Imagine this: You’ve just wrapped up that report, the one that was due yesterday, but you powered through the evening to get it done. You sacrificed precious family time to meet the deadline, but hey, it’s all worth it now. As you hit the submit button, it’s like a weight has been lifted off your shoulders. You let out a long sigh, feeling the tension melt away. With a satisfying stretch, a yawn escapes, signalling it’s time for bed. Welcome to the first stage of sleep, where you embark on a gentle journey into the land of nod. We know this feeling well, but how does our brain transport us from this light slumber to the deeper depths of sleep? In this article, we will unravel the fascinating journey your brain takes as you transition from that initial drowsiness to the tranquil depths of slumber.
Neuroanatomical and neurotransmitter basis of sleep
Advancements in molecular biology, genomics, and neurophysiology during the 21st century have deepened our understanding of how sleep functions on a cellular level. However, the traditional view of sleep still holds sway, suggesting that the timing and quality of sleep are mainly controlled by the interplay of three factors: ultradian, homeostatic, and circadian rhythms. In the study of biological rhythms, known as chronobiology, ultradian rhythms are recurring cycles or periods within a single day, while circadian rhythms complete one cycle daily.
Adenosine and the homeostatic urge to sleep
When we refer to the term homeostasis, think of a thermostat. In simple terms, homeostasis refers to the body’s ability to maintain a stable and balanced internal environment despite changes happening outside or within the body. It’s like the body’s way of keeping things in check to ensure everything works properly, like a thermostat regulating temperature to keep a room comfortable.
The build-up of naturally occurring adenosine in the brain after extended periods of wakefulness forms the biological foundation of the homeostatic urge to sleep. This means that the longer someone stays awake, the greater the inclination to fall asleep. This regulatory process that influences sleep is referred to as “Process S” in Borbely’s two-process model of sleep propensity.1
The second factor shaping sleep is the circadian rhythm, known as “Process C.” The interplay between these two mechanisms dictates the inclination to sleep at specific times. Both these processes, homeostatic and circadian, are chiefly regulated by the hypothalamus:
The hypothalamus and its role in transitioning to deep sleep
Neurotransmitters originating from the hypothalamus, an ancient brain region, facilitate the transition from light to deep sleep. Responsible for hormone production and regulating bodily functions such as homeostasis and sleep, the hypothalamus reveals a remarkable level of compartmentalisation. With so much depending on it, it has learnt the art of delegation. Consequently, scientists have assigned various names to these subdivisions, so brace yourself for some scientific terminology.
What does VLPO stand for?
The hypothalamus delegates the control of light to deep sleep to an area within its frontal regions called the VLPO. Unfortunately, VLPO doesn’t stand for Very Lazy Pillow Operative but rather ventrolateral preoptic nucleus. Imagine your brain as a bustling office building, with neurons buzzing around like busy employees. Now, picture the VLPO (ventrolateral preoptic nucleus) as that one office manager who’s always trying to get everyone to clock out and head home for some well-deserved rest. It’s like the brain’s sleep sheriff, ensuring all the neurons know when to switch off the lights and hit the sack. The VLPO coordinates the sleep-wake cycle and ensures that the correct parts of the brain go to sleep to get some well-deserved rest. So, when you’re feeling sleepy, you know that the VLPO is on duty, ready to usher you into dreamland.
So, the sleep sheriff, the hypothalamus, is the regulatory centre for sleep homeostasis, with its main office located in the anterior hypothalamus’s ventrolateral preoptic nucleus (VLPO). During sleep, this region becomes activated and employs inhibitory neurotransmitters like gamma-aminobutyric acid (GABA) and galanin to induce sleep by suppressing arousal areas in the brain. The VLPO is prompted to initiate sleep onset by circadian cues from the anterior hypothalamus and feedback regarding sleep-wake balance from internal chemical signals like adenosine, which build up with wakefulness.2
The VLPO and the orexins
It’s time to get more granular and introduce some neuropeptides called orexins to the sleep narrative. The ventrolateral preoptic nucleus (VLPO) instructs other brain cells to cease the release of orexins, which are neuropeptides with significant roles in brain function. Essentially, orexins act as our brain’s workday managers, ensuring the release of wake-promoting neurotransmitters like noradrenaline, serotonin, and dopamine to maintain alertness. However, the VLPO disrupts this process by diminishing orexin activity, shifting the balance towards a more drowsy state. This transition marks the onset of non-rapid eye movement (NREM) sleep.
The reduction in the levels of orexins means they have a limited ability to stimulate neurons in a part of the brain called the locus coeruleus, which makes the arousal-promoting neurotransmitter noradrenaline. Hence, if there is less of this arousal promoter overall, it will favour sleep. Incidentally, neurotransmitters work like dominoes, with the effects on one determining the release of others. For example, the reduced noradrenaline levels have a knock-on effect downstream of less serotonin being released from an area in the brainstem called the raphe nucleus.
