aula de ciclos circadianos II

Prévia do material em texto

*
*
Sleep – continued	
Chapter 14
*
*
4 Areas of the Brain Involved in Sleep
Posterior hypothalamus - wakefulness 
Anterior hypothalamus - sleep
Reticular formation
Lesions disrupted normal sleep/wake cycle
Electrical stimulation of the RF of sleeping cats awakened them
Low levels of activity in RF – sleep
High levels of activity in RF - wakefulness
Caudal reticular formation
REM sleep
Different areas of RF are responsible for different aspects of REM 
Fig. 14.10, 14.11
*
*
*
*
The Circadian Clock: Neural & Molecular Mechanisms
Circadian sleep-wake cycles persist in the absence of cues from the environment
Internal timing mechanism – circadian clock
*
*
Location of the Circadian Clock: SCN
*
*
Location of the Circadian Clock: SCN
Richter (1967) – large medial hypothalamic lesions disrupt circadian cycles of eating, drinking, and activity in rats
Specific lesions of the suprachiasmatic nuclei (SCN) of medial hypothalamus disrupt various circadian cycles, including sleep-wake cycles
SCN display circadian cycles of electrical, metabolic, and biochemical activity that can entrained by the light-dark cycle
*
*
Confirmation that the SCN is the Location of the Circadian Clock
Ralph et al., 1990.
Removed the SCN from the fetuses of mutant hamsters that have short (20-hr) sleep-wake cycle
Transplanted the SCN into normal adult hamsters (25 hr sleep-wake cycle) whose SCN was abolished (lesioned)
Results
Transplants restored sleep-wake cycle – 20 hr
*
*
Other Circadian Timing Mechanisms in the Body
Under certain conditions, bilateral SCN lesions have been shown to leave some circadian rhythms unaffected while abolishing others
Bilateral SCN lesions do not eliminate the ability of all environmental stimuli to entrain circadian rhythms
Like SCN neurons, cells from other parts of the body display free-running circadian cycles of activity when maintained in tissue culture
*
*
Mechanism of Entrainment
How does the 24-hr light-dark cycle entrain the sleep-wake cycle?
Eye 
Cutting the optic nerves before the optic chiasm
Eliminated the ability of the light-dark cycle to entrain circadian rhythms
Cutting the optic tracts (after optic chiasm)
No effect
Conclusion
Visual axons critical for the entrainment of circadian rhythms branch off from the optic nerve near optic chiasm
*
*
Mechanisms of Entrainment
Retinohypothalamic tracts – leave optic chiasm and project to SCN
Retinohypothalamic tracts mediate the ability of light to entrain photoreceptors
Retinal ganglion cells
Photopigment - melanopsin
*
*
Genetics of Circadian Rhythms
Tau – 1st circadian mammalian gene identified
Clock – circadian mammalian gene
*
*
Genetics of Circadian Rhythms
Same or similar circadian genes have been found in many species
Key mechanism – transcription of proteins by the circadian genes
In some SCN cells, expression of clock genes is on a circadian cycle
In some SCN cells, expression is triggered by exposure to light
Molecular circadian timing mechanisms exist in most cells of the body
Normally entrained by neural and hormonal signals from SCN
*
*
Drugs that Affect Sleep
Hypnotic drugs – increase sleep
Antihypnotic drugs – reduce sleep
Melatonin – influences circadian rhythms
*
*
Hypnotic Drugs
Benzodiazepines (Valium and Librium)
Anxiolytics
Most commonly prescribed hypnotic medication
Short-term
Increase drowsiness
Decrease the time it takes to fall asleep
Reduce the number of awakenings
Increase total sleep time
*
*
Negative Consequences of Benzodiazepines
Tolerance develops
Cessation causes insomnia
Addictive
Distort normal pattern of sleep
Increase the duration of sleep by increasing the duration of stage 2 sleep, while decreasing the duration of stage 4 and REM
*
*
Alternative Anxiolytics as Sleep Aids
Raphe nuclei – plays a role in sleep (5-HT)
5-HTP – precursor of 5-HT
Passes the BBB
Injections of 5-HTP do reverse the insomnia produced in both cats and rats by the 5-HT antagonist PCPA
No therapeutic benefit in the treatment of human insomnia
*
*
Antihypnotic Drugs
2 classes
Stimulants (cocaine and amphetamine)
Tricyclic antidepressants
Increase the activity of catecholamines (NE, E, DA) by increasing release, blocking reuptake, or both
Act preferentially on REM sleep
Totally suppress REM even at doses that have little total effect on total sleep time
Dangerous to treat chronic sleepiness
Addictive
Adverse side effects – loss of appetite
*
*
Melatonin
Hormone synthesized from 5-HT in the pineal gland
Fish, birds, reptiles, amphibians – pineal gland has timing properties & regulates circadian rhythms and seasonal changes in reproductive behavior through its release of melatonin
Mammals (including humans) ???
Circulating levels of melatonin display circadian rhythms under control of SCN
Highest levels – darkness (sleep)
Melatonin – promoting sleep
*
*
Melatonin
Pinealectomy (loss of melatonin) – little effect
Pineal gland – plays a role in mammalian sexual maturity
Function after puberty is not known
*
*
Does Exogenous Melatonin Improve Sleep?
Meta-analysis of 17 studies indicated that exogenous melatonin has a slight, but significant, sleep-promoting effect
Shift the timing of mammalian circadian cycles (chronobiotic)
Melatonin – sleep disorders
Insomniacs who are melatonin-deficient
Blind people who have sleep problems due to the lack of the synchronizing effects of the light-dark cycle
*
*
Sleep Disorders
Insomnia
Hypersomnia
REM-Sleep-Related Disorders
*
*
Insomnia
Major cause
Iatrogenic (physician created) – due to sleeping pills
Insomnia – not necessarily a problem of too little sleep; often a problem of too little undisturbed sleep
*
*
Sleep Restriction Therapy – 
Effective Treatment for Insomnia
The amount of time that an insomnia is allowed to spend in bed is substantially reduced
After a period of sleep restriction, the amount of time spent in bed is gradually increased in small increments
As long as sleep latency remains normal
*
*
Medical Causes of Insomnia
Sleep apnea
Periodic limb movement disorder
Restless legs syndrome
*
*
Sleep Apnea
Patient stops breathing many times each nigh
Each time, the patient awakens, begins to breathe again, and drift back to sleep
Sense of poor sleep – often diagnosed as insomnia/hypersomnia
 
