L1 - SLEEP: Saper B. Nature. 2005

Question 1

intro

Answer 1

• constantin von economo –> discovered new type of encephalitis –> “lethargica” which targeted brain regions controlling sleep & wakefulness
• his observations on brain lesions remained significant –> revealed key brain areas involved in regulating sleep & wakefulness eg. brainstem, hypothalamus, basal forebrain (BF); neurons in these regions promote arousal & are inhibited during sleep by GABA-containing neurons in VLPO
• mutual inhibition between arousal & sleep circuitry results in distinct wake & sleep stages w/ sharp transitions –> orexin neurons in LH stabilise this switch (their loss leads to narcolepsy)

Question 2

the ascending arousal system promotes wakefulness

Answer 2

• 2 major branches: one ascending to the thalamus (activating thalamic relay neurons crucial for transmitting information to the cerebral cortex), and another to the reticular nucleus of the thalamus

1) primary upper brainstem input to these nuclei comes from Ach-producing cell groups in the pedunulopontine + laterodorsal tegmental nuclei (PPT/LDT) –> these neurons are most active during wake/REM; less during NREM
- their input to the reticular nucleus is crucial for gating transmission between the thalamus & cerebral cortex, crucial for maintaining wakefulness

2) second branch activates neurons in the LH & BF & throughout cerebral cortex; pathway originates from monoaminergic neurons
- inputs to the cortex are enhanced by LH peptidergic neurons containing melanin-concentrating hormone (MCH) or orexin, and BF neurons containing Ach or GABA
- lesions = profound & long-lasting sleepiness/coma; impaired arousal
- neurons in monoaminergic nuclei fire fastest during wake, slowest NREM, absent in REM
- orexin neurons in LH = most active in wake; MCH neurons most active in REM
- many BF neurons, incl. cholinergic, are active during both wake/REM

Question 3

the VLPO promotes sleep

Answer 3

• small % of encephalitis patients had insomnia rather than sleepiness –> had lesions in basal ganglia & adjacent anterior hypothalamus
• later, animal experiments identified the lateral PO of hypothalamus as a site where lesions caused similar insomnia
• discovery of VLPO –> neurons primarily active during sleep & contain inhibitory neurotransmitters like galanin & GABA –> these neurons form dense clusters & play a crucial role in sleep regulation
• damage to the VLPO was suggested as a potential cause of insomnia in von Economo’s patients
• experiments w/ cell-specific lesions of VLPO in animals revealed reduction in both NREM & REM sleep by more than 50%
• lesions impacting the extended VLPO disrupted REM –> neurons project to the LC & DR crucial for gating REM sleep
• lesions impacting the VLPO cluster affect NREM –> contains histaminergic neurons, linked to transitions between arousal & NREM sleep
• VLPO receives inputs from major monoaminergic systems, w/noradrenaline & serotonin inhibiting VLPO neurons
• VLPO can be inhibited by arousal systems

Question 4

the flip-flop switch

Answer 4

• a circuit featuring mutually inhibitory elements creates a self-reinforcing loop, where activity in one side suppresses inhibitory inputs form the other, promoting its own action
• flip-flop minimises transitional states, swiftly shifting between states when one side dominates
• rapid transitions = adaptive advantages –> alertnesss & avoid inefficient periods of half-sleep
• can lead to unexpected transitions (eg. microsleeps when driving)
• animals w/lesions in VLPO –> more frequent transitions –: resemble sleep disturbances in von Economo’s patients
• elderly with similar issues have neuronal loss in the human equivalent of the VLPO

Question 5

orexin/hypocretin neurons & state stability

Answer 5

• following encephalitis, Willson & Spiller observed a surge in cases of narcolepsy (condition characterised by uncontrolled sleepiness & cataplexy)
• orexins produced by neurons in the posterior LH –> deficiency in orexins or receptors lead to narcoleptic symptoms
• individuals w/narcolepsy have reduced orexin in LHA & CSF –> however, not primarily associated w/ mutations in orexin genes, mainly considered an autoimmune or potentially neurodegenerative causes
• loss of orexin neurons in LHA is specific, w/o affecting adjacent neurons
• orexin neurons = active during wake & motor activity, projecting to the cerebral cortex & monoaminergic/ cholinergic cell groups, reinforcing arousal systems –> do not directly inhibit the VLPO, but relation w/ arousal systems could stabilise the sleep-wake flip-flop swtich

Question 6

homeostatic regulation of sleep

Answer 6

• VLPO neurons don’t accumulate sleep need, but show increased activity in recovery sleep
• adenosine = proposed homeostatic sleep regulator –> accumulates during wakefulness (extracellularly) due to energy systems depletion in the brain; result from ATP degradation (accumulate in the BF)
• injection of adenosine or agonists into specific brain regions (eg. BF or VLPO) induces sleep in animals
• may enhance sleep-promoting cell’s activities whilst inhibiting wake-promoting neuron’s activities, possibily through disinhibiting VLPO

Question 7

circadian regulation of sleep

Answer 7

• SCN = brains master clock; neurons fire in a 24hr cycle driven by transcriptional/translational loop
• loss of SCN disrupts the circadian rhythms w/o external timing cues
• light inputs from retina during the day, and melatonin secretion from pineal gland during dark, resets the SCN daily –> specialised retinal ganglion cells containing melanopsin receive light signals to synchronise the clock w/external day-night cycle
• SCN has modest projections to VLPO or orexin neurons; its main output targets the adjacent subparaventricular zone (SVZ) & dorsomedial nucleus of the hypothalamus (DMH)
• lesions of ventral SVZ disrupt sleep-wake & locomotor activity rhythms; lesions of dorsal SPZ affect body temp
• direct projections from SCN to sleep or thermoregulatory regions are weak, relay neurons in SPZ are essential for maintaining circadian rhythms
• the SPZ serve’s as an amplifier of the SCN’s output to the sleep-wake regulatory system, particularly targeting the DMH
• animals w/DMH lesions sleep more & show reduced locomotor activity, suggesting DMH’s output is primarily activating
• DMH projections include GABAergic neurons to VLPO & glutamatergic neurons to LHA, suggesting roles in promoting wakefulness
• DMH = higher activity during wake, indicated by fos expression patterns
• lab rat’s circadian rhythms can be altered w/ restricting food, etc –> behavioural shifts correlate w/ changes in DMH activation, suggesting its role in integrating clock information w/ environmental cues
• DMH flexibility allows animals to maximise survival chances by aligning their cycles w/environmental changes

Question 8

alloteric regulation of sleep

Answer 8

• external factors like food, temp changes can modify sleep patterns & circadian cycles
• “allostatic drive” –> McEwen & Stellar 1993 = describes physiological fluctuations in response to external demands
• mechanisms by which cognitive & emotional systems impact sleep or circadian control remain poorly understood
• PET studies in humans w/ insomnia = heightened activity in corticolimbic areas like the medial PFC & medial temporal lobe –> inputs likely sustain a hyperaroused state
• when arousal systems override S or C = insomnia (eg. during periods of stress/ depression)