Hypothalamic regulation of Hypothalamic regulation of sleep and circadian rhythms sleep and circadian rhythms

AWAKE group meetingAWAKE group meetingAlex Dimitriu, MDAlex Dimitriu, MD

Saper, Scammel, Lu

Nature, Volume 437

October 2005

Baron Constantin von Economo - Baron Constantin von Economo - 19161916

Viennese neurologistViennese neurologist Discovered new type of Discovered new type of

encephalitis that attacked encephalitis that attacked regions of brain involved in regions of brain involved in sleep and wakefullness sleep and wakefullness

Called it Encephalitis Called it Encephalitis LethargicaLethargica– Von Economo’s sleeping Von Economo’s sleeping

sickness sickness Disease swept through Europe Disease swept through Europe

/ North America during 1920’s / North America during 1920’s Disease disappears next Disease disappears next

decade, virus never identified decade, virus never identified

AgendaAgenda

Recent advances in understanding brain Recent advances in understanding brain circuitry involved in sleep / wake circuitry involved in sleep / wake

Properties of the switch that controls sleep Properties of the switch that controls sleep and wakefulness; narcolepsy and wakefulness; narcolepsy

How basic drives (need for sleep) affect this How basic drives (need for sleep) affect this switch switch

Effects of drugs on sleep and wakefulnessEffects of drugs on sleep and wakefulness

Von Economo’s EncephalitisVon Economo’s Encephalitis

Majority of patients slept 20+ hrs/dayMajority of patients slept 20+ hrs/day Arising only to eat and drink Arising only to eat and drink Cognitive function intact, but would soon Cognitive function intact, but would soon

return to sleep return to sleep This cycle lasted several weeks before This cycle lasted several weeks before

recoveryrecovery

Von EconomoVon Economo

Found lesion to Found lesion to occur at the junction occur at the junction of the midbrain and of the midbrain and the diencephalonthe diencephalon

Proposed there was Proposed there was an ascending an ascending arousal system arousal system originating in the originating in the brainstem, keeping brainstem, keeping the forebrain awake the forebrain awake

HypothalamusHypothalamus

HypothalamusHypothalamus

RASRAS

Von Economo proposes ascending arousal Von Economo proposes ascending arousal system system

During WWII Moruzzi and Magoun describe During WWII Moruzzi and Magoun describe ascending arousal pathway originating in ascending arousal pathway originating in rostral pons and runs through midbrain rostral pons and runs through midbrain reticular formation reticular formation

Coin the term “ascending reticular activating Coin the term “ascending reticular activating system” (RAS)system” (RAS)

Reticular Activating System – 2 Reticular Activating System – 2 branchesbranches

Ascending pathway to Ascending pathway to thalamus (thalamus (YellowYellow))

Activates thalamic relay Activates thalamic relay neurons, crucial for neurons, crucial for transmission of information transmission of information to cerebral cortex to cerebral cortex

2 acetylcholine cell groups2 acetylcholine cell groups– Major source of input to Major source of input to

thalamic relay nucleii, thalamic relay nucleii, and reticular nucleus of and reticular nucleus of the thalamus is pair ofthe thalamus is pair of

– Pedunculo-pontine and Pedunculo-pontine and laterodorsal tegmental laterodorsal tegmental nucleii (PPT, LDT)nucleii (PPT, LDT)

PPT LDT NeuronsPPT LDT Neurons

Major input to thalamic relay nucleusMajor input to thalamic relay nucleus Produce Acetyl-choline (ACH) Produce Acetyl-choline (ACH) Fire rapidly during wakefulness and REMFire rapidly during wakefulness and REM

– Most active periods of brain activityMost active periods of brain activity– In REM; cortical activation, loss of tone in muscles and In REM; cortical activation, loss of tone in muscles and

active dreaming active dreaming Much less active during non-REM (NREM) sleep when Much less active during non-REM (NREM) sleep when

cortical activity is low cortical activity is low Input of these neurons is crucial as they act as a gating Input of these neurons is crucial as they act as a gating

mechanism that can block transmission between thalamus mechanism that can block transmission between thalamus and cortex; ACH important to wakefulnessand cortex; ACH important to wakefulness

Other inputs to thalamus include, reticular formation, Other inputs to thalamus include, reticular formation, PPT/LDT, monoaminergic systems, parabrachial nucleus. PPT/LDT, monoaminergic systems, parabrachial nucleus. Also midline and intralaminar nucleii in the thalamus. Also midline and intralaminar nucleii in the thalamus.

