Slide 1

The cholinergic system

Topicsdefinition and phenomenology of sleepinvertebratesvertebrates (humans)

regulation of sleepcircadianhomeostatic humoral regulation the function of sleepluxury sleep neuronal regulation3/30Definition of sleeprest-activity NOT= sleep-wakefulness

general criteria of sleeplack of movementselevated sensory thresholdfull reversibilitystereotypic posturespecific resting placecircadian organizationhomeostatic regulation: deprivation rebound

mammals (and birds) - polygraphic criteria4/30Sleep in invertebratessleeping cockroach

sleeping scorpion5/30Stages in human sleepBerger 1929: arousal level is related to EEG patterns: , , , , later Loomis 1937: 5 stages of the sleep-wakefulness 1 W and 4 SWSAserinsky and Kleitman 1953: discovery of paradoxical sleep related to dreamingRechtschaffen-Kales criteriaLA1: 2-7 Hz, slow eye movements, 50%REM: cortical activation, lack of muscle tone, rapid eye movements, PGO spikes 6/30

7/30EEG waves

Steriade, M., et al., J. Neurophysiol. 85 (2001): 1969-1985Slow cortical rhythm8/30Physiological variables in sleep

9/30Polygraphic sleep stages

in animals only light and deep NREM sleep and REM sleep are usually distinguished10/30Sleep stages in rats

11/30REM sleep in cats

12/03

REM sleep in humans13/30

Sleep and age

14/30Diurnal and polycyclic sleep

15/30Humoral regulation of sleepclosely related to homeostatic regulationsomething is being accumulated or used upsleep can be easily disturbed, but difficult to induce, appropriate control is a main issue

two approaches: harmful effects of sleep deprivationstress is difficult to eliminatemotivation to sleep is almost as strong as motivation to avoid pain - tortureisolation of sleep factorsfollowing sleep deprivationduring natural or experimentally evoked sleeptesting prospective signal molecules normally present in our body16/30Sleep deprivation

NREM deprivation: set-point of thermo-regulation increasesREM deprivation: heat dissipation increasesenergy homeostasis becomes disturbed17/30Sleep factorsIshimori, Pieron, ~1910: dogs kept awake by forced walking for 10 days successful sleep transfermethodological problems repeated with positive results in goat-rat experimentsdeprivation is not needed for the effect collection of human urineend result: muramyl peptideUchinozo extractions from the brainstem of sleep deprived rats - uridine, oxidized glutathione (glu-cys-gly)Monnier sleep induced by thalamic stimulation in rabbits: DSIP (9 aa-s)these are not natural sleep factorsnatural signal molecules: GHRH, adenosine, interleukin-1, TNF, PGD218/30Transfer of natural sleepparabiotic animals: Matsumoto, 1972 higher synchronity of NREM and REM sleep than between animals joined by their skin onlyde Andres, 1976 transplantation of an additional head to dogs independent sleep, 108 h survivalSiamese twins independent sleep is possible, but contradicting results existMukhametov, 1985-87 sleep in dolphins the two hemispheres can sleep separatelydescribed in other animals as well: birds, whale, etc. complete decussation of the visual pathway is a prerequisite19/30Unihemispheric sleep in dolphins

20/30Two process theory of sleep

21/30Synthesis

22/30Neuronal regulation of sleepancient theories about sleep (Mesopotamia)neuronal and humoral theoriesactive hypothesis basal state: wakefulnessPavlov: irradiation of inhibitionvon Economo: encephalitis plaguepassive hypothesis basal state: sleepclassical transsections of Bremer, 30s Moruzzi and Magoun, 1959Shute and Lewis, 1967sleep centerscriteria: lesion, stimulation, correlated activitymidpontine pretrigeminal transsectiontractus solitarius Dell, 1963raphe Jouvet, 1967thalamus Andersen and Anderson, 1968basal forebrain von Economo, 20s23/30

Arousing areas

midline and intralaminar nuclei (glu)midbrain and pontine nuclei(NA, ACh, glu, 5-HT, DA)posterior-lateral hypothalamus(HA, ORX)magnocellular BF sytem(ACh, GABA, ?)24/30Ascending activating systems

25/30Thalamo-cortical connections

26/30Functional states of thalamus

27/30Role of the basal forebrainvon Economo: BF-POA promotes sleep, posterior HT promotes wakefulnessSterman and Clemente 1962- lesion causes decreased or fragmented sleepstimulation sleep (also at high frequency!)conditioned response to soundswarming, ACh crystals sleeplate 70s, early 80s description of the cholinergic system cholinergic cells disappear or shrink in Alzheimers diseaseelectrical excitotxic selective lesioncorticopetal projection is not exclusively cholinergicSCN, thermoregulation, proximity of HT, VLPO, prefrontal cortex high importance28/30

Unilateral lesion of BF I.

Vanderwolf, C.H., Int. Rev. Neurobiol., 30 (1988): 225-34029/30

scopolaminescopolamineno drugno drugbefore lesionafter R. NB lesionmodified from Buzski et al., J.Neurosci 8 (1988): 4007-4026Unilateral lesion of BF II.30/30

Berger - 192933br voltak korbi prblkozsok llatok feltrt agykrgn (Richard Caton, 1875, Liverpool, majom s nyl, tle fggetlenl Adolf Beck, 1891, Krakow, majd Lvov, nyl s kutya lertk a ritmikus oszcillcikat, az ingerek hatst, s a ritmusok fggst az llat llapottl), az els, aki emberi EEG-t regisztrlt a hajas fejbrrl, s lerta annak kapcsolatt az bersgi szinttel, Hans Berger volt Jenaban.az els regisztrls sajt fin 1925-ben a Siemens igen modern berendezseivel1929 s 1938 kztt 23 cikk (mr akkor is fontos volt a publikcis lista)

Sleep stages

namefrequencygeneratoroccurrence

slow cortical rhythm0 1 Hzcortexsleep, anesthesia

delta waves1 4 Hzcortex, thalamus?sleep, anesthesia

theta waves/oscill.4 9 Hzhippocampusfalling asleep, REM

alpha oscillation9 12 Hzthalamusresting state, closed eyes

sigma spindles12 14 Hzthalamusfalling asleep

beta waves12 20 Hzcortexwakefulness, REM

gamma oscillation20 80 Hzcortical interneuronsattention, activation

ripple oscillation80 200 Hzcortex, hippocampusattention