Interaction between Process C&S Flashcards
Explain what is meant by the “two process” model of sleep
In 1982, it was proposed by Borbély that two processes play a dominant role in sleep regulation: a sleep-dependent, homeostatic process (Process S) and a sleep-independent circadian process (Process C). Process S, represents sleep drive or pressure and whilst the physiology of homeostatic sleep drive has not been completely determined, it increases during wakefulness and declines during sleep. Experiments have shown sleep pressure is relieved only by periods of deep NREM slow wave sleep. As the correlation between Process S and SWS is so strong that slow wave activity (SWA) has become a marker for measuring sleep pressure.
Process C however is determined by our circadian clock; the SCN, which is entrained to the light-dark cycle over a 24-hour period, and regulates the body’s sleep patterns and feeding patterns amongst other biological activities. It’s function is to provide an overall timing mechanism for sleep regulation and is thought to prevent polyphasic sleep that we see in small animals. Markers for process C are core body temperature and melatonin rhythms.
Desribe the two ascending pathways that stimulate wake maintenance
The first is a pathway from the pons to the thalamus that activates thalamic relay neurons crucial for transmission of information to the cortex. It consists of acetylcholineproducing neurons in the pedunculopontine nucleus (PPT) and the laterodorsal tegmental nuclei (LDT) (Hallanger et al., 1987). These cells are active during waking and REM sleep and much less active during NREM sleep (McCormick 1989).
The second pathway originates from monoaminergic neurons, like the noradrenergic locus coeruleus (LC), serotonergic dorsal and medial raphe, dopaminergic ventral periaqueductal grey matter and histaminergic tuberomammillary neurons. They project to the cerebral cortex.
These neurons are most active during waking, reduce activity during NREM sleep and are silent during REM sleep
Desribe the major sleep-promoting area.
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 VLPO neurons contain GABA and most also contain galanin; as a result these are inhibitory neurons which project to the various nuclei in the ascending arousal system and hence promote sleep. Examination of brains of animals that were asleep prior to death shows increased expression of the intermediate easily gene c-fos in VLPO neurons during sleep (Sherin et al., 1996). Ablation of VLPO neurons caused 40% less sleep (Lu et al., 2000) and activation of VLPO neurons caused increased sleep (Kroeger et al 2018).
In addition, the VLPO receives afferents from all the major monoaminergic neuronal areas it is inhibiting.
What does the mutual inhibition between the VLPO and the ascending arousal system result in? Is this advantageous or disadvantageous?
It results in two discrete states which sharp state transitions. In electrical engineering this is called a ‘flip-flop switch’ and this term has therefore been coined to describe the sleep-wake regulator network (Saper et al. 2005). In simple terms it means activity on one side immeadiately shuts down input from the other side, 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 flip-flop switch is not stable; without stabilsation uncontrolled switching back and forth between states is likely to occur.
How is stabilisation of the flip-flop switch achieved?
Specific neurons in the lateral hypothalamus (LH), releasing orexin (also called hypocretin) are suggested to be the stabilizing component of the network. Their function was discovered at the end of the 1990s when it was shown that narcoleptic dogs,(a condition where there is sudden entry into REM sleep when in a wake state), show mutations in orexin receptors or completely lack orexin (Chemelli et al., 1999,).
Orexin neurons are mainly active during waking (Lee et al., 2005) and orexin levels in the brain increase in the course of the main waking period and after sleep deprivation (Zhang et al., 2004). As a result it is thought that orexin neurons reinforce arousal during wakefulness, without inhibiting the VLPO (Saper et al., 2005).
How does the circadian clock infuence the various sleep promoting and inhibiting centres?
The SCN does not have any direct output to these centres. However the main output of the SCN is to the dorsal and ventral subparaventricular zone, which in turn have strong inputs to the dorsomedial hypothalamus. From there GABA containing neurons project to the VLPO and glutamatergic neurons project to lateral hypothalamus (Chou et al., 2003). The SCN therefore seems to be able to influence the main centres that maintain sleep or waking via this indirect pathway.
How may a lack of the circadian clock affect sleep pressure/homeostasis?
In rats it was shown that sleep homeostasis still functions without the endogenous circadian clock, as NREM sleep and SWA still increase after a sleep deprivation in SCN lesioned animals (Tobler et al., 1983,), or when the SCN is not functioning because of genetic manipulation (Wisor et al., 2002), or manipulations with light pulses (Larkin et al., 2004).This supports the view that circadian and homeostatic influences on sleep regulation are independent processes and so don’t have a significant influence on each other.
In simple terms, explain the two processes that regulate sleep.
