Flip-flop model/ narcolepsy Flashcards
What is narcolepsy?
Narcolepsy is a disabling neurological disease and affects approximately one in 2000 individuals. It is characterized by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep (American Academy of Sleep Medicine, 2001) and is related to a severe orexin deficiency (hypocretin) (Ripley et al., 2001).
How is wakefulness/arousal achieved?
Wakefulness and arousals are believed to be regulated mainly by two ascending neuron networks in the brain, referred to as the ascending reticular activation system (ARAS). The first activating neuron network consists of the cholinergic neurons in the pedunculopontine (PPT) and laterodorsal tegmental (LDT) nuclei in the brainstem, which project to the thalamic nuceli. These cholinergic neurons are most active during wakefulness and REM sleep.
The second activating neuron network consists of thenoradrenergic locus coeruleus (LC), the serotoninergic dorsal raphe (DR) nucleus, the dopaminergic neurons in the ventral periaqueductal ducal gray matter and histaminergic neurons in the tuberomammilary nucleus (TMN) project to the cortex and promote wakefulness also. Neurons in the LC, DR and TMN show the highest firing rates during wakefulness, the lowest during REM sleep and an intermediate rate during NREM sleep.
In the lateral hypothalamus, orexin neurons, which also produce glutamate, have connections to the ascending arousal system and increase the firing rates of the neurons in these various nuclei, thus maintaining wakefulness. This is also shown in experiment where inserting a light-active channel (channelrhodopsin) into orexin cells and shining a light on them results in the mouse waking up (Adamantis et al 2007).
What area of the brain is responsible for the onset of sleep?
The first evidence for an active role of a specialized brain region in controlling sleep came from the brains of patients, which, as a consequence of infectious encephalitis, experienced insomnia. All of the insomnia patients had brain lesions in the anterior hypothalamus, providing the first evidence of a dedicated brain area that controls sleep. As a result, von Economo (1930) was the first to propose the existence of an anterior hypothalamic sleep-promoting area and a posterior hypothalamic waking center.
Since then, through the use of Fos immunohistochemistry, which identifies neurons that have been recently active, a cluster of sleep-active neurons was identified in the ventrolateral preoptic nucleus (VLPO) (Sherin et al., 1996). Single-unit recordings targeting this area confirmed that it contains sleep-active neurons (Szymusiak et al.,1998). Similarly it has been shown that ablation of VLPO neurons caused 40% less sleep (Lu et al., 2000) and activation of VLPO neurons caused increased sleep (Kroeger et al 2018).
Single-unit recordings and Fos studies have defined another preoptic nucleus containing a large population of GABAergic sleep-active neurons, the median preoptic nucleus (MnPO). Like VLPO neurons, MnPO neurons project to and inhibit wake-promoting neurons of the ARAS .
Why is the regulation of wake/sleep called the flip/flop model? Describe the advantge and disadvantage of this model?
This mutual inhibition between the VLPO and the ascending arousal system results in two discrete states with sharp state transitions. This means if a perturbation would push a state close to its midpoint (where both sides are equally as active), one state would rapidly “gain advantage of the other” and turn the other off resulting in a complete transition, instead of moving through intermediate states. This flip-flop model is advantageous for animals as being awake whilst not fully alert would pose numerous risks, for instance, coming easy prey for predators. However this switch isn’t necessarily stable. It is thought that the orexin (Hrct) neurons in the lateral hypothalamus may help stabilise this system by exciting arousal regions during wakefulness. The importance of this stabilising role is apparent in narcolepsy, in which an absence of orexin neurons causes numerous unintended transitions in and out of sleep, causing fragments of REM sleep to intrude into wakefulness (Chemelli et al 1999).
What is thr role of the ventrolateral preoptic nucelus?
Unlike the large number of nuclei involved in arousal, there are relatively few populations of neurons positioned to inhibited the arousal system and promote sleep.
The ventrolateral preoptic nucelus (VLPO) is an area in the hypothalamus. Its neurons contain GABA and most also contain galanin; two inhibitory neurotransmitters. VLPO neurons send projections to another hypothalamic area, the tuberomammillary nucleus, which is part of the AAS and therefore inhibit activity of the TMN. From neurons in the neighborhood of the VLPO (extended VPLO), other parts of the AAS, such as the locus coeruleus and the dorsal raphe, are also inhibited. As a result, VLPO neuons promotes/induces sleep.
Evidence for this comes from the finding that ablation of VLPO neurons cause 40% less sleep (Lu et al., 2000) and activation of VLPO neurons caused increased sleep (Kroeger et al 2018).
How is this flip-flop model of sleep formed? Is this advantageous?
The VLPO not only sends inhibitory projections to components of the AAS, it also in turn inhibited by various components of the AAS. It has been shown that the VLPO neurons can themselves be inhibited by norepinephrine, serotonin, and ACH (Gallopin et al., 2000), resulting in mutual inhibitory system, known as the flip-flop model of sleep.
Saper et al. (2001) referred to this as a “flip-flop switch” in an analogy to an electronic switch because this system results in two discrete states with sharp state transitions.If a perturbation would push a state close to its midpoint (where both sides are equally as active), one state would rapidly “gain advantage of the other” and turn the other off resulting in a complete transition, instead of moving through intermediate states. This flip-flops model is advantageous for animals as being in an intermediate state e.g. being awake whilst not fully alert would pose numerous risks, for instance, becoming easy prey for predators.
