Alex Bäcker, alex@caltech.edu
Bi 150 Sleep Lecture
Why stay awake? i.e. Why care about sleep?
It is one of the greatest standing mysteries of life: We spend 1/3rd of our life sleeping and still don’t know what for.
People who cannot sleep die.
Sleep is a window on conscious & unconscious states of the brain.
We might be able to learn how to make sleep productive, what the minimum amount of sleep is, etc.
Overview
What is sleep?
What is sleep? Sleep stages.
Sensory unresponsiveness during sleep
Electrophysiology in sleeping birds shows the brain ‘is still on’!
Methods in Sleep Research
Experimental methods in sleep research.
Sleep Deprivation
What happens when animals are sleep-deprived? What about humans?
Unihemispheric Sleep
Dolphins and birds unihemispheric sleep: Sleep is required by the brain even when there's no behavioral rest.
Thermoregulation, Hibernation and Sleep
Sleep and Memory
Relationship between sleep and memory. Rat & bird physiology and human psychophysics experiments.
Sleep & Development
Evolution of Sleep
Sleep Disorders
Human & canine narcolepsy. Video.
What is sleep?
Sleep reduces responsiveness to sensory stimulation
The thalamus, sensory gate to the cortex, seem to be overall de-activated during SWS sleep (brain imaging study).
But higher association areas in the bird forebrain respond to bird's own song during sleep! (Dave & Margoliash ’98 & ‘00, Nick & Konishi ‘00).
Sleep reduces motor output
Sleep deprivation leads to sleep recovery (homeostasis)
What's the substance accumulated during wakefulness?
Adenosine is one.
Porkka-Heiskanen et al. (1997)
Mammalian sleep has distinct stages, distinguished by EEG
REM sleep is associated with dreams
Hallucinations
Delusion
Amnesia
- Passage of time in dreams is not compressed:
- # words describing dream correlates with amount of time in REM
- Subjects woken up 5 or 15 mins after REM onset chose short or long dream correctly in 83% of cases. Suggests dreams are often longer than 5 minutes and dream memory persists more than 5 minutes (Dement).
- Dream imagery is not only visual:
- Congenitally blind have auditory dreams.
- Acquired blind gradually lose their ability to dream visually.
- REM sleep deprivation has no effect on the level of sleepiness/alertness as measured by the Mean Sleep Latency Test.
Why do we sleep?
Why did sleep and its different features evolve?
Why is it currently necessary for survival?
Or
- What vital functions happen during sleep?
- Do they need to happen during rest & sensory isolation? Why?
Saying sleep serves to rest is meaningless, it just postpones the question to "Why do we die if we do not rest?". Besides, sleep is an active process.
Methods in Sleep Research
How can we figure out what sleep is for?
Sleep deprivation.
Sleep disorders.
Physiology: electrophysiology, imaging.
Phylogeny: Evolution.
Ontogeny: Development.
Variability in sleep patterns within a population.
Now also fly genetics (Tononi et al, 2000),
- Molecular biology & knock-out technology
(e.g. Siegel, J. (1999). "Narcolepsy: A key role for hypocretins (orexins)." Cell 98(4): 409-412).
Facts to be explained by a theory of sleep:
Sleep is an active process
- Moruzzi & Magan
- Kleitman & Dement
Sleep is necessary:
- Rats die after ~17 days of total sleep deprivation (TSD, Rechtschafffen experiments).
- Main symptoms are temperature drop & skin lesions.
Keeping warm does not ameliorate sleep deprivation symptoms in rats (Shaw & Rechtschaffen, 1997):
- Rats who can regulate ambient temperature upregulate it to 9 deg C above baseline during total sleep deprivation (TSD).
- True even while brain temp. was above baseline.
- Demonstrates TSD induces an elevation in temp. set point.
- Nonetheless, rats lose temperature and die.
- Surprisingly, survival time was shorter than in previous studies.
