Sleep and rhythms

• BIOLOGICAL RHYTHMS

  • organisms on earth have adapted to the 24 hour changes in their environement by developing biological rhythm
  • biological clocks generate biological rhythms 
  • most organisms on earth have biological rhythms 
  • clocks are important because the impact of the clock --> component genes is wide-spread
• PHYSIOLOGICAL CLOCKS:

  1. sleep/wake
  2. body temp
  3. cardiac output
  4. memory
  5. energy metabolism
  6. eating behaviour
  7. immune response
  8. detoxification
• CELLULAR CLOCKS:

  1. cell cycle progression
  2. dna damage repair
  3. cellular energy metabolism
  4. cell detoxification
  5. neuronal excitability 
• LINK BETWWEN RHYTHMS AND DISEASE:

  • affective disordesr (bipolar, depression)
  • sleep disorders
  • neurodegenerative disease (alzheimer)
  • obesity/metabolic syndrome
  • inflammation (asthma, copd)
  • cancer
• MODER LIFESTYLE OFTER OPPOSE THEIR NATURAL RHYTHM

  • chronic shift work 
  • sleep deprivation
  • altered eating habit 
  • jet lag 
• WHEN CLOCKS GO WRONG:

  • social jet lag --> where out bodys situation is not quiet aligned with our environment

  1. tend to wake up earlier than what we would do for weekdays 
  2. the bigger the misalignment  the worse the health problems
  3. shift work --> high risk of car accidents + industrial accidents 
• MECHANISMS OF RHYTHMS- classification

  • daily == circadian (20-28h)

  1. sleep wake rhythms 

  • several times over the day == ultradian (<20h)

  1. heart beat

  • period longer than 28h == infradian 

  1. periods
  2. migration of birds
  3. hibernation of bears
• CIRDAIAN RHYTHM MECHANISM

  • sel-sustained oscillator  generate maintain rhtym indefinetyly
  • runs 24 hours --> circadian
  • entrained/synchronized by environment (light)
  • driving rhythmical outputs 
  • suprachiasmatic nucleus --> scn

  1. principle biological pacemaker is located in the scn
  2. in hypothalamus 
  3. directly connected to the eyes 
  4. light is detected in photoreceptors in the back of the eyes --> carried to the scn
  5. pair of nuclei situated side by side
  6. 10000 nuerons each
• CIRDAIAN RHYTHM MECHANISM cont.

  8. info coming from the hypothalamic track reaches the base of the scn (core scn) --> process info and adjust circadian rhythm accordinyl --> send information to the shell scn --> send projections to other parts of the brain 

  9. core --> uses vasointestinal polypeptide (vip) and receives input from the eys (rht)

  10. ventrolateral scn

  11. shell -> arginine vasopressin (avp) and sends output to other brain areas

  11. dorsomedial scn
• MOLECULAR CLOCK

  • bunch of clock genes that are expressed in a rhythmic fashion
  • generates circadian rhythms in enruonal function 
• PINEAL GLAND AND MELATONIN

  • melatonin is secreted by pineal gland 
  • indirectly connected to scn
  • melatonini --> hormone of sleep

  1. secreted at night 
  2. prescribed in elderly or people with issues with sleep
• CLOCK GENES ARE FOUND THROUGHOUT THE BODY

  • circadian rhything found throughout the body
  • allows us to adapt and optimize physiology to changes in our environment
  • scn --> master pacemaker --> synchronize all the clocks in the body
• CHRONOPHARMACOLOGY

  • study of the manner and extent to which the kinetics and dynamic of medication afre affected by endogenous biological rhythm + how dosing time of medication affect biological timekeeping and features (period, amplitude) of biological rhythm
  • time of day affects the drug + how drugs affect the biological clock
• CANCER CHRONOTHERAPY

  • conventional chemotherapy considers that the wrose the toxcitiy ecperienced by the patient  better the overall survival

  1. wrong for chronotherapy --> survival rates were higher in patients who don’t experience toxcity

  • most anti-cancer drugs are tolerated best at the same time it is most efficient 
  • oxaliplatin

