes (e.g., Per, Cry, Bmal1, Clock, Rev-Erbα) exhibit circadian expression within SCN neurons.
  • This generates circadian rhythms in neuronal function.
  • Per and Cry genes are transcribed and translated, then form a complex that inhibits their own transcription.
  • Bmal1 and Clock genes promote the transcription of Per and Cry genes.
  • Rev-Erbα regulates Bmal1 expression.

The Pineal Gland and Melatonin

  • The biological clock (SCN) regulates melatonin secretion from the pineal gland.
  • Light information from the retinohypothalamic tract inhibits melatonin production.
  • Melatonin is often referred to as the "hormone of sleep."

Circadian Rhythms Throughout the Body

  • Clock genes are expressed throughout the body, not just in the brain.
  • Examples include the SCN in vitro and in vivo, lung, liver and fibroblasts.
  • These rhythms synchronize physiology to environmental changes.

The Circadian Timing System

  • Synchronizes clocks across the entire body.
  • Adapts and optimizes physiology to changes in our environment.

Body Rhythms

  • Examples of body rhythms:
    • Melatonin secretion: Starts at 21:00, stops at 07:30
    • Body temperature: Lowest at 04:30, highest at 19:00
    • Blood pressure: Sharpest rise at 06:45, highest at 18:30
    • Alertness: High at 10:00
    • Coordination: Best at 14:30
    • Reaction time: Fastest at 15:30
    • Cardiovascular efficiency and muscle strength: Greatest at 17:00

Rhythms in Disease

  • Various diseases exhibit rhythms in their symptoms or exacerbations.
    • Examples include: Epileptic Seizure, Peptic Ulcer Disease, Congestive Heart Failure, Apnea, Chronic Pain, Dermatoses, Osteoarthritis.
    • Time of day influences various conditions such as: Hemorrhagic / Thrombotic Stroke, Asthma, Migraine Headache, Allergic / Infectious Rhinitis.

Chronopharmacology

  • Chronopharmacology studies how biological rhythms affect medication kinetics and dynamics.
  • Also, how the timing of medication affects biological timekeeping.
  • Time of day influences drug activity.
  • Drugs can affect the biological clock.

Cancer Chronotherapy

  • Conventional chemotherapy's concept is not applicable for chronotherapy.
  • Better survival rates are found among patients who do not experience toxicity.
  • Time of best tolerability should coincide with the best efficacy when administering cancer drugs.

Oxaliplatin

  • The first anticancer drug to undergo chronotherapeutic development (circadian vs. constant rate).
  • Constant rate: 10 times higher incidence of neutropenia and distal paraesthesias, 55% higher vomiting
  • Circadian rhythm-modulated rate: The mean dose of oxaliplatin and its maximum tolerated dose could be increased by 15%.
  • Approved for colorectal cancer.

Drugs Affecting the Biological Clock

  • Lithium is a first-line treatment for bipolar disorder.
  • Lithium affects the expression of numerous circadian genes, including activation of Clock transcription.
  • Lithium causes period lengthening and phase delay of the sleep-wake and body temperature rhythms.

Bright Light Therapy

  • Light can affect the biological clock.
  • Benefits include improved mood and enhanced sleep efficiency.
  • Can take some weeks to show benefit
  • Target conditions include: mood disorders (seasonal affective disorders, unipolar and bipolar depression, antepartum depression, and premenstrual depression), elderly, Alzheimer's Disease, jet lag, insomnia.

Sleep: Why Is It Necessary?

  • Problems associated with sleep deprivation:
    • Cognitive impairment
    • Performance impairment
    • Immune system impairment
  • Basic homeostatic need.
  • Important for learning and memory, growth and repair.

Sleep Structure

  • REM: Rapid Eye Movement (dreaming stage)
  • NREM: Non-Rapid Eye Movement
    • NREM stages 3 + 4 = Slow Wave Sleep (deep sleep)
  • Classification of sleep stages was updated in 2007 by the American Academy of Sleep Medicine. Experts now talk of four sleep stages instead of five.

Sleep Stages and Their Characteristics

  • Stage 1 (N1): NREM (light sleep), 1-7 minutes, 5% total sleep time
  • Stage 2 (N2): NREM (deeper sleep), 10-25 minutes, 45% total sleep time
  • Stage 3 (N3): NREM (deepest sleep), slow-wave sleep, delta sleep, 20-40 minutes, 25% total sleep time
  • Stage 4 (REM sleep): Dreaming, 10-60 minutes, 25% total sleep time

How Is Sleep Regulated?

  • Brain areas controlling sleep
  • The drive to sleep and the circadian clock
  • External factors that influence sleep

Brain Control of Sleep: Encephalitis Lethargica

  • Constantin von Economo studied encephalitis lethargica.
  • The epidemic affected millions of people in Europe and North America after the first World War
  • Only 1/3 patients made full recovery
  • Patients slept > 20 hours/day
  • Causing virus never identified. Last case reported in the 1920s.
  • Patients had lesions at the junction of the midbrain and the diencephalon
  • Von Economo proposed the existence of an arousal system

Brain Control of Sleep: Brain Areas

  • Brain areas involved in sleep and wakefulness:
    • SCN, SPZ, DMH: Circadian control
    • LDT, PPT, Raphe, LC: Awake
    • VLPO:Sleep
    • Lateral hypothalamic area (LHA): Awake

The "Flip-Flop Switch" Model

  • Model illustrating the interaction between sleep and wakefulness promoting areas.
  • Orexin (ORX) neurons promote wakefulness by exciting:
    • LC (Locus Coeruleus)
    • TMN (Tuberomammillary Nucleus)
    • Raphe nuclei
  • VLPO (ventrolateral preoptic area) promotes sleep by inhibiting the arousal system.

Circadian Control of Sleep: Brain regions and signals

  • SCN modulates sleep through various pathways and brain regions:
    • VLPO (Sleep)
    • PVH (Thermoregulation)
    • dSPZ (dorsal Suprachiasmatic Zone)
    • MPO (Medial Preoptic area)
    • vSPZ (ventral Suprachiasmatic Zone)
    • VMH (Ventromedial Hypothalamus)
    • ARC (Arcuate Nucleus)
    • LHA (Lateral Hypothalamic Area)
    • DMH (Dorsomedial Hypothalamus)
  • Lesions of the DMH attenuate or eliminate circadian rhythms of sleep-wake.
  • Hormones: Leptin, Ghrelin

Interaction of Sleep Drive and Circadian Alerting Signal

  • Sleep drive increases
  • Melatonin decreases
  • Core temperature decreases
  • Governs sleep and wakefulness.

External Factors Influencing Sleep

  • Light
  • Jet lag
  • Shift work
  • Pain
  • Stress
  • Medical conditions
  • Sleep environment
  • Medications
  • Other substances

Summary

  • The SCN in the hypothalamus regulates the 24-hour rhythms in physiology and behavior in animals.
  • Chronopharmacology takes into account time of day to maximize drug efficiency and minimize side effects.
  • Two systems regulate sleep and wakefulness: the homeostatic drive to sleep and the circadian drive for arousal.