REM sleep deprivation in rats leads to death after about 37 days, with symptoms similar to TSD (Kushida et al, 1989).
Fatal familial insomnia
A 53-year old industrial manager consulted the clinician Elio Lugaresi about his increasing difficulty in falling asleep. A few months later, insomnia was almost total and dreamlike episodes were intermixed in the waking period. He died nine months after the onset of the symptoms. His father and two sisters died in the same manner! (Luagersi E. et al, 1998).
Sleep is universal, by the brain and for the brain:
- All mammals and birds sleep. Insects appear to sleep too, as demonstrated by rest homeostasis, decreased responsiveness, pharmacology & brain gene expression patterns (Shaw, … & Tononi '00, Heindricks et al '00). Bees show circadian periodicity in locomotor activity with a period slightly less than 24 hs. in the dark.
- Sleeping & dreaming animals show characteristic brain activity.
- Dolphins and other marine mammals, as well as migrating birds, show EEG sleep signs with one hemisphere at a time (Geier).
Unihemispheric Sleep: Even animals who cannot afford to rest sleep
Marine mammals
- Dolphins must emerge at surface to breathe, and must therefore move permanently.
- Drug-induced BSWS causes breathing halt.
Fig. 7.1 Horne 1988 &/or Fig. 1 Mukhametov 1987.
Blind indus dolphin sleeps 7 hs a day in bouts of several seconds (Pilleri, in Horne 1988).
Asymmetrical sleep predominated in Amazonian dolphin (49% of day out of 57% of day taken by total sleep) (Mukhametov, 1987).
Behaviorally indistinguishable from symmetrical sleep. No behavioral asymmetry noted in mammals (but see birds).
Sleep deprivation of one hemisphere leads to compensation during recovery of that hemisphere only (Supin et al, 1978; Oleksenko et al, 1992).
One report observed USWS in whales too (Serafetinides et al, 1972).
Dolphins have complete optical decussations and poorly developed corpus callosum (cc). Is this the unihemispheric sleep enabler?
- Unihemispheric sleep occurs in birds with binocular vision.
- Unihemispheric sleep is also observed in regions below the hemispheres (e.g. the thalamus).
- Opposum and other mammals with poorly developed cc have no unihemispheric sleep.
- Mammals with severed cc carry on with bihemispheric sleep.
- Some seals show USWS; others do not. Seals show prolonged (15-30 mins) breath holding during sleep.
Birds
- 17% of sleep in the glaucous winged gull is USWS (Amlaner et al, in Horne 1988).
- Unihemispheric sleep in ducks is accompanied by asynchronous contralateral eye closure (Rattenborg et al, 1999).
- Perhaps used in transoceanic flights, although this remains untested (Rattenborg, personal communication).
Is sleep for temperature regulation?
All mammals and birds are homeothermic.
When devoid of a light-dark cycle, they sleep every ~25 hs or so and do it in good agreement with a body temperature cycle.
One of the first thing to change after ~1 week of sleep deprivation in rats is an increase in food consumption and a drop in body temperature even as the rats attempt to keep themselves warmer. In humans, one of the first thing to happen, even after a single night of sleep deprivation, is a subjective feeling of cold.
During dream sleep, there is no thermal regulation.
Most animals sleep at night, but not all of them do.
But if sleep is for thermoregulation…
- Why do insects sleep?
- Why do sleep-deprived rats kept above normal temperature die?
- Why would heating require sleep?
Conclusion
: Although temperature and sleep seem closely linked, this may be just due to a necessity of higher temperatures for activity and that of having sleep occur during inactivity. It appears improbable that the noxious effects of sleep deprivation are due to increased energy expenditure or even to temperature changes.
Sleep for energy conservation?
- Smallest animals have the highest metabolic rate (i.e. energy consumption per kg body weight): small shrew eats its body weight each day, elephant eats 1/20th of its own. Thus, small animals are place to look for energy savings from sleep.
Fig. 7.3 Horne '88.
