The VLPO and Ascending Arousal System in Sleep

Melatonin and Sleep Disorders: The Neurobiology of Sleep, Circadian Rhythm Sleep Disorders, and Various Treatment Methods

The VLPO and Ascending Arousal System in Sleep

2.1 Introduction to Sleep

Sleep is thought to be an essential, cyclic, physiologic state defined by a marked decrease in consciousness, a reduction in muscle movement and a general slowing-down of metabolism (Zisapel, N., 2010). About one-third of our lives is spent sleeping.

The sequence of stages in sleep is controlled by a group of nuclei in the brainstem and various functions are attributed to this highly conserved behavior even though its exact purpose has not yet been established.

Hypothetical functions include the replenishment of glycogen levels in the brain, energy conservation as body temperature falls during the night-time and more recently, consolidation of memories by increasing connection strength between synapses. (Purves et al., Neuroscience – 4th ed. 2008)

Sleep in mammals occurs in two forms: rapid eye movement (REM) and non-REM (NREM), which alternate in four or five cycles lasting 70-90 minutes each (Pandi-Perumal et al., 2008). The two are distinguished by the use of polysomnography: the combination of electroencephalography (EEG), electromyography (EMG) and electroculography (EOG) measurements (Pace-Shott and Allan Hobson, 2002).

2.2 The Sleep-Wake Cycle

The waking state is largely controlled by what is known as the ascending reticular activating system, located in the diencephalon and the upper brainstem.

One division of this ascending arousal system projects to thalamic nuclei whereas a second division extends to the lateral hypothalamus all the way to the cerebral cortex. The sleep state, in contrast, is promoted by what is known as the ventrolateral preoptic nucleus (VLPO).

During sleep, its neurons become active whilst its efferents silence the ascending reticular activating system via the inhibitory neurotransmitters GABA and galanin. Afferents from the arousal system, in turn, project to the VLPO and inhibit it during wakefulness.

Essentially, a feedback loop between the arousal and VLPO systems, represented by the ‘flip-flop’ switch model, exists to create dynamic state stability (Schwartz and Roth, 2008).

2.3 Homeostatic and Circadian Regulation of Sleep

Sleep is controlled by two different regulatory processes: the ‘C’ circadian system, in charge of sleep induction and arousal, and the ‘S’ sleep debt homeostatic mechanism. The latter implies that in the case of sleep deprivation, a number of hours of recovery sleep need to ensue which are proportional to the loss of sleep.

One substance thought to act as a somnogen (sleep-promoter) in the homeostatic regulation of sleep is adenosine. This accumulates as ATP levels are depleted and ATP is itself degraded.

Both ‘S’ and ‘C’ processes interact with the SCN in the lateral region of the hypothalamus, that functions as the ‘master clock’ of the brain (Pandi-Perumal et al., 2008).

The circadian regulation of sleep involves a three-stage sequence of steps starting from the SCN, which mainly projects to the nearby subparaventricular zone. This, in turn, relays information to the dorsomedial nucleus of the hypothalamus.

The DMH is one of the GABAergic inputs to the VLPO and the orexin neurons (component of the ascending arousal system) located within the hypothalamus (Pace-Schott and Allan Hobson, 2002; Saper et al., 2005).

Such a complex pathway provides us with the capacity to flexibly adapt physiological cycles in view of external, environmental indicators (Schwartz and Roth, 2008).

The SCN, under physiologic or normal circumstances, is reset diurnally by different mechanisms, depending on the light-dark cycle. During the day it is synchronized via light signals from the retina, specifically by the circadian photopigment melanopsin.

It is melatonin secretion that synchronizes the SCN at night. With loss or damage of the SCN and no external timing cues, the circadian rhythms of a range of physiological bodily processes become disrupted (Pace-Schott and Allan Hobson, 2002; Saper et al.

, 2005).

Figure 2.1. The Circadian and Homeostatic Components of Sleep. Sleep deprivation may cause the two intricately-linked components to become uncoupled.

Figure 2.2: The ‘flip-flop’ switch model. A) during wakefulness: ascending arousal system activated; B) during sleep: ascending arousal system inhibited. ORX: orexin neurons; LC: locus coeruleus; VLPO: ventrolateral preoptic nucleus; eVLPO: extended VLPO; TMN: tuberomamillary nucleus.

