Sleep is a process which is defined as a consolidated period of rest and inactivity coupled with reduced response to external stimuli (Cirelli et al. 2005; Cirelli 2009; Bushey et
al. 2010; Crocker and Sehgal 2010). Sleep or sleep-like behaviour is a recurring state in many
organisms and is a unique behavioural trait that contradicts the basis of survival, temporarily reducing awareness and putting muscles in a state of inactivity. While in such a state, the organism is vulnerable to risks such as predation and therefore to be prevalent in such a diverse set of species sleep must serve an important purpose
1.7.1
Sleep Regulation
It is known that sleep is governed by genetics, though environmental factors can have an impact on the quality of a sleep episode (Cirelli 2009; Sehgal and Mignot 2011).
Discovery of hereditable sleep traits led to investigating suitable model organisms for sleep research, from which some of the molecular mechanisms behind sleep have been uncovered (Cirelli 2009, Sehgal and Mignot 2011). Sleep is regulated by two independent mechanisms, circadian and homeostasis. Circadian rhythm dictates the cycle of sleep within a 24-hour period, restricting the behaviour to times that are ecologically suitable (Cirelli 2009; Crocker and Sehgal 2010). The homeostatic mechanism is reflected in the perceived increase of pressure to sleep throughout the waking period, which is reset when having slept (Crocker and Sehgal 2010; Donlea et al. 2013). Both mechanisms have a set of genes already associated with them, some of which overlap. Circadian genes interact and determine circadian rhythmicity, mutations of which result in phenotypes such as abnormal sleep duration but no difference in sleep pattern following deprivation (Cirelli 2009).
48 Some genes’ level of expression changes in the brain between sleep and waking states, lending further evidence to a molecular function of sleep (Cirelli 2009). This molecular function is likely to be conserved across many organisms, as has been proven with other genetic pathways. Sleep-like behaviour has been documented in widely used model
organisms such as mice, zebrafish, D. melanogaster, and even worms (Crocker and Sehgal 2010; Bidaki et al. 2011; Sehgal and Mignot 2011). In mammalian and avian species, sleep can be recognised through criteria detected on an electroencephalogram (EEG) which cannot easily be done for many other species (Crocker and Sehgal 2010). Many sleep disorders, such as insomnia and narcolepsy, have had some underlying genetic mechanisms exposed through genome analysis and model organism research (Bidaki et al. 2011; Sehgal and Mignot 2011). Some disorders are also found to be caused by singular gene mutations such as chronic primary insomnia and sleep-phase syndrome. Many neurological disorders also have sleep variations reported as a symptom (Lane et al. 2017). While individual genes have been statistically or experimentally linked to the onset of sleep disorders, not all have had the molecular mechanisms behind their involvement exposed.
The underlying process of sleep being governed by genetics but heavily influenced by external factors implies that the purpose of sleep is simply to recover from a bout of activity and prolonged consciousness. However, the exact purpose is unclear.
Genetically and chemically, sleep and the abundance of certain chemicals or gene expression can be correlated. Furthermore, there are sleep promoting drugs which act as sedatives and other substances which act as stimulants that temporarily help reduce sleep pressure.
There are several medical disorders which have sleep dysfunction as either a cause or symptom. Many psychiatric disorders such as SZ and BD exhibit differences in sleep
49 behaviour than would be expected of “normal” sleep. Alongside differences in sleep/wake cycle, symptoms such as catatonia are comparable to being sleepy and fatigued. It is also possible that dysfunctional sleep can lead to the deterioration of proper neurological
functions, potentially describing a cause of the neurological disorders rather than symptom. Sleep dysregulation can cause a multitude of problems for the function of the body. Simply delaying sleep results in immediate negative impacts on performance and health (Bidaki et al. 2011), followed with a rebound effect of increased sleep duration in the next sleep period. Sleep issues have been linked to poor memory retention (Tomita et al. 2015), and abnormal total sleep amount has been linked to a reduced lifespan (Bushey et al. 2010). Disordered sleep may also play an important role in the aetiology and maintenance of physical and mental health (Lane et al. 2017). Links between fractured or curtailed sleep behaviour and type 2 diabetes are demonstrated by a rise in blood-glucose levels in individuals chronically deprived of sleep (Spiegel et al. 2005; Knutson and Cauter 2008). Sleep curtailment has also been linked to dysregulation of appetite, higher body mass, and a decrease in energy expenditure (Spiegel et al. 2005; Knutson and Caulter 2008). Chronic sleep deprivation has even been statistically correlated with increased suicide ideation in teenagers (Whitmore and Smith 2018).