What is the problem with the flip-flop switch system of sleep? How is this “fixed”?
However, whilst this system may help produce sharp transitions between discrete behavioural states, which is advantageous, it is not necessarily stable.
It is thought that the orexin (Hrct) neurons in the lateral hypothalamus may help stabilise this system by exciting arousal regions during wakefulness, minimising the time spent in intermediate states and preventing unwanted transitions between wakefulness and sleep. The importance of this stabilising role is apparent in narcolepsy, in which an absence of orexin neurons causes numerous unintended transitions in and out of sleep, causing fragments of REM sleep to intrude into wakefulness (Chemelli et al 1999).
What causes narcolepsy in humans?
While it is evident that loss of function mutations in the HCRT gene does cause narcolepsy, it should be noted that such mutations are rare in cases of human narcolepsy and the loss of hypocretin neurons are thought to arise by a different mechanism, possibly an immunological response.
How are hypocretin neurons involved in REM sleep?
In relation with the control of REM (Rapid eye movement) sleep generation, Hcrt/Orx projections and receptors have been identified in cholinoceptive areas of the pontine reticular formation involved in REM sleep generation demonstrating an inhibitory effect on REM sleep generation.
The loss of Hcrt/Orx signalling in narcolepsy would impair these actions and could remove the inhibiting actions on REM generation in these pontine regions during wakefulness; consequently, patients would fall directly into REM while still in a wakefulness period. Also, the wake promoting neurons may not receive adequate excitatory drive in the absence of orexins, leading to reduced arousal, disinhibition of sleep promoting pathways and inappropriate transitions in to sleep. This hypothesis could best explain the frequent transitions between wakefulness and sleep, REM sleep fragmentation and excessive sleepiness present in narcoleptic patients (Nunez et al., 2009)
What is cataplexy?
Cataplexy is brief episodes of muscle weakness often triggered by strong emotions. The loss of muscle tone could be partial affecting just the face and the neck or complete resulting in postural collapse. However, consciousness is fully preserved during cataplexy.
How do the loss of hypocretin neurons cause cataplexy?
Hypocretin/Orexin neurons may be also involved in triggering cataplexy. A study by Yamuy J et al., has shown that hypocretinergic neurons also project to the motor neurons and have an excitatory effect on them (Yamuy et al., 2004). It is possible that a loss of hypocretinergic neurons could lead to atonia. However, the finer details of neural pathways that regulate sleepiness and cataplexy remain to be sorted out.
Furthermore, the sublaterodorsal nucleus (SLD) (area of REM-ON neurons) is a key region for triggering muscle atonia during REM sleep, and the SLD is normally inhibited during wake by GABAergic neurons of the ventrolateral PAG (area of REM-OFF neurons) and adjacent lateral pontine tegmentum (vlPAG–LPT) The heavy innervation of the vlPAG–LPT by orexin neurons may typically ensure strong suppression of REM sleep during the active period The vlPAG–LPT also receives inputs from GABAergic neurons of the central nucleus of the amygdala (CeA) Signals related to positive emotions normally engage the medial prefrontal cortex, which excites orexin neurons and the CeA; under normal conditions, the inhibitory effects of the CeA on the vlPAG–LPT are offset by excitatory signals from the orexin neurons. However, in narcolepsy, this orexin tone is absent, and the CeA can inhibit the vlPAG–LPT, thus disinhibiting the SLD and other atonia-promoting brain regions, resulting in cataplexy. In support of this model, chemoactivation of GABAergic neurons in the CeA of orexin-null mice increases cataplexy, whereas chemoinhibition or lesioning of the CeA reduces cataplexy (Burgess et al., 2013, Mahoney at al., 2017).
What causes sleep paralysis? Why doesn’t this occur normally?
At other times, the atonia of REM sleep can persist for a minute or two upon awakening (sleep paralysis) or vivid, dream-like hypnagogic hallucinations can occur around the onset of sleep.
These phenomena rarely occur in healthy, well-rested individuals because the orexin neurons reinforce the activity of the monoaminergic neurons in the LC and dorsal raphe nucleus (Bourgin et al., 2000;Kohlmeier et al., 2008), which in turn activate REM-off neurons and inhibit REM-on neurons, thus locking the individual out of REM sleep and its component behaviors during wakefulness.
Overal what is narcolepsy seen as?
Overall, many researchers view the abnormal sleep architecture in narcolepsy as ‘behavioural state instability’, with low thresholds for transitions between states and poor coherence within states that allows for frequent transitions between states and strange, intermediate states, such as cataplexy and hypnagogic hallucinations.
Do people with narcolepsy have normall amounts of sleep?
Across 24 hours, people and animals with narcolepsy have essentially normal amounts of wake and sleep, but they have many more transitions between states. Under normal conditions, the sleep/wake switch resists switching until a sufficiently strong stimulus such as homeostatic sleep drive accumulates to a critical level. In contrast, most individuals with narcolepsy can rapidly doze off at any time of day, especially when they are sedentary. Narcoleptic mice also transition quickly and frequently from well-established wake into NREM sleep (Kantor et al., 2009).