The timing and quality of both sleep and wakefulness are thought to be regulated by the interaction of two processes. One of these two processes keeps track of the prior sleep–wake history and controls the homeostatic need for sleep while the other sets the time-of-day that sleep preferably occurs
What evidence is there that the circadian clock does have an influence on sleep homeostasis?
Clock genes might play a role in integrating the two processes at a molecular level because, although clock genes are thought to be exclusively involved in setting up the negative feed-back loops driving circadian rhythms, they seem also involved in the homeostatic regulation of sleep.
In 2002, Wisor et al., showed that Cry1,2−/− mice lack a functional circadian clock and are behaviorally arrhythmic when kept under constant dark conditions. Quantification of the sleep–wake dependent dynamics of EEG delta power revealed that lack of Cry1,2 resulted in a more rapid build-up of homeostatic sleep need during wakefulness which explains the higher levels in EEG delta power observed in these mice despite spending more time in NREM sleep and having more consolidated NREM sleep (i.e. longer, uninterrupted episodes), compared to wild-type mice. The observations of higher EEG delta power and increased consolidation of sleep diametrically opposes observations made in animals rendered arrhythmic through lesioning of the SCN [1]. Thus, sleep in Cry1,2−/− mice under baseline conditions has all the characteristics of sleep observed in sleep-deprived wild-type mice suggesting that a fundamental aspect of the sleep homeostat was altered. The smaller relative increase in EEG delta power and NREM sleep duration after sleep deprivation support this interpretation.
Similarly,Per1,2 double knockout mice seemed to show an increase in EEG SWA (Shiromani et al., 2004), suggesting increased sleep pressure in these mice. The latter would mean that Per signalling is also involved in sleep homeostasis.
However, removal of the SCN never resulted in an overall change in sleep amount in rodents (Tobler et al., 1983,), indicating that arhythmicity caused by loss of the SCN may not be the same as arhythmicity caused by deletion of clock genes.
Does the functioning of the circadian clock change under influence of the level of the sleep homeostat?
Properly timed light pulses will phase shift the circadian clock. In mice and hamsters, sleep deprivation attenuates these phase shifts induced by light (Challet et al., 2001), suggesting that increased sleep pressure reduces circadian clock responses to this zeitgeber. Similarly, in humans attenuated phase advances to light were found after sleep restriction (Burgess, 2010). These data suggest that sleep deprivation reduces light responsiveness or phase shifting capacity of the clock in diurnal and nocturnal animals.
Furthermore in 2009, Schmidt et al., demonstrated thatincreased sleep pressure reduces SCN neuronal activity and the circadian amplitude of the output of the SCN.
What is a possible mechanism underlying how sleep pressure/process S affects the SCN/process C?
Data shows that sleep deprivation reduces activity of SCN neurons and diminishes the phase shifting capacity of the circadian clock in response to light. As a result it could be a possibility that there is inhibition of SCN neuronal activity coming from sleep regulatory centres.
Interestingly,serotonin levels have been show to increase in the SCN during sleep deprivation (Grossman et al., 2000), and serotonin is known to reduce SCN neuronal activity in vitro (Yu et al., 2001). Moreover, impairment of serotonin transmission could partially restore the phase shifting capacity of light (Challet et al., 2001).
Alternatively, the reduction in neuronal activity may also be caused by an unspecific increase in adenosine levels, which are known to increase due to prolonged waking (Porkka-Heiskanen et al., 1997) and generally induce a suppression of neuronal activity. (more info is on another flash card)
How is adenosine thought to underlie the effects of sleep deprivation on the circadian clock/SCN?
Light shifts the clock in the SCN via retinal ganglion cells and the retino-hypothalamic tract (RHT). Following activation by light, glutamate is released at the nerve terminals of the RHT, leading to increased neuronal activity in the SCN. Application of glutamate to the SCN mimics this effect of light (Ding et al., 1994). Sleep deprivation may reduce the phase shifting capacity by diminishing the strength of the photic signal from the RHT, possibly through blocking of glutamate release.
One of the possible inhibiting signals may be an increase in adenosine, which is thought to be involved in sleep regulation. This may, therefore, be the mechanism by which sleep deprivation reduces the light responsiveness of the circadian clock. The conclusion would be that the sleep homeostat reduces light responsiveness of the circadian clock in mammals on the input side of the SCN by excess adenosine reducing the release of glutamate when light information is transmitted from the retina to the SCN. This is supported by data showing that application of an adenosine agonist attenuates light-induced phase delays in behaviour, which subsequently can be restored by an adenosine receptor antagonist (Elliot et al., 2001, Sigworth and Rea, 2003). Similarly caffeine, a general antagonist of adenosine, restores this response also (Van Diepen et al., 2014).