The 2nd activating PathwayThe 2nd activating Pathway Bypasses the thalamusBypasses the thalamus Activate neurons in basal Activate neurons in basal

forebrain and lateral forebrain and lateral hypothalamic area hypothalamic area

Originates from monoaminergic Originates from monoaminergic neurons in upper brainstem neurons in upper brainstem including;including;– Noradrenergic locus ceruleus Noradrenergic locus ceruleus

(LC)(LC)– Serotonergic dorsal and Serotonergic dorsal and

median raphe median raphe – Dopaminergic periaqueductal Dopaminergic periaqueductal

grey mattergrey matter– Histaminergic Histaminergic

tuberomamillary neurons tuberomamillary neurons

Second Pathway (RED)Second Pathway (RED) Monoaminergic Neurons Monoaminergic Neurons

– Norepinephrine, Norepinephrine, Serotonin, Dopamine, Serotonin, Dopamine, HistamineHistamine

Input to cortex also Input to cortex also augmented by augmented by – Lateral hypothalamic Lateral hypothalamic

(LHA) neurons(LHA) neurons Melanin concentrating Melanin concentrating

hormone hormone hypocretin / hypocretin /

hypocretin – most hypocretin – most active during active during wakefulness wakefulness

Also basal forebrain Also basal forebrain neurons, including neurons, including cholinergic and GABA cholinergic and GABA neurons neurons

Second Pathway (RED)Second Pathway (RED)

Lesions along this pathway, esp the LHA Lesions along this pathway, esp the LHA result in coma or long-lasting sleepiness. result in coma or long-lasting sleepiness.

Neurons in this pathway fire fastest during Neurons in this pathway fire fastest during wakefulness, slower during NREM, and stop wakefulness, slower during NREM, and stop during REM sleep.during REM sleep.

ACH – Cholinergic neurons most active ACH – Cholinergic neurons most active during wake and REMduring wake and REM

Von Economo’s – block ascending Von Economo’s – block ascending pathways; produce impairment of arousalpathways; produce impairment of arousal

Ascending Arousal SystemAscending Arousal System

Encephalitis LethargicaEncephalitis Lethargica

http://www.youtube.com/watch?v=5lNVtUlroZchttp://www.youtube.com/watch?v=5lNVtUlroZc

Hypersomnia vs. InsomniaHypersomnia vs. Insomnia

Von Economo also observed an Von Economo also observed an oppositeopposite response in some victims of Encephalitis response in some victims of Encephalitis lethargicalethargica

Rather than sleepy, some became Rather than sleepy, some became insomniac and only slept for few hours each insomniac and only slept for few hours each dayday

Became tired, difficulty falling asleep, slept Became tired, difficulty falling asleep, slept short time, then awoke unable to return to short time, then awoke unable to return to sleep.sleep.

VLPO promotes sleepVLPO promotes sleep

Later experiments revealed a hypothalamic site Later experiments revealed a hypothalamic site involving lateral preoptic area where lesions involving lateral preoptic area where lesions caused similar insomniacaused similar insomnia

VLPO neurons then found to send major outputs VLPO neurons then found to send major outputs to cells that participate in arousalto cells that participate in arousal

Damage to these neurons caused insomnia in Von Damage to these neurons caused insomnia in Von Economo’s pts.Economo’s pts.

In animals, lesions to VLPO reduced both REM In animals, lesions to VLPO reduced both REM and NREM sleep by 50%and NREM sleep by 50%

VentroLateral Preoptic Nucleus VentroLateral Preoptic Nucleus (Hypothalamus)(Hypothalamus)

VLPOVLPO

VLPO neurons particularly active during sleep, VLPO neurons particularly active during sleep, and project inhibitory neurotransmitter and project inhibitory neurotransmitter GABAGABA, and , and Galanin.Galanin.

VLPO ClusterVLPO Cluster– More heavily innervates histaminergic neurons, closely More heavily innervates histaminergic neurons, closely

linked to transitions b/w arousal and wakefulness.linked to transitions b/w arousal and wakefulness. VLPO ExtendedVLPO Extended

– Damage to extended VLPO inhibits REM sleep more Damage to extended VLPO inhibits REM sleep more specificallyspecifically

– Also the extended VLPO is main output to the LC and Also the extended VLPO is main output to the LC and DR; key in gating REM sleep DR; key in gating REM sleep

VLPOVLPO

Norepinephrine (NE) and Serotonin (5HT) Norepinephrine (NE) and Serotonin (5HT) inhibit the VLPO. inhibit the VLPO.

Tuberomammillary secrete Histamine, Tuberomammillary secrete Histamine, GABA GABA – No VLPO receptor for HistamineNo VLPO receptor for Histamine– GABA inhibits VLPO neuronsGABA inhibits VLPO neurons

““Therefore, the VLPO can be inhibited by Therefore, the VLPO can be inhibited by the same arousal systems that it inhibits the same arousal systems that it inhibits during sleep”during sleep”

The Flip Flop SwitchThe Flip Flop Switch

““A circuit containing mutually inhibitory elements A circuit containing mutually inhibitory elements sets up a self-reinforcing loop, where activity in sets up a self-reinforcing loop, where activity in one of the competing sides shuts down inhibitory one of the competing sides shuts down inhibitory inputs from the other side, and therefore reinforces inputs from the other side, and therefore reinforces its own action”its own action”

Flip Flop circuits avoid transitional states because Flip Flop circuits avoid transitional states because when either side begins to overcome the other, the when either side begins to overcome the other, the switch switch flipsflips into alternative state. into alternative state.

