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.