Orexins and REM sleep
Orexins have a mean independent streak and, like any petulant teenager, don’t like to be told what to do, so they sneak off to another area of the brain called the pontine tegmentum. Here, they signal brain cells to release abundant acetylcholine, a crucial neurotransmitter that usually promotes alertness but, in this instance, allows us to enter REM since we are still asleep. We know our brains are active during this phase of sleep due to the presence of beta waves, which are also present when we are awake, but it begs the question, if this alert-promoting region is activated, then why don’t we wake up? This is where we can truly appreciate the level of genius coordination of the sleep cycle. At the same time, the orexins are stimulating the cholinergic neurons in the pontine tegmentum, brain cells in the Tuberomammillary nucleus (TMN) within the hypothalamus, responsible for releasing histamine to promote wakefulness, begin to quiet down. As histamine levels decline, we remain in the REM sleep phase.3 This helps to explain how we get the “woke” beta waves during REM sleep but remain asleep; it’s all due to the orexins!
Medicines and neurotransmitters
The process can be influenced by medications that alter the balance of neurotransmitters, fooling our brains into inducing drowsiness. For example, the antihistamines we take for our allergies also have another side effect you may have experienced or figured out if you read carefully. Histamine is associated with wake-promoting circuits in the brain, so when we take an antihistamine, we block its stimulating effect on our consciousness, making us tired. Conversely, certain drugs can enhance alertness (think cocaine). For instance, certain antidepressants boost levels of noradrenaline or serotonin, which may impact REM sleep duration. It’s crucial to remember that REM sleep is vital for processing daily information, underscoring its importance.
It’s crucial to recognise that while neurotransmitters play a significant role in the sleep-wake cycle, particularly during the transition from light sleep (NREM) to deep sleep (REM), they don’t tell the whole story. Neuroscientists have gained substantial insight into sleep through various brain activities like brain wave patterns, memory activation, and dreaming. However, there’s still much we don’t fully understand. Simply adjusting neurotransmitter levels doesn’t account for everything, underscoring the complexity of sleep regulation and the need for further research to unravel its intricacies.
VLPO switches off parts of the brain
The VLPO can achieve control over the sleep-wake cycle by having the capacity to suppress the brain’s wake-promoting areas, which are dispersed across the midbrain and brainstem. Consequently, the VLPO may trigger sleep onset (and suppress REM sleep) by reciprocally inhibiting the brainstem’s cholinergic, noradrenergic, and serotonergic arousal systems. It also exerts similar effects on the histaminergic arousal systems in the posterior hypothalamus and the cholinergic systems in the basal forebrain.
Orexins and narcolepsy
In accordance with this sleep model, hypocretin (orexin) neurons situated in the lateral hypothalamus play a role in stabilising the “switch,” and the loss of these neurons can lead to narcolepsy.
The circadian rhythm
The circadian sleep rhythm is one of several innate body rhythms regulated by the hypothalamus. Circadian rhythmicity operates through an intricate positive-negative feedback loop governing gene transcription in the suprachiasmatic nucleus (SCN) of the hypothalamus:
• Light stimulation of specific cells in the retina (retinal ganglion cells) prompts the SCN to signal the pineal gland to cease melatonin secretion. Melatonin is also known as the Dracula hormone since it only comes out at night and helps us drift off to sleep. It’s the hormone that gets disrupted after long-haul flights, leading to jet lag.
• The SCN sets the body’s internal “clock” to approximately 24.2 hours, and various factors, such as light exposure (known as Zeitgebers), synchronise it to the 24-hour cycle.
• SCN cells influence neighbouring brain nuclei in the anterior hypothalamus, synchronising other structures responsible for regulating rhythmic physiological functions, including sleep, body temperature, and hormonal secretion
The mesopontine junction
Once you’re snoozing away, a special part of your brain called the mesopontine junction takes over. It acts like a conductor, making you switch between different sleep stages smoothly. Think of it like a dance between two groups of cells—one that turns on REM sleep (the dreaming phase) and another that turns it off. They chat with each other through circuits that either excite or calm things down. These neuronal circuits are known to involve different brain chemicals, such as glutamate, serotonin, noradrenaline, and acetylcholine.4
Summary
So, there you have it—quite the journey to catch some Z’s, right? The intricate dance between all these factors shows how delicate the balance of sleep can be. Mess with one piece of the puzzle, and you might find yourself tossing and turning all night long. But now that you’ve got a glimpse into the inner workings of sleep, you can truly marvel at the stunning complexity of it all!
References:
- Borbély, A.A., Daan, S., Wirz?Justice, A. and Deboer, T., 2016. The two?process model of sleep regulation: a reappraisal. Journal of sleep research, 25(2), pp.131-143.
- Lüthi, A., 2019. Sleep: The Very Long Posited (VLPO) Synaptic pathways of arousal. Current Biology, 29(24), pp.R1310-R1312.
- Torterolo, P. and Chase, M.H., 2014. The hypocretins (orexins) mediate the “phasic” components of REM sleep: a new hypothesis. Sleep Science, 7(1), pp.19-29.
- Leschziner G. Oxford Handbook of Sleep Medicine, 2022, Oxford University Press, Oxford
