Hypothalamic regulation of sleep and circadian rhythms

1. Hypothalamic regulation of sleep and circadian rhythms Saper, Scammel, Lu Nature, Volume 437 October 2005 AWAKE group meetingAlex Dimitriu, MD

2. Baron Constantin von Economo - 1916 • Viennese neurologist • Discovered new type of encephalitis that attacked regions of brain involved in sleep and wakefullness • Called it Encephalitis Lethargica • Von Economo’s sleeping sickness • Disease swept through Europe / North America during 1920’s • Disease disappears next decade, virus never identified

3. Agenda • Recent advances in understanding brain circuitry involved in sleep / wake • Properties of the switch that controls sleep and wakefulness; narcolepsy • How basic drives (need for sleep) affect this switch • Effects of drugs on sleep and wakefulness

4. Von Economo’s Encephalitis • Majority of patients slept 20+ hrs/day • Arising only to eat and drink • Cognitive function intact, but would soon return to sleep • This cycle lasted several weeks before recovery

5. Von Economo • Found lesion to occur at the junction of the midbrain and the diencephalon • Proposed there was an ascending arousal system originating in the brainstem, keeping the forebrain awake

6. Hypothalamus

7. Hypothalamus

8. RAS • Von Economo proposes ascending arousal system • During WWII Moruzzi and Magoun describe ascending arousal pathway originating in rostral pons and runs through midbrain reticular formation • Coin the term “ascending reticular activating system” (RAS)

9. Reticular Activating System – 2 branches • Ascending pathway to thalamus (Yellow) • Activates thalamic relay neurons, crucial for transmission of information to cerebral cortex • 2 acetylcholine cell groups • Major source of input to thalamic relay nucleii, and reticular nucleus of the thalamus is pair of • Pedunculo-pontine and laterodorsal tegmental nucleii (PPT, LDT)

10. PPT LDT Neurons • Major input to thalamic relay nucleus • Produce Acetyl-choline (ACH) • Fire rapidly during wakefulness and REM • Most active periods of brain activity • In REM; cortical activation, loss of tone in muscles and active dreaming • Much less active during non-REM (NREM) sleep when cortical activity is low • Input of these neurons is crucial as they act as a gating mechanism that can block transmission between thalamus and cortex; ACH important to wakefulness • Other inputs to thalamus include, reticular formation, PPT/LDT, monoaminergic systems, parabrachial nucleus. Also midline and intralaminar nucleii in the thalamus.

11. The 2nd activating Pathway • Bypasses the thalamus • Activate neurons in basal forebrain and lateral hypothalamic area • Originates from monoaminergic neurons in upper brainstem including; • Noradrenergic locus ceruleus (LC) • Serotonergic dorsal and median raphe • Dopaminergic periaqueductal grey matter • Histaminergic tuberomamillary neurons

12. Second Pathway (RED) • Monoaminergic Neurons • Norepinephrine, Serotonin, Dopamine, Histamine • Input to cortex also augmented by • Lateral hypothalamic (LHA) neurons • Melanin concentrating hormone • hypocretin / hypocretin – most active during wakefulness • Also basal forebrain neurons, including cholinergic and GABA neurons

13. Second Pathway (RED) • Lesions along this pathway, esp the LHA result in coma or long-lasting sleepiness. • Neurons in this pathway fire fastest during wakefulness, slower during NREM, and stop during REM sleep. • ACH – Cholinergic neurons most active during wake and REM • Von Economo’s – block ascending pathways; produce impairment of arousal

14. Ascending Arousal System

15. Encephalitis Lethargica http://www.youtube.com/watch?v=5lNVtUlroZc

16. Hypersomnia vs. Insomnia • Von Economo also observed an opposite response in some victims of Encephalitis lethargica • Rather than sleepy, some became insomniac and only slept for few hours each day • Became tired, difficulty falling asleep, slept short time, then awoke unable to return to sleep.

17. VLPO promotes sleep • Later experiments revealed a hypothalamic site involving lateral preoptic area where lesions caused similar insomnia • VLPO neurons then found to send major outputs to cells that participate in arousal • Damage to these neurons caused insomnia in Von Economo’s pts. • In animals, lesions to VLPO reduced both REM and NREM sleep by 50%

18. VentroLateral Preoptic Nucleus (Hypothalamus)

19. VLPO • VLPO neurons particularly active during sleep, and project inhibitory neurotransmitter GABA, and Galanin. • VLPO Cluster • More heavily innervates histaminergic neurons, closely linked to transitions b/w arousal and wakefulness. • VLPO Extended • Damage to extended VLPO inhibits REM sleep more specifically • Also the extended VLPO is main output to the LC and DR; key in gating REM sleep

20. VLPO • Norepinephrine (NE) and Serotonin (5HT) inhibit the VLPO. • Tuberomammillary secrete Histamine, GABA • No VLPO receptor for Histamine • GABA inhibits VLPO neurons • “Therefore, the VLPO can be inhibited by the same arousal systems that it inhibits during sleep”

