These group of neurons could well form the target of future therapies for sleep apnea
Sleep and alertness are two opposite conditions, disbalance in any of them may disturb the functioning of various organs and the overall health condition. Globally almost one-fourth of people suffer from some kind of sleep disorder, and obstructive sleep apnea is one of the most common of these ailments.
In sleep apnea, due to various reasons, respiratory tract is blocked when the person is sleeping, as the muscles of the throat are relaxed. This unprovoked blockade awakens a person several times at night, thus disturbing the sleep and limiting its rejuvenating effect on the body and the brain.
If a person is not able to have enough or good quality sleep, there is an increased risk of cardiovascular diseases, insulin resistance, and other disorders.
Researchers are looking for a drug target that could help to improve the sleep quality in those suffering from an obstructive sleep disorder, and yet not compromising on the ability to clear the airway.
Neural regulation of sleep
Neurons use the chemical signals to communicate with each other; these messages are exchanged via chemicals called neurotransmitters. There are several types of neurotransmitters in the brain that affect the different parts differently. Movement of the neurotransmitters up and down the various centers of the brain helps to maintain sleep and alertness.
There were days when scientists use to think that there is one specific center in the brain stem that is responsible for sleep and alertness, but now it is known that things are far more complicated. The balance between sleep and alertness is maintained through interaction between several parts of brain and brain stem. This communication between various centers is made possible through a cocktail of neurotransmitters. Hence histamine, serotonin, acetylcholine, noradrenaline, dopamine all play an essential role in the maintenance of alertness. Thus as an example, antihistamine drugs used to treat allergies may also decrease alertness. Similarly, drugs acting on serotonin, dopamine and so on would also alter the alertness and sleep patterns in patients.
Various neurons located in the locus coeruleus, tuberomammillary nucleus (TMN), dorsal and median raphe nucleus, and the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT) keep firing in a specific pattern to keep us awake and alert.
GABA-ergic and galaninergicneurons in the ventrolateral preoptic nucleus (VLPO) are responsible for the inhibition of arousal system, thus helping a person to fall asleep.
Neurons firing from VLPO and those from arousal system are mutually inhibiting, thus helping to maintain the balance and stability in the state of sleep and wakefulness. If this balance between the arousal pathways and inhibiting effect of VLPO is disturbed, it will lead to disturbances of either sleep or alertness.
Undoubtedly, the above explanation does not provide the complete picture, but a simplified overview of sleep and neural regulation. In reality, too many other brain centers are also involved in more complex manner.
Neural regulation of respiration
Sleep apnea refers to the disturbances in sleep due to the respiratory problem, or obstruction of the airway to be precise. Hence, to understand what causes sleep disturbances in the sleep apnea, it is essential to know how our brain controls respiration.
In the normal state, respiratory centers in the brain play a vital role in the neural regulation of our breathing. Respiratory control is not only crucial for oxygen supply, but also for maintaining the pH in our body. Our body and functioning are highly susceptible to pH changes. Apart from the neural control by the brain centers, there are central and peripheral chemoreceptors that play a critical role in the regulation of breathing.
If the concentration of carbon dioxide increases in our blood, it stimulates the chemoreceptors leading to the increase in the force of respiration. These chemoreceptors are located in the carotid artery (peripheral) and brain (central). They can sense even the slightest of changes in the pH and thus either stimulate or inhibit the respiratory center in the brain stem.
But apart from the respiratory center in the brain stem and chemo reflexes, there are many other ways to control the respiration that are yet to be fully understood. For example, during the moderate aerobic exercise, there is not much change in the blood pH, yet a significant change in respiration rate, indicating the involvement of other brain centers.
The question then arises: What are the other mechanisms involved, apart from the above mentioned?
The house alarm: emergency response system
Obstruction of the airway during sleep is not a standard situation, but rather an emergency. It seems that there is some alarm system in the brain that is activated in such a case, forcing us to become alert and correct the respiration.
In a research study, Kaur et al. demonstrated that parabrachial nucleus (PBel) containing calcitonin gene-related peptide (CGRP) works as an emergency box, raising an alarm that leads to arousal in case of CO2 elevation or hypoxia. To prove their concept, Kaur et al. mimicked the obstructive sleep apnea in the mice by changing the levels of oxygen and carbon dioxide every five minutes for thirty seconds.
Researchers found that it is due to this alarm system that a person wakes up several times at night in order to take voluntary control of respiration. Once the breathing is corrected, a person falls back asleep. But if this alarm is raised too often and too quickly it would result in deprivation from a deep sleep and the various harmful effects related to lack of proper sleep.
Kaur et al. stated that the long-term purpose of this research is to identify a drug that could affect this specific alarm pathway. So that a person is not woken up by minor changes in the respiration and thus improving the quality of sleep in those suffering from sleep apnea.
What we see is that sleep, alertness, and respiration is controlled by various centers in the brain in a very sophisticated manner. There are multiple checks and balances to ensure the smooth functioning and survival of a human being. Any disturbances in this intricate balance have grave consequences for our well-being. We are still trying to demystify all the mechanisms behind the balancing act of sleep and alertness. The more we learn about the functioning, better are the chances of finding an innovative treatment of sleep disorders.
- Kaur S, Wang JL, Ferrari L, et al. A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia. Neuron. October 2017. doi:10.1016/j.neuron.2017.10.009.
- Guyenet PG, Bayliss D. Neural control of breathing and CO2 homeostasis. Neuron. 2015;87(5):946-961. doi:10.1016/j.neuron.2015.08.001.
- Schwartz JRL, Roth T. Neurophysiology of Sleep and Wakefulness: Basic Science and Clinical Implications. Current Neuropharmacology. 2008;6(4):367. doi:10.2174/157015908787386050.
- Schwartz JR., Roth T. Neurophysiology of Sleep and Wakefulness: Basic Science and Clinical Implications. Curr Neuropharmacol. 2008;6(4):367-378. doi:10.2174/157015908787386050.
- Saper CB. The House Alarm. Cell Metabolism. 2016;23(5):754-755. doi:10.1016/j.cmet.2016.04.021