The Physiological Basis of Sleep Regulation
By Vaitheswaran Gopiram
Neurotransmitters and Sleep Regulation:
Sleep is the period when the body and mind are both relaxed and inactive. Sleep gives time for the brain to organize information, solidify memories, and clear out harmful toxins. Multiple parts of the brain come together to manage sleep, and neurotransmitters, small particles that travel between neurons to pass messages along in electrical impulses, act as the tools the brain uses to regulate sleep. One of the most important parts of the brain that is used in sleep is the hypothalamus. The hypothalamus produces neurotransmitters such as y-aminobutyric acid (GABA). GABA is the principal inhibitory neurotransmitter in the brain which inhibits cells that are involved in arousal functions.
GABAergic neurons, which produce the GABA neurotransmitter, suppress many other neurotransmitters that play a part in the body’s arousal systems, paving the way for sleep. One of these neurotransmitters is histamine which works in the histaminergic system. This system in the hypothalamus affects histamine receptors on cells, specifically the H1 receptors. When the H1 receptor is triggered in the cell, it promotes wakefulness. Norepinephrine is another neurotransmitter subdued by GABA. High levels of norepinephrine are seen when the body is in a state of activity; norepinephrine is a hormone involved in the synthesis of melatonin: a chemical that helps the body enter and stay asleep. Another neurotransmitter that helps control the muscles is Serotonin. Serotonin acts on various receptors in the brain: 5-HT1A, 5-HT2A, 5-HT3, and more. Overall serotonin’s influence on these receptors can be summarized as promoting wakefulness; therefore, inhibiting serotonin allows the body to slip into sleep. Finally, Orexin (hypocretin) is the neurotransmitter that triggers the release of the amino acid glutamate. Glutamate has excitatory and inhibitory functions which work to stabilize the arousal system.
Sleep is a cycle that keeps running by various neurotransmitters. Acetylcholine and norepinephrine, in particular, play crucial roles in the smooth transition from the stages of sleep and the balance of the sleep-wake cycle. The sleep-wake cycle can be divided into four stages: wakefulness, the period during which the mind is alert and awake; light sleep, a stage of sleep characterized by rapid eye movements (REM) and light muscle activity; deep sleep, a stage of sleep described by delta brain waves (oscillating electrical signals in the brain); and rem sleep, a stage where there are dreams and rapid eye movements. Acetylcholine helps the transition into REM sleep by its interactions with muscarinic receptors, particularly the M2 subtype. The muscarinic receptors in the brain are responsible for numerous signaling pathways that modulate neuron excitability. Norepinephrine is important for promoting wakefulness and sustaining a state of arousal to help the body wake up. Its levels are regulated differently in the various sleep stages and correlate with how deep the body is in sleep.
There needs to be a specific balance of these neurotransmitters in the brain for the body to have a smooth sleep-wake cycle. An imbalance of these neurotransmitters allows for sleep disorders to happen. For example, imbalances in the neurotransmitter GABA can lead to sleep disorders such as insomnia. If the acetylcholine balance is disrupted, the body struggles to enter REM sleep smoothly and this can lead to the development of REM sleep behavior disorder (RBD). Sleep disorders can also develop from multiple neurotransmitters, such as Sleep Apnea which develops from low GABA levels and high Glutamate levels in the insular cortex of the brain.
In conclusion, the intricate dance of neurotransmitters within the brain is vital for the consolidation of memories, the clearance of toxins, and the boost of learning. Understanding the complex interplay of neurotransmitters in sleep regulation not only provides insight into the mechanisms underlying sleep disorders but also opens up new avenues for research and potential therapeutic interventions. As we continue to explore the intricate workings of the brain, the importance of a balanced neurotransmitter environment for optimal sleep becomes increasingly clear.
Sleep Architecture and Memory Consolidation:
In everyday life, our brains constantly absorb new information and need to process this information for it to be accurately stored in our long-term memory. This process is called memory consolidation. When the body is asleep, the brain has low levels of stimulation and high levels of neurotransmitter activation allowing different parts of the brain to communicate freely. This is the ideal environment for the brain to create and strengthen the connections that form our memories. Sleep also gives the brain time to remove any old and unnecessary neural connections allowing it to stay efficient. Also, each stage of sleep has its characteristics and functions for memory consolidation. For example, the dual process hypothesis argues that “different sleep stages serve the consolidation of different types of memories” Rasch and Born. Overall, the intricate relationship between sleep and memory consolidation underscores the critical role sleep plays in the brain’s ability to efficiently process and store new information.