  1. first anticancer drug to undergo chronotherapeutic development (circadian vs constant rate)
  2. constant rate --> 10x higher incidence of neutropenia
  3. mean dose of drug + max tolerated dose could be increased by 15% if given in a criadian rhythm modulated rate 
• DRUG AFFECTING THE BIOLOGICAL CLOCK

  • lithium --> first line treatment for bipolar disorders
  • affects the expression fo numerous circadian genes --> including activation of clock transcription
  • lithium causes period lengthing and pahse delay of the sleep-wake and body temperature rhythms 
  • light therapy:

  1. used for mood disorders (seasonal affective disorders, unipolar and bipolar depression, antepartum depression, premenstrual depression)
  2. also used for elderly, jet lag, insomnia
  3. benefits --> imporves mood and enhance sleep efficiency
  4. takes a few weeks to show benefits 
• SLEEP

  • basic homestatic need
  • important for learning and memory, growth and repair 
  • problem associated with sleep deprivation

  1. cognitive impairment
  2. performance impairment
  3. immune system impairment 

  • sleep has been classified into different stages

  1. rem --> rapid eye movement (dreaming stage)
  2. nrem -->non-raid eye movement (3+4 == deep sleep)(70-90 mins)(~5 per night)

  
• REGULATION OF SLEEP

  • controlled by the brain

  1. encephalitis lethargica --> affected millions of people in north america and europe
  2. patients slept for over 20h a day
  3. virus never identified --> it had disapperead 
  4. patients had lesions at the junction of the midbrain and the diencephalon --> economo found this out 
  5. ascending arousal system that kept the brain awake
  6. scn, spz and dmh controlled circadian rhthms 
  7. vlpo in the brain hypothalamus controlled sleep
  8. ldt, ppt, raphe, lc (pons) controlled us being awake
  9. lateral hypothalamic area (lha) in the hypothalamus controlled us being awake

  
• REGULATION OF SLEEP- flip-flop switch model

  • when we are awake --> alerting areas of the brains are most active + inhibit activity responsible for sleep --> stable wakefulness
  • when sleep promoting areas of the brain are most active --> inhibit activity in areas of the brain responsible for promoting wakefulness --> stable sleep
• CIRCADIAN CONTROL OF SLEEP

  • scn project to the dspz + vspz --> projects to the mpo which controls body temperature 
  • scn projects to the dmh  projects to vlpo 

  
• SLEEP DRIVE

  • interaction between the homeostatic drive to sleep and the circadian altering signal governs sleep and wakefulness
  • when body temp falls  we shiver 
  • if we remain awake  structures in the brain promotes sleep
  • melatonin increase and decrease in core temperature  signal for us to wake up 
• EXTERNAL FACTORS THAT INFLUENCE SLEEP

  • LIGHT

  1. making it difficult for people to sleep
  2. influencing the timing of our internal clock and influencing when we wiuld like to sleep

  • JET-LAG/ SHIFT WORK

  1. moving across the timezone or work late shifts
  2. insomnia or excessive sleep when they should be asleep

  • PAINS/ STRESS/ MEDICAL CONDITIONS

  1. limit depth of sleep 
  2. more rem sleep than deep sleep
  3. because our body responds to stressful or painful situations 
• EXTERNAL FACTORS THAT INFLUENCE SLEEP

  • MEDICATIONS AND OTHER SUBSTANCE

  1. caffeine activates waking areas of the brain
  2. alcohol acts as a sleep aid  quality is compromised + worsen symptoms of sleep apnea
  3. antidepressant decrease duration of rem sleep

  • SLEEP ENVIRONMENT

  1. can influence quality and quantity
  2. light/ noise and temp
• NARCOLEPSY

  • sleep disorder
  • sufferes suffer from profound daytime sleepiness
  • causes them to fall asleep at inappropriate moments 
  • caused by disriptions to the brains orexin pathway --> influence the flip-flop model of sleep/wake states

  1. orexin --> neuropeptide produced by small number of neurons in the hypothalamus and acts on a gcpr (hctr2) in target tissues 

  • can occur in dogs

  1. results in premature stop codon in the hcrtr2 receptors --> makes it non-functional