21. The Flip Flop Switch • “A circuit containing mutually inhibitory elements sets up a self-reinforcing loop, where activity in one of the competing sides shuts down inhibitory inputs from the other side, and therefore reinforces its own action” • Flip Flop circuits avoid transitional states because when either side begins to overcome the other, the switch flips into alternative state. • Explains why sleep wake transitions are abrupt • Dangerous for animals to have impaired alertness when awake • Useless for animals to spend sleep periods half awake

22. Instability of the Switch • Small pertubation can give one side advantage, turn off alternative state abruptly • Falling asleep while driving • Mathematical models of these biologic switches show: • Weakening either side of a switch causes switch to ride closer to the transition point between both states • Increase number of transitions regardless of which side is weakened • Animals with VLPO lesions • Fall asleep twice as often • Wake more often during sleep cycle • Only sleep for ¼ of time per session

23. Unstable Switch • Mid-Sleep, wake up unable to fall back asleep, chronically tired, falling asleep briefly and fitfully during wake cycle • Similar pattern seen in elderly pts • Have similar loss of neurons in VLPO associated with aging.

24. Monoamine nucleii inhibit VLPO = inhibit supression of monoamine nucleii, hypocretin, cholinergic PPT, LDT neurons • hypocretin reinforces monoaminergic tone (no hypocretin receptors on VLPO)

25. In sleep, firing of VLPO inhibits monoaminergic cell groups, relieving its own inhibition. (enhancing its own activity) VLPO then inhibits hypocretin • hypocretin, in both cases, believed to stabilize this unstable switch

26. Narcolepsy • 1998 – 2 groups of scientists discover group of neuropeptides produced by neurons in posterior LHA (lateral hypothalamus). • One year later, discovery that lack of these neuropeptides results in narcolepsy in animals. • Next year deficiency in human in CSF found in narcoleptics

27. Hypocretin • Narcolepsy;Believed to be autoimmune / neurodegenerative disease • Begins in 2nd / 3rd decade of life • hypocretin neurons very active in wakefulness and while exploring environment • hypocretin neurons have ascending pathways to cortex, and descending pathways to midbrain cholinergic/monoaminergic nucleii of arousal centers

28. Hypocretin • hypocretin and VLPO have mutual projections, but VLPO does not have hypocretin receptors • So, hypocretin neurons reinforce arousal centers, but do not inhibit VLPO • Asymmetric relationship helps stabilize the flip flop switch • Narcoleptics (lack hypocretin) have de-stabilized switch; easily doze off during day, wake often at night

29. Why we sleep… • Like body temperature, the body always tries to return sleep to a set-point. • Sleep deprivation, followed by compensatory recovery • Model proposed by Borberly and colleagues describes 2 drives for sleep • Circadian • Homeostatic

30. Why we sleep… Homeostatic • Homeostatic influence results from accumulation of “some substance” during prolonged wakefulness • VLPO neurons do not accumulate need for sleep; just start firing 2x as fast with sleep onset – so influenced by something else • During prolonged wakefulness, energy producing brain systems run down and ATP levels deplete, ADP levels accumulate • Extracellular adenosine levels rise with time • Adenosine injected into BF of cats induces sleep

31. …blocks adenosine receptors.

32. Circadian regulation • Confirmed 24 hour circadian rhythm in sleep drive • Cells in suprachiasmatic (SCN) nucleus fire in 24 hour cycle, even on their own in cell culture – reset daily by light • Bulk of SCN output projected to SPZ (supraventricular zone) • Ventral lesions disrupt sleep – wake rhythms • Dorsal lesions impair body temperature rhythms • Major output of SPZ is DMH (Dorsomedial nucleus of hypothalamus)

33. Circardian Regulation Light  SCN  SPZ  DMH  VLPO and hypocretin neurons • Dorsomedial nucleus of hypothalamus projects to inhibitory signals (GABA) to VLPO and excitatory signals (glutamate) to LHA (activating) • Complex 3 stage system allows varying sleep/wake cycle behavior despite fixed daylight schedule • SCN always active in light cycle and VLPO active in sleep

34. Circadian Regulation - DMH • Allows animals to vary sleep wake behavior based on food source, daylight hours – Finland bats become diurnal for ½ of the year to eat more insects • Lesions of DMH prevent these shifts • DMH lets you adjust to new time zones

36. Conclusion • RAS Reticular Activating System (ON) • LDT, PPT (via ACH)  Activate thalamic relay • Monoaminergic Pathways (ON) • Norepinephrine, Serotonin, Dopamine, histamine  Activate Basal forebrain, hypocretin, and cortex • Hypocretin (ON) • enhances Monoaminergic tone • VLPO (OFF) • Inhibited by monoamines, and inhibits monoamines • Adenosine (OFF)

37. Conclusion • Circadian Cycles (ON) • Light  SCN  SPZ  DMH  • Inhibit VLPO • Activate hypocretin neurons • VLPO vs Hypocretin • Hypocretin cannot turn off VLPO but… • VLPO can turn off hypocretin • so they function independently

38. FIN