While it feels that the transition from being awake to fast asleep happens in an instant, the process of falling asleep is more complex and involves multiple stages, each with its characteristics and functions. The main stages are wakefulness, light sleep, deep sleep, and REM (Rapid Eye Movement) sleep. A single cycle will typically take anywhere from 90–110 minutes, and a normal night of sleep will consist of multiple repetitions of this cycle. The cycle can also be divided into 4 other stages: N1, N2, N3, and REM sleep; N1–3 make up the light and deep sleep sections. Stage 1, also known as N1, is when the body first falls asleep and brain activities begin to slow down. If the person hasn’t woken up, they slip into N2 where the body’s temperature drops, the muscles relax, and the heart rate along with breathing slows down. N3, also known as deep sleep, is when the brain starts emitting delta waves which are the slowest type of brain waves. In N3, the body strengthens the immune system and repairs bones and muscles; this stage is also important for storing memories and learning. Research shows that during this stage, the brain’s hippocampus is the most active and reactivates memories allowing for changes in the neural networks through a process called long-term potentiation. Finally, REM sleep is the stage where you experience dreams and undergo atonia which is when the brain paralyzes the muscles to prevent you from moving in your dreams. REM sleep plays a crucial role in learning, memory, and even mood since it stimulates areas of the brain and is also associated with increased production of proteins.
The main difference between REM sleep and slow-wave sleep is the types of memories that are consolidated during this time. During slow-wave sleep, the brain reactivates already-formed memories to review them and decides whether these memories are important enough to be strengthened and kept. This process is known as memory pruning. Also, slow-wave sleep is known to consolidate declarative memories: memories about events, facts, and personal experiences. During REM sleep, the brain works to consolidate non-declarative memories which are typically emotional, motor, and learning memories. Also, during REM sleep the brain transfers short-term memories to the temporal lobe where they will be stored as long-term memories through long-term potentiation.
Overall, the consolidation of memories is a unique process associated with the unique characteristics of sleep stages. The ongoing research in this field continues to uncover the nuances of how sleep influences memory consolidation, including the underlying neurophysiological mechanisms that enable these processes. However, many questions do remain about the specific roles of REM sleep in memory consolidation and the precise mechanisms by which sleep enhances memory formation and retention. Sleep is not just a passive state of rest but an active process, and by providing the brain with the optimal environment for memory processing, sleep ensures that we can efficiently learn from our experiences and adapt to new information.
Sleep Deprivation and Cognitive Performance:
While the recommended amount of sleep that a person needs depends widely on many factors, such as their age and environment, most people will be healthy if they get around 7–9 hours of sleep per night. However, according to the Centers for Disease Control and Prevention (CDC), approximately 1 in 3 adults in the United States don’t get enough sleep per night. Getting enough sleep is important since sleep gives the body time to rest and recover. A lack of sleep can impact a person’s mood, attention, memory, emotions, and judgment. During sleep, the brain undergoes many stages which are linked to memory consolidation and cognitive processing. When people experience sleep deprivation, they often exhibit similar symptoms of memory lapses, difficulty focusing, and reduced problem-solving skills.
Sleep deprivation can lead to a range of impairments that affect daily life and performance in different tasks. For example, sleep deprivation can lead to deficits in a person’s short-term memory. This reduced performance is mainly because the brain is working overtime and its neural activation is reduced. A person can keep working because of the neural compensatory response which is when brain regions or networks that aren’t typically used come into play. A lack of sleep also affects the long-term memory of a person since sleep is the time when the brain consolidates its memories. A disruption of this process prevents the memories from being fully secured into the long-term memory. Memory isn’t the only process that is impeded by no sleep, verbal; visual; and auditory tasks also are meddled with since the respective parts of the brain that are associated with these tasks are working past their extended limit. Overall the effects of the task can vary based on the type of task and the duration of sleep deprivation.