Explains why sleep wake transitions are abruptExplains why sleep wake transitions are abrupt– Dangerous for animals to have impaired alertness when Dangerous for animals to have impaired alertness when

awake awake – Useless for animals to spend sleep periods half awakeUseless for animals to spend sleep periods half awake

Instability of the SwitchInstability of the Switch

Small pertubation can give one side advantage, turn off Small pertubation can give one side advantage, turn off alternative state abruptlyalternative state abruptly– Falling asleep while driving Falling asleep while driving

Mathematical models of these biologic switches show:Mathematical models of these biologic switches show:– Weakening either side of a switch causes switch to ride closer to Weakening either side of a switch causes switch to ride closer to

the transition point between both states the transition point between both states – Increase number of transitions regardless of which side is Increase number of transitions regardless of which side is

weakened weakened Animals with VLPO lesionsAnimals with VLPO lesions

– Fall asleep twice as oftenFall asleep twice as often– Wake more often during sleep cycle Wake more often during sleep cycle – Only sleep for ¼ of time per sessionOnly sleep for ¼ of time per session

Unstable SwitchUnstable Switch

Mid-Sleep, wake up unable to fall back Mid-Sleep, wake up unable to fall back asleep, chronically tired, falling asleep asleep, chronically tired, falling asleep briefly and fitfully during wake cyclebriefly and fitfully during wake cycle

Similar pattern seen in elderly pts Similar pattern seen in elderly pts Have similar loss of neurons in VLPO Have similar loss of neurons in VLPO

associated with aging. associated with aging.

Monoamine nucleii inhibit VLPO = inhibit supression of Monoamine nucleii inhibit VLPO = inhibit supression of monoamine nucleii, hypocretin, cholinergic PPT, LDT neurons monoamine nucleii, hypocretin, cholinergic PPT, LDT neurons

hypocretin reinforces monoaminergic tone (no hypocretin hypocretin reinforces monoaminergic tone (no hypocretin receptors on VLPO)receptors on VLPO)

In sleep, firing of VLPO inhibits monoaminergic cell groups, In sleep, firing of VLPO inhibits monoaminergic cell groups, relieving its own inhibition. (enhancing its own activity) VLPO then relieving its own inhibition. (enhancing its own activity) VLPO then inhibits hypocretininhibits hypocretin

hypocretin, in both cases, believed to stabilize this unstable switchhypocretin, in both cases, believed to stabilize this unstable switch

NarcolepsyNarcolepsy

1998 – 2 groups of scientists discover group 1998 – 2 groups of scientists discover group of neuropeptides produced by neurons in of neuropeptides produced by neurons in posterior LHA (lateral hypothalamus). posterior LHA (lateral hypothalamus).

One year later, discovery that lack of these One year later, discovery that lack of these neuropeptides results in narcolepsy in neuropeptides results in narcolepsy in animals.animals.

Next year deficiency in human in CSF found Next year deficiency in human in CSF found in narcolepticsin narcoleptics

HypocretinHypocretin

Narcolepsy;Believed to be autoimmune / Narcolepsy;Believed to be autoimmune / neurodegenerative disease neurodegenerative disease

Begins in 2Begins in 2ndnd / 3 / 3rdrd decade of life decade of life hypocretin neurons very active in wakefulness hypocretin neurons very active in wakefulness

and while exploring environmentand while exploring environment hypocretin neurons have ascending pathways hypocretin neurons have ascending pathways

to cortex, and descending pathways to to cortex, and descending pathways to midbrain cholinergic/monoaminergic nucleii of midbrain cholinergic/monoaminergic nucleii of arousal centers arousal centers

HypocretinHypocretin

hypocretin and VLPO have mutual projections, hypocretin and VLPO have mutual projections, but VLPO does not have hypocretin receptorsbut VLPO does not have hypocretin receptors

So, hypocretin neurons reinforce arousal So, hypocretin neurons reinforce arousal centers, but do not inhibit VLPOcenters, but do not inhibit VLPO

Asymmetric relationship helps stabilize the flip Asymmetric relationship helps stabilize the flip flop switch flop switch

Narcoleptics (lack hypocretin) have de-Narcoleptics (lack hypocretin) have de-stabilized switch; easily doze off during day, stabilized switch; easily doze off during day, wake often at night wake often at night

