Sleep and Arousal

1. Sleep and Arousal Lecture 9 NRS201S John Yeomans

2. EEG Changes in Sleep • Waking: Alpha (10 Hz) and beta/gamma waves (40 Hz). • Slow-Wave sleep: From alpha to spindles (14 Hz) and delta (1-4 Hz). • REM sleep: Cortical arousal and muscular atonia. Also called paradoxical or dream sleep. • Triggered in pontine reticular formation.

3. Gamma Alpha Hours

4. REM Sleep • Brain is active, and eyes are active. • Muscles of body are profoundly inhibited (atonia). • Subjects report dreams, when awoken. • NE and 5HT neurons silent. Ch neurons active. • In slow-wave sleep, brain and eyes are quiet, but muscles are more active.

5. Transection studies

6. Brain Areas--Early Studies • Coma (prolonged unconsciousness) due to injury in dorsal reticular formation. • Stimulation of RF leads to arousal. • Ascending path for cortical arousal. • Descending path for atonia. • Critical area in dorsal pontine reticular formation.

7. Diffuse Arousal Systems • Locus coeruleus Norepinephrine neurons (A6). • Mesopontine Cholinergic neurons (Ch5,6). • Raphe Serotonin neurons (B5,6). • Tuberomammilary Histamine neurons. • Lateral hypothalamus Orexin/Hypocretin neurons. • Basal forebrain Cholinergic neurons (Ch1-4).

9. Norepinephrine and Serotonin Active in Waking and in Slow-Wave Sleep

10. Mesopontine Ch5,6 Basal Forebrain Ch1-4) Cholinergic Arousal Systems Active in Waking and REM Sleep

11. Model of REM Sleep Systems

12. Sleep Disorders • Insomnia (too little sleep). • Sleep apnea (loss of breathing in REM, too much atonia?). • Narcolepsy/cataplexy (daytime sleepiness and REM/atonia attacks). • Triggered by arousal (e.g. laughing, running). • Due to loss of orexin/hypocretin neurons in humans, or receptors in dogs and mice.

14. Narcolepsy • Orexin 2 receptors lost in dogs (Mignon). • O/H neurons lost in humans. • O/H gene or receptors in mice. • O/H neurons active in waking arousal, and needed to inhibit atonia. • In narcolepsy, arousal can activate REM/atonia neurons, if O/H signal is lost. • Which neurons and how? Ch5,6?

15. Loss of O/H neurons: Daytime sleepiness, Cataplexy (atonia) induced by arousal.

16. Circadian Rhythms March 17, 2006 PSY391S John Yeomans

17. Timing of Motivated Behaviors • When is best season to feed and mate? Seasonal periods of activity and breeding based on availability of food. Based on axis of earth around sun. • When is best time of day to feed? Diurnal/nocturnal to find food and avoid predators. Based on earth’s rotation relative to sun. • Circadian clock built into all plants and animals to help survival.

18. Measuring Rhythms in Hamsters

19. Rhythms • Endogenous clock: Measured in constant conditions, still 23-25 hr. “free running” • Rhythm is lost when SCN lesioned in mammals, or pineal gland in birds. • Rhythm is restored by transplanting new SCN. Period of donor SCN. • Tau mutant hamster has 20 hr rhythm. • Therefore, SCN is endogenous clock for activity.

20. Free running 24.1 hr No rhythm Tau mutant SCN 19.8 hr rhythm of donor SCN Ralph et al. 1990

21. Retinal Paths to SCN and IGL

22. Entrainment • Entrainment by light, temperature, or • arousing stimuli. • Photic entrainment in mammals due to • retinohypothalamic path to SCN. • Rods and cones not needed for entrainment! • Search for new receptors in ganglion cell • layer led to melanopsin. • Melanopsin ganglion cells directly activated • by light, indirectly by rods and cones. • Huge dendrites and receptive fields, • insensitive to light, but stable (no adaptation)

24. Projections of Melanopsin Neurons • Melanopsin neurons provide most of input to SCN. • Provide input to pretectal nucleus for pupillary reflex. • Provide input to intergeniculate leaflet of thalamus. IGLSCN. • IGL needed for arousing inputs to clock.

25. Entrainment by Arousal • Clock can be shifted by food, exercise, footshock and sex. • Allow animals to adjust rhythms to biologically significant opportunities. • Like light, shift can be up to 3 hours. • Shifts depend on phase—Light shifts best in dark phase, arousal shifts best in light phase.

26. Intergeniculate Leaflet: Arousal Shifts Circadian Rhythms Cain et al. 2001

27. Arousal Shifts Circadian Rhythms in Hamsters * Arousal (footshock, exercise, reward) Cain et al. 2001

28. Evolution of Retina? • How could eye evolve? Greatest problem for Cajal. • Circadian clock with direct access to light. • Light detectors, no spatial information—direct input to clock. • Eye cup—Spatial information, focussing, with pupil and lens later. • Dark and light vision (cones and rods) with adaptation. • Two eyeballs with muscles, for distance perception and fast movements in space.

29. Non-photic entrainment: IGL to SCN SCN Clock ?

30. Circadian Genes • How does endogenous clock work? • Clock mechanism found in plants, simple animals and many body cells. • Clock genes found in mutant fruit flies. How? • Take the flies who fly at odd hours. Map genes. • per: No rhythm, long rhythms, short rhythms. • Tim, cry, dbt. • Map genes onto 4 fly chromosomes. • Study functions of proteins: PER, TIM, DBT.

31. Mutations Alter Rhythms in Flys and Mice • per, tim are needed for 24 hr rhythms. • Mutations lead to short, long or no rhythm. • dbt mutations alter enzyme, casein kinase, leading to short rhythm in Drosophila. • Homologous genes (per1-3, cry, tau) found in mice and humans. • Transcription factors Clock and Cycle start each cycle. These are also regulated.

32. Clock Genes and Negative Feedback • per, cry genes transcribed in nucleus. • Per, Cry proteins are translated in cytoplasm. • Per/Cry dimers inhibit Clock/Cycle transcription factors in nucleus. • Less Per, Cry less inhibition. • New per, cry transcribed 24 hrs later. • Tau gene makes a casein kinase that degrades Per.

33. Molecular Model of Clock Nonphotic input from thalamus IGL? Gene transcription proteins Negative feedback loop Photic input from retina