2.4 Melatonin’s role in the regulation of the Sleep-Wake cycle

Sleep periodicity is adjusted to a circadian rhythm which is entrained by external cues.

However, the body’s ‘internal clock’, as previously mentioned, still operates even when such ‘zeitgebers’(from the German term ‘time givers’) are removed and no information indicating the time of day is communicated.

In this case, it is said to run freely and the daily 24-hour cycle lengthens to about 26. The sleep-wake cycle therefore, needs to be photoentrained to the day-night cycle so that sleep and wakefulness states are maintained appropriately.

Changes in light levels must be detected by specialized photoreceptors which project to that part of the anterior hypothalamus known as the SCN via the retino-hypothalamic tract (Purves et al., Neuroscience – 4th ed. 2008; Sharma and Feinsilver, 2009).

In the absence of daylight, melatonin resets the SCN during the dark cycle. It affects circadian rhythms by altering the SCN’s metabolic and electrical activity via the protein-kinase C second-messenger system (Pace-Shott and Allan Hobson, 2002; Pandi-Perumal et al., 2006).

Light, however, can repress secretion of nocturnal melatonin as well as contribute to chronodisruption. The extent of this depends on duration and intensity. Maximum suppression occurs at intensities of 2000-2500 lux for 2 hours between 2:00 and 4:00am (Claustrat et al., 2005).

Phases of free-running melatonin rhythms may be reset with light. Such phase shifts can be displayed as PRCs – Phase Response Curves.

Melatonin and light PRCs mirror each other thereby reinforcing melatonin’s label as the ‘darkness hormone’ and thus a transmitter of time-of-day information (Arendt, 1998).

It has been shown through human studies that melatonin administration, in both physiologic as well as pharmacologic doses, induces phase shifts and promotes sleep induction and maintenance (Arendt, 1998, Zhdanova et al., 1995&1996).

As a rule, increased neuronal activity in the SCN and sleep proclivity result after the endogenous rise in nocturnal melatonin secretion. Synthesis and secretion of melatonin runs parallel to sleep rhythm.

This association between melatonin and sleep has been confirmed in studies on blind people, whose SCN cannot be synchronized to the circadian rhythm (Lockley et al., 1997). Dim light melatonin onset (50 lux) timing is used as a consistent marker of circadian phase, even though this may vary between individuals (Cajochen et al.

, 2003; Sletten et al., 2010). Ultimately, melatonin is thought to regulate the sleep-wake cycle by inhibiting the brain network involved in the ascending arousal system of the hypothalamus (Shochat et al., 1998).

Conditions such as aging, diabetic neuropathy, Alzheimer’s Disease as well as particular drugs such as β-blockers and NSAIDs stop synthesis of nocturnal melatonin and thus lead to impaired sleep (Zisapel, 2000). Fatigue and somnolence were also induced with daytime melatonin administration, at a time when endogenous levels in the body are minimal (Cajochen et al., 2003).

Figure 2.3: Regulation of melatonin secretion – light signals are conveyed to the SCN via the retino-hypothalamic tract. At the SCN it entrains the circadian pace-maker to 24 hours and efferent circadian signals are subsequently relayed to different parts of the brain. This includes the pineal gland which is the site of melatonin synthesis.

Source: http://www.inquiriesjournal.com/articles/743/2/melatonin-and-sleep-disorders-the-neurobiology-of-sleep-circadian-rhythm-sleep-disorders-and-various-treatment-methods

A quantitative model of sleep-wake dynamics the physiology of the brainstem ascending arousal system

The VLPO and Ascending Arousal System in Sleep
Info

A quantitative model of sleep-wake dynamics the physiology of the brainstem ascending arousal system

This CellML model runs in both OpenCell and COR to replicate figure 2 in the paper. The units have been checked and they are consistent.

Model Structure

Abstract: A quantitative, physiology-based model of the ascending arousal system is developed, using continuum neuronal population modeling, which involves averaging properties such as firing rates across neurons in each population.

The model includes the ventrolateral preoptic area (VLPO), where circadian and homeostatic drives enter the system, the monoaminergic and cholinergic nuclei of the ascending arousal system, and their interconnections.

The human sleep-wake cycle is governed by the activities of these nuclei, which modulate the behavioral state of the brain via diffuse neuromodulatory projections. The model parameters are not free since they correspond to physiological observables.