The recovery period for sleep deprivation is simple as the main treatment is to get more high-quality sleep. Recovery sleep differs from natural sleep as it’s made up of increased amounts of slow-wave sleep and REM sleep and less time spent on stage 1 sleep and wakefulness. Research shows that one full night, or around 8 hours, of recovery sleep may be enough to reverse the effects of acute sleep deprivation. However, other factors such as age and gender may influence recovery times. Studies have shown that women report more sleeping problems than men and that sex hormones may affect sleep and cognitive performance differently in men and women. Finally, the variability in recovery times is also influenced by the duration and severity of sleep deprivation. Typically the brain adapts to stressful situations to maintain performance at a reduced level, postponing the restoration of normal functioning.
In conclusion, the importance of adequate sleep cannot be overstated, as it plays a crucial role in maintaining overall health, cognitive function, and emotional well-being. The consequences of sleep deprivation are far-reaching, affecting not only memory and attention but also impairing performance in various tasks and daily activities. Recovery from sleep deprivation is facilitated by obtaining high-quality sleep, which includes increased amounts of slow-wave sleep and REM sleep.
References:
Siegel JM. The neurotransmitters of sleep. J Clin Psychiatry. 2004;65 Suppl 16(Suppl 16):4–7. PMID: 15575797; PMCID: PMC8761080.
Marcin, A. (2023, March 17). What Is Deep Sleep and Why Is It Important? Healthline. https://www.healthline.com/health/deep-sleep#:~:text=Deep%20sleep%20or%20slow%2Dwave,heart%20disease%20and%20Alzheimer%27s%20disease.
de Leon AS, Tadi P. Biochemistry, Gamma Aminobutyric Acid. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551683/
Schomerus C, Korf HW. Mechanisms regulating melatonin synthesis in the mammalian pineal organ. Ann N Y Acad Sci. 2005 Dec;1057:372–83. doi: 10.1196/annals.1356.028. PMID: 16399907.
Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev. 2011 Aug;15(4):269–81. doi: 10.1016/j.smrv.2010.11.003. Epub 2011 Apr 2. PMID: 21459634.
Abrams P, Andersson KE, Buccafusco JJ, Chapple C, de Groat WC, Fryer AD, Kay G, Laties A, Nathanson NM, Pasricha PJ, Wein AJ. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol. 2006 Jul;148(5):565–78. doi: 10.1038/sj.bjp.0706780. Epub 2006 Jun 5. PMID: 16751797; PMCID: PMC1751864.
Abrams P, Andersson KE, Buccafusco JJ, Chapple C, de Groat WC, Fryer AD, Kay G, Laties A, Nathanson NM, Pasricha PJ, Wein AJ. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol. 2006 Jul;148(5):565–78. doi: 10.1038/sj.bjp.0706780. Epub 2006 Jun 5. PMID: 16751797; PMCID: PMC1751864.
Rasch B, Born J. About sleep’s role in memory. Physiol Rev. 2013 Apr;93(2):681–766. doi: 10.1152/physrev.00032.2012. PMID: 23589831; PMCID: PMC3768102.
Patel AK, Reddy V, Shumway KR, et al. Physiology, Sleep Stages. [Updated 2024 Jan 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526132/
Suni, E., & Suni, E. (2023, December 8). Stages of Sleep: What Happens in a Sleep Cycle. Sleep Foundation. https://www.sleepfoundation.org/stages-of-sleep
Daum I, Ackermann H. Nondeklaratives Gedächtnis — neuropsychologische Befunde und neuroanatomische Grundlagen [Nondeclarative memory — neuropsychological findings and neuroanatomic principles]. Fortschr Neurol Psychiatr. 1997 Mar;65(3):122–32. German. doi: 10.1055/s-2007–996316. PMID: 9173034.
Greer, M. (n.d.). Strengthen your brain by resting it. https://www.apa.org. https://www.apa.org/monitor/julaug04/strengthen#:~:text=During%20REM%20sleep%2C%20the%20brain%20transfers%20short%2Dterm%20memories%20in,it%20in%20long%2Dterm%20memory.
Frenda, S. J., & Fenn, K. M. (2016, December 1). Sleep less, think worse: The effect of sleep deprivation on working memory. Journal of Applied Research in Memory and Cognition. https://doi.org/10.1016/j.jarmac.2016.10.001
Liberalesso PB, D’Andrea KF, Cordeiro ML, Zeigelboim BS, Marques JM, Jurkiewicz AL. Effects of sleep deprivation on central auditory processing. BMC Neurosci. 2012 Jul 23;13:83. doi: 10.1186/1471–2202–13–83. PMID: 22823997; PMCID: PMC3411400.