Why we sleep…Why we sleep…

Like body temperature, the body always Like body temperature, the body always tries to return sleep to a set-point. tries to return sleep to a set-point. – Sleep deprivation, followed by compensatory Sleep deprivation, followed by compensatory

recovery recovery

Model proposed by Borberly and colleagues Model proposed by Borberly and colleagues describes 2 drives for sleepdescribes 2 drives for sleep– Circadian Circadian – Homeostatic Homeostatic

Why we sleep… HomeostaticWhy we sleep… Homeostatic

Homeostatic influence results from accumulation Homeostatic influence results from accumulation of “some substance” during prolonged of “some substance” during prolonged wakefulness wakefulness

VLPO neurons do not accumulate need for sleep; VLPO neurons do not accumulate need for sleep; just start firing 2x as fast with sleep onset – so just start firing 2x as fast with sleep onset – so influenced by something elseinfluenced by something else

During prolonged wakefulness, energy producing During prolonged wakefulness, energy producing brain systems run down and ATP levels deplete, brain systems run down and ATP levels deplete, ADP levels accumulateADP levels accumulate

Extracellular adenosine levels rise with time Extracellular adenosine levels rise with time Adenosine injected into BF of cats induces sleepAdenosine injected into BF of cats induces sleep

…blocks adenosine receptors.

Circadian regulationCircadian regulation

Confirmed 24 hour circadian rhythm in sleep drive Confirmed 24 hour circadian rhythm in sleep drive Cells in suprachiasmatic (SCN) nucleus fire in 24 Cells in suprachiasmatic (SCN) nucleus fire in 24

hour cycle, even on their own in cell culture – reset hour cycle, even on their own in cell culture – reset daily by light daily by light

Bulk of SCN output projected to SPZ Bulk of SCN output projected to SPZ (supraventricular zone) (supraventricular zone) – Ventral lesions disrupt sleep – wake rhythms Ventral lesions disrupt sleep – wake rhythms – Dorsal lesions impair body temperature rhythmsDorsal lesions impair body temperature rhythms

Major output of SPZ is DMH (Dorsomedial nucleus Major output of SPZ is DMH (Dorsomedial nucleus of hypothalamus)of hypothalamus)

Circardian RegulationCircardian Regulation

Light Light SCN SCN SPZ SPZ DMH DMH VLPO and hypocretin neuronsVLPO and hypocretin neurons

Dorsomedial nucleus of hypothalamus projects Dorsomedial nucleus of hypothalamus projects to inhibitory signals (GABA) to VLPO and to inhibitory signals (GABA) to VLPO and excitatory signals (glutamate) to LHA (activating)excitatory signals (glutamate) to LHA (activating)

Complex 3 stage system allows varying Complex 3 stage system allows varying sleep/wake cycle behavior despite fixed daylight sleep/wake cycle behavior despite fixed daylight schedule schedule – SCN always active in light cycle and VLPO active in SCN always active in light cycle and VLPO active in

sleep sleep

Circadian Regulation - DMHCircadian Regulation - DMH Allows animals to Allows animals to

vary sleep wake vary sleep wake behavior based on behavior based on food source, daylight food source, daylight hours – Finland bats hours – Finland bats become diurnal for become diurnal for ½ of the year to eat ½ of the year to eat more insects more insects

Lesions of DMH Lesions of DMH prevent these shiftsprevent these shifts

DMH lets you adjust DMH lets you adjust to new time zonesto new time zones

ConclusionConclusion

RAS Reticular Activating System (ON)RAS Reticular Activating System (ON)– LDT, PPT (via ACH) LDT, PPT (via ACH) Activate thalamic relay Activate thalamic relay

Monoaminergic Pathways (ON)Monoaminergic Pathways (ON)– Norepinephrine, Serotonin, Dopamine, histamine Norepinephrine, Serotonin, Dopamine, histamine

Activate Basal forebrain, hypocretin, and cortexActivate Basal forebrain, hypocretin, and cortex Hypocretin (ON) Hypocretin (ON)

– enhances Monoaminergic tone enhances Monoaminergic tone VLPO (OFF)VLPO (OFF)

– Inhibited by monoamines, and inhibits monoaminesInhibited by monoamines, and inhibits monoamines Adenosine (OFF)Adenosine (OFF)

ConclusionConclusion

Circadian Cycles (ON)Circadian Cycles (ON)– Light Light SCN SCN SPZ SPZ DMH DMH

Inhibit VLPO Inhibit VLPO Activate hypocretin neuronsActivate hypocretin neurons

VLPO vs HypocretinVLPO vs Hypocretin– Hypocretin cannot turn off VLPO but… Hypocretin cannot turn off VLPO but… – VLPO can turn off hypocretinVLPO can turn off hypocretin– so they function independentlyso they function independently

FINFIN