Taylor et al, Duke (1970): Oxygen consumption increases linearly with running speed within each species analyzed, from mouse to dog. Thus, immobility does save energy. Fig. 7.4 Horne 1988
Pearson, Harvard (1947): Oxygen consumption of mice decreases by over 50% by huddling. Fig. 7.5 Horne 1988
Small mammals cannot show useful amounts of relaxed wakefulness. They spend most of their awake life moving. Perhaps sleep is the easiest way to immobilize them; in any case it seems to be the only way they have. Active sleep may be necessary to avoid long periods of no brain stimulation.
In cows and sheep, 10% and 13%, respectively, decrease in oxygen consumption from relaxed wakefulness to sleep. 9-12% in humans at thermoneutrality excluding the change due to circadian rhythm (Fraser et al., 1989).
But exposed to Tamb of 21 deg C, the metabolic rate (MR) of naked white humans decreased by as much as 40% after sleep onset (Palca, Walker & Berger, 1986). Australian aborigines slept naked at temp. near freezing, and displayed MR decline (Hammel, … & Milan, 1959).
Small birds downregulate temperature during sleep more when fasted (Heller et al, 1989; Reinertsen et al, 1986; Berger et al, 1991), so sleep might be most useful w.r.t. energy savings when food supply is low. Fig. 3 Berger 1995
But…
- Exercise per se does not increase or change subsequent sleep (Horne et al).
Hibernation & Sleep: A Historical Aside
- Ground squirrels show increased SWS after long hibernation bouts in cold ambients (-5 to 0 deg C) as compared with short ones (Trachsel, Edgar & Heller, 1991,
Figs. 3 & 4; Canguilhem & Boissin, 1996, Figs. 4 & 5), saturating after ~ 6 days.
The same increase in SWS is true for sleep EEG after daily torpor in hamster (Deboer & Tobler, 1994).
Electrophysiology of hibernating animals at 14-36 deg C shows alternation of NREM & wake-like states (Heller et al, 1988).
But…
- Ground squirrels do not show increased SWS after hibernation in warmer ambients (Larkin & Heller, 1996; Strijkstra & Daan, 1997).
- Sleep-deprivation of animals just aroused from hibernation eliminates recovery sleep (Larkin & Heller, 1999). 3 papers on sleep & hibernation ‘81-’90, 53 ‘91-00.
Dreaming to develop:
Infants sleep much more than adults, mostly dream sleep. The fetus seems to spend all or most of its time in dream sleep.
Birds, independently evolved from mammals, essentially only have dream sleep during early life.
Young flies also sleep more (Shaw, … & Tononi '00).
In babies and children, as well as in napping adults, dream sleep occurs at sleep onset.
Sleeping to learn?
Some skills improve abruptly while we sleep (Karni & Sagi '94).
Some neurons replay events of wake state during sleep (Wilson & McNaughton '94, Skaggs & McNaughton '96, Dave & Margoliash '00).
But why do we need to sleep for the improvement to happen?
Sleep & Emotion
64% of dreams are unpleasant; 18% were happy or exciting.
- Penile erections accompany virtually every REM period, regardless of dream content.
- The amygdala (involved in processing of emotion) is activated in humans during sleep (fMRI).
Evolution of Sleep
Circadian rhythms are ubiquitous in the animal kingdom, and are a cellular property –i.e. neurons in a dish can act as clocks. The genes responsible for this cyclic behavior have begun to be identified.
Insects show sleep-like rest too (Bee: Kaier & Steiner-Kaiser ’83; fly: Hendricks et al, 2000; Shaw et al, 2000).
Echidna and platypus are the only living monotreme species, a primitive branching of mammals.
Echidna sleep, first thought to show no REM (Allison et al, 1972), shares characteristics of REM & non-REM: brainstem activation and high amplitude EEG (Siegel et al, 1998).
