410 likes | 877 Views
Hypothalamic regulation of sleep and circadian rhythms. Saper, Scammel, Lu Nature, Volume 437 October 2005. AWAKE group meeting Alex Dimitriu, MD. Baron Constantin von Economo - 1916. Viennese neurologist
E N D
Hypothalamic regulation of sleep and circadian rhythms Saper, Scammel, Lu Nature, Volume 437 October 2005 AWAKE group meetingAlex Dimitriu, MD
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
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
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
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
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)
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)
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.
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
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
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
Encephalitis Lethargica http://www.youtube.com/watch?v=5lNVtUlroZc
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.
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%
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
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”
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
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
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.
Monoamine nucleii inhibit VLPO = inhibit supression of monoamine nucleii, hypocretin, cholinergic PPT, LDT neurons • hypocretin reinforces monoaminergic tone (no hypocretin receptors on VLPO)
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
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
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
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
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
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
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)
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
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
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)
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