1.7.2
Sleep in Drosophila melanogaster
While physiologically very different to humans, the fruit fly has a sleep state which demonstrates some clear parallels to human sleep. In flies, the documented sleep state is classified as a period of quiescence for 5 minutes or longer (Cirelli et al. 2005; Cirelli 2009; Bushey et al. 2010). Numerous studies have identified similarities between the human and D.
50 thresholds and molecular mechanisms like Dopamine signalling (Shaw et al. 2000; Bushey et
al. 2010; Tomita et al. 2015). If deprived of sleep through continuous stimuli, D.
melanogaster exhibit decreased vigilance and upon being allowed to rest, display a sleep-
rebound effect of a longer and less fragmented sleep following sleep deprivation (Shaw et al. 2000; Bushey et al. 2010). Another similarity with humans is that fruit flies are also
predominantly diurnal, with most of the rest periods being consolidated in the night/lights off period (Bushey et al. 2010; Liu et al. 2015).
Circadian rhythms and the regulating clock neurons which dictate the daily oscillations of most physiological and behavioural processes have been widely researched in the D.
melanogaster model. The circadian rhythm or biological clock enables an organism to
anticipate changes in environmental factors such as lights on or sunrise (Renn et al. 1999). The standard activity graph for flies in controlled conditions over a 24-hour period includes clear pre-emptive behaviour of increased activity before the programmed lights on or lights off timing (Cirelli et al. 2005; Cirelli 2009; Bushey et al. 2010). In mammals, the pacemaker for daily activity cycles is in the hypothalamus while the fly neurons regulating this cycle are associated with the brain’s visual centres (Renn et al. 1999). The fly brain contains
approximately 150 dedicated clock neurons, divided into distinct subsets by function and anatomical location (Cavanaugh et al. 2014). Of these, the small lateroventral neurons appear to be one of the most dominant regulators of the sleep/wake cycle as loss of these neurons result in arrhythmic behaviour patterns in constant dark conditions, yet ablation of all but these neurons can allow a robust activity pattern even in total darkness (Renn et al. 1999; Cavanaugh et al. 2014). The neuropeptide pigment-dispersing factor (pdf) is expressed within most of the lateroventral neurons, and is implicated as the principal circadian transmitter, with flies deficient in this gene expression showing entrainment to the light/dark cycle but losing regular patterns in constant darkness (Renn et al. 1999). The requirement of rho for
51 sleep is localized to the pars intercerebralis part of the fly brain that is developmentally and functionally analogous to the hypothalamus in vertebrates (foltenyi k 2007; Cavanaugh et al. 2014). This region is also proven to be responsible for the D. melanogaster ortholog of human corticotrophin releasing factor regulation of proper sleep/wake cycles, dysfunction of which results in arrhythmicity (Cavanaugh et al. 2014).
The alternative, and less understood, component of sleep regulation is the sleep
homeostat. This is responsible for creating an increased need to sleep in response to stimuli or prolonged periods of wakefulness, and the cause for the sleep rebound effect seen after sleep- deprivation (Donlea et al. 2014). This function in D. melanogaster has been linked to fan- body region of the brain, which is similar in function to the mammalian hypothalamic ventrolateral preoptic nuclei (Donlea et al. 2014). The fan-body is modulated by
dopaminergic neurons, and artificial stimulation induces sleep on command (Lui et al. 2012). Sleep in both fruit flies and humans has been linked to longevity, with numerous genetic mutations in D. melanogaster affecting sleep amount often having a negative effect on average lifespan (Bushey et al. 2010).