The Chemistry of Sleep
Melatonin
Melatonin has gained considerable attention recently as sleep-inducing pills. It is widely used to combat the effects of jet-lag. It is a natural hormone produced by the pineal gland (top of the midbrain, between the superior colliculi). It only affects the latency to sleep and not the sleep structure. It seems to have a powerful hypnotic effect on birds as well as humans.
Adenosine & Cis 9,10 -octadecenoamide, a long fatty-acid amide
Induce sleep in rats, increase during wakefulness and slowly decrease during sleep.
The Sleep Research Guide for Sleep-deprived Techers
Brief naps during post-lunch rest: effects on alertness, performance, and autonomic balance.
TAKAHASHI M, FUKUDA H, ARITO H.
National Institute of Industrial Health, Kawasaki, Japan
…groups taking one of three 'lengths of nap (0, 15, and 45 min) after lunch. Subjective sleepiness was lower after both naps than after no nap. The task performance was significantly better during the second half of the last task session after the 15-min nap than after no nap. Mean total sleep times during the 15- and 45-min naps were 7.3 and 30.1 min, respectively.
Sleep at least 3 hours every night, at least 5 hours on average
Duration of SWS increases linearly with prior wakefulness. Figs. 5.1 & 5.2 Horne 1988
- Slope increases after one waking day (16 hours).
- Time of day has little influence on SWS.
- Minimum sleep for normal performance in a detection task after 1 night of reduced sleep is 3 hs. (Wilkinson). There is little REM during first 3 hours of sleep. Fig. 2.5 Horne 1988
- Minimum sleep for normal performance in a detection task after several nights of reduced sleep is 5 hs. (Wilkinson).
A warm bath induces 25-33% increase in SWS
(Horne et al, 1983, 1985).
- Increased metabolic rate may cause an increase in adenosine production, which in turn causes sleep (Brundegge et al, 1996; Porkka-Heiskanen et al, 1997).
References
Canguilhem & Boissin (1996): Are the animals in deep hibernation awake?
Daan et al (1991): Warming up for sleep? - ground squirrels sleep during arousal from hibernation.
Dave & Margoliash (1998). Science 282: 2250.
Dave & Margoliash (2000): Song replay during sleep and computational rules for sensorimotor vocal learning. Science 290: 812-816.
Dawson, D. & Reid, K. 97 Fatigue, alcohol and performance impairment. Nature 388, 235-235.
Deboer & Tobler (1994): Sleep EEG after daily torpor in the Djungarian hamster: similarity to the effects of sleep deprivation.
Everson, C. A. 95 Functional Consequences of sustained sleep deprivation in the rat. Behavioural Brain Research 69, 43-54.
Hobson, J. A. 88 The dreaming brain. New York: Basic Books, Inc. Publishers.
Hofle, N., Paus, T., Reutens, D., Fiset, P., Gotman, J., Evans, A. C. & Jones, B. E. 97 Regional cerebral blood flow changes as a function of delta and spindle activity during slow wave sleep in humans. Journal of Neuroscience 17, 4800-4808.
Horne & Moore (1985): Sleep EEG effects of exercise with and without additional body cooling.
Horne & Reid (1985): Night-time sleep EEG changes following body heating in a warm bath.
Horne & Staff (1983): Exercise and sleep: Body-heating effects
Horne, J. 88 Why we sleep: Oxford University Press.
Kandel, Schwartz & Jessel (1991): Principles of Neural Science, 3rd edition.
Karni, A., Tanne, D., Rubenstein, B. S., Askenasy, J. J. M. & Sagi, D. 94 Dependence on REM sleep of overnight improvement of a perceptual skill. Science 265, 679-681.
Kilduff, T. S. & Wang, L. C. H. 93 Sleep and Mammalian hibernation: Homologous adaptations and homologous processes ? Sleep 16, 372-386.