*
*
Sleep Apnea
2 types
Obstructive sleep apnea
Obstruction of the respiratory passages by muscle spasms or atonia (lack of muscle tone)
Central sleep apnea
Failure of the CNS to stimulate respiration
More common
Males
Overweight people
Elderly
*
*
Medical Causes of Insomnia
Periodic limb movement disorder
Periodic, involuntary movements of the limbs,
Twitches of legs during sleep
Often unaware
Restless legs syndrome	
Complain of hard-to-describe tension or uneasiness in legs that prevents sleeping 
Treatment - DA agonists 
*
*
Hypersomnia
Narcolepsy
1in 2000 individuals
*
*
Narcolepsy
Symptoms
*
*
*
*
Cause of Narcolepsy
Narcolepsy with cataplexy appears to be caused by a lack of peptide neurotransmitters – OREXINS
Cell bodies of orexin neurons are located in the hypothalamus and have widespread projections. 
One study found that the brains of narcoleptics contained almost no orexin
*
*
Treatment of Narcolepsy
Stimulants (amphetamine)
Addiction 
Bad side effects 
Modafil (newly available stimulant) acts more specifically to reduce sleepines
*
*
REM Sleep Behavior Disorder
Rare, almost opposite of cataplexy
Some people with this disorder “act out their dreams”
If dreams are active, or violent - dangerous
Caused by lack of inhibition of motor neurons that normally occurs during REM sleep
Nucleus magnocellularis – structure of the caudalRF that controls muscle tone during REM sleep
*
*
Long-term Reduction in Sleep
Increased sleepiness
No effects on mood, medical, or performance
indicating that circadian genes evolved early and are conserved
*
*
*