Approximate parameter bounds are obtained by requiring consistency with physiological and behavioral measures, and the model replicates the human sleep-wake cycle, with physiologically reasonable voltages and firing rates.

Mutual inhibition between the wake-promoting monoaminergic group and sleep-promoting VLPO causes 'flip-flop' behavior, with most time spent in 2 stable steady states corresponding to wake and sleep, with transitions between them on a timescale of a few minutes.

The model predicts hysteresis in the sleep-wake cycle, with a region of bistability of the wake and sleep states. Reducing the monoaminergic-VLPO mutual inhibition results in a smaller hysteresis loop. This makes the model more prone to wake-sleep transitions in both directions and makes the states less distinguishable, as in narcolepsy. The model behavior is robust across the constrained parameter ranges, but with sufficient flexibility to describe a wide range of observed phenomena.

The original paper reference is cited below:

A quantitative model of sleep-wake dynamics the physiology of the brainstem ascending arousal system, A.J.K. Phillips and P.A. Robinson, 2007, Journal of Biological Rhythms, 22, 167-179. PubMed ID: 17440218

This CellML model runs in both OpenCell and COR to replicate figure 2 in the paper. The units have been checked and they are consistent.

Ca 2+ in the dorsal raphe nucleus promotes wakefulness via endogenous sleep-wake regulating pathway in the rats

The VLPO and Ascending Arousal System in Sleep

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A peek into the interplay between sleep and wakefulness

The VLPO and Ascending Arousal System in Sleep

Sleep is an autonomic process and is not always under our direct, voluntary control. Awake or asleep, we are basically under the regulation of two biological processes: sleep homeostasis, commonly known as 'sleep pressure', and the circadian rhythm, otherwise known as the 'body clock'. These two processes work in harmony to promote good consolidated sleep at night.

The ventrolateral preoptic nucleus (VLPO) in the brain plays a critical role in falling — and staying — asleep, while the lateral posterior part of the hypothalamus contains neurons (brain cells) that play a role in the maintenance of staying awake, including orexin neurons in the lateral hypothalamic area (LHA) and histaminergic neurons in the tuberomammillary nucleus (TMN). To date, however, the precise connectivities among these cell populations remain unclear.

“In our study, we aimed to identify the important players implicated in arousal regulation,” explains Yuki Saito, who co-led a University of Tsukuba-centered study recently reported in The Journal of Neuroscience.

“To achieve the study objective, we focused on populations of hypothalamic neurons, histidine decarboxylase-positive (HDC+) histaminergic neurons (HDC neurons) in the TMN and orexin neurons in the LHA,” adds co-lead author Takashi Maejima.

The team used recombinant rabies-virus-mediated trans-synaptic retrograde tracing in the mouse brain to analyze the architecture and function of hypothalamic circuits that link neuronal populations implicated in sleep/wakefulness regulation. They found that these arousal-related neurons are heavily innervated by GABAergic neurons in the preoptic area, including the VLPO.

The team further characterized GABAergic neurons in the VLPO (GABAVLPO neurons) that make direct synaptic contact with hypothalamic arousal-related neurons. These two groups of neurons were overlapped each other, and both potently inhibited by the hormones noradrenaline and serotonin, showing typical electrophysiological characteristics of sleep-promoting neurons in the VLPO.

“Taken together, our findings provide direct evidence of monosynaptic connectivity between GABAVLPO neurons and hypothalamic arousal neurons and identifies the effects of monoamines on these neuronal pathways,” says study corresponding author Takeshi Sakurai. “This information is important for us to gain a deeper understanding of mechanisms that control sleep and wakefulness, which may lead to the development of reliable recommendations for a restful sleep.”

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Journal Reference:

  1. Yuki C. Saito, Takashi Maejima, Mitsuhiro Nishitani, Emi Hasegawa, Yuchio Yanagawa, Michihiro Mieda and Takeshi Sakurai. Monoamines Inhibit GABAergic Neurons in Ventrolateral Preoptic Area That Make Direct Synaptic Connections to Hypothalamic Arousal Neurons. Journal of Neuroscience, 11 July 2018 DOI: 10.1523/JNEUROSCI.2835-17.2018

Source: https://www.sciencedaily.com/releases/2018/07/180720112846.htm

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