KRILOWICZ BL; GLOTZBACH SF; HELLER HC (1988): NEURONAL-ACTIVITY DURING SLEEP AND COMPLETE BOUTS OF HIBERNATION
Kushida, Bargmann and Rechtschaffen (1989): Sleep deprivation in the rat. IV. Paradoxical sleep deprivation. Sleep 12, 22.
Larkin & Heller (1996): Temperature sensitivity of sleep homeostasis during hibernation in the golden-mantled ground squirrel.
Larkin & Heller (1999): Sleep after arousal from hibernation is not homeostatically regulated. Am. J. Physiol 276:R522-R529.
LAZAREV SG (1981): SLEEP-DEPRIVATION IN THE REPTILE TESTUDO-HORSFIELDI - THE COMPARATIVE-PHYSIOLOGICAL ASPECT. DOKLADY AKADEMII NAUK SSSR 261: (6) 1492-1495.
Macquet, P. & Franck, G. 96 Functional neuroanatomy of human rapid eye movement sleep and dreaming. Nature 383, 163-166.
McCormick, D. A. & Bal, T. 97 Sleep and arousal: thalamocortical mechanisms. Annual review of neuroscience 20, 185-215.
Mechoulam, R., Fride, E., Hanus, L., Sheskin, T., Bisogno, T., Di Marzo, V., Bayewitch, M. & Vogel, Z. 97 Anandamide may mediate sleep induction. Nature 389, 25-27.
Miller & South (1981): Entry into hibernation in M. Flaviventris: Sleep & Behavioral Thermoregulation.
Mukhametov (1987): Unihemispheric slow-wave sleep in the Amazonian dolphin, Inia geoffrensis. Neurosci Lett 79, 128.
Mukhametov, L. M. 84 Sleep in Marine Mammals. Experimental Brain Research Suppl. 8, 227-237.
Mukhametov, L. M. 87 Unihemispheric slow-wave sleep in the Amazonian dolphin, Inia geoffrensis. Neuroscience Letters 79, 128-132.
Nick & Konishi (2000): Submitted.
Obal et al (1995): Promotion of sleep by heat in young rats.
Oleksenko, Mukhametov et al (1992). Sleep Research 1, 40.
Porkka-Heiskanen et al. (1997): Adenosine: A Mediator of the Sleep-Inducing Effects of Prolonged Wakefulness.
Rechtschaffen, A., Gilliland, M. A., Bergmann, B. M. & Winter, J. B. 83 Physiological correlates of prolonged sleep deprivation effects in rats. Science 221, 182-184.
Serafetinides et al (1972): Int'l Journal of Psychobiol. 2, 129.
Shaw, Bergmann and Rechtschaffen (1997): Operant control of ambient-temperature during sleep-deprivation.
Siegel et al (1998): Monotremes and the evolution of rapid eye movement sleep. Phil. Trans. Roy. Soc. B 353, 1147.
Skaggs, W. E. & McNaughton, B. L. 96 Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience. Science 271, 1870-1873.
Steriade, M., McCormick, D. A. & Sejnowski, T. J. 93 Thalamocortical oscillations in the sleeping and aroused brain. Science 262, 679-685.
Strijkstra & Daan (1996): Sleep during arousal episodes as a function of prior torpor duration in hibernating European ground squirrels.
Strijkstra & Daan (1997): Ambient temperature during torpor affects NREM sleep EEG during arousal episodes in hibernating European ground squirrels.
Supin … & Mukhametov (1978): Electrophysiological study of dolphins brain.
TRACHSEL L; EDGAR DM; HELLER HC (1991): ARE GROUND-SQUIRRELS SLEEP-DEPRIVED DURING HIBERNATION?
Walker, … & Berger (1983): Cessation of thermoregulation during REM sleep in the pocket mouse.
Wilson, M. A. & McNaughton, B. L. 93 Dynamics of the Hippocampal Ensemble Code for Space. Science 261, 1055-1058.
Wilson, M. A. & McNaughton, B. L. 94 Reactivation of Hippocampal Ensemble Memories During Sleep. Science 265, 676-679.