Cells, Chemicals, and Structures Responsible for Sleep
Anatomy of Sleep
Although the entire brain chemistry changes during sleep, certain functional structures within the brain play a central role in the regulation of certain sleep cycles. The brain functions understood to play a role in sleep, compiled by the National Institute of Neurological Disorders and Stroke, a division of the National Institute of Health, are detailed below.
The amygdala is an almond shaped mass of grey matter in each cerebral hemisphere. It is thought to play a primary role in the experience of emotions. Because of this, the amygdala is thought to play a large role in experiencing emotions during a dream. The REM sleep stage is when dreaming happens, so the amygdala is most active during this sleep stage.
The basal forebrain, near the front and bottom of the brain, promotes sleep and wakefulness. Adenosine-triphosphate, the main energy source for cellular processes, is composed of adenosine with three removable phosphate groups. When a phosphate group is released, it provides the energy necessary for a reaction to occur. As the day goes on, the concentration of adenosine to adenosine-triphosphate increases, signaling to the brain that it needs rest for cells to build up their adenosine-triphosphate stores. The basal forebrain is especially sensitive to the buildup of adenosine, which leads to a drowsy effect overall.
The brain stem, consisting of the pons, medulla, and midbrain, connects to the hypothalamus to regulate transitions between wakefulness and sleep. The brain stem is in charge of essential functions like breathing, heart rate, and digestion. Sleep promoting cells in the hypothalamus and the brain stem produce GABA, which serves to reduce the level of activity in brain arousal centers. The pons and medulla play a role in REM sleep, sending signals to relax muscles essential for body posture and limb movement so that a person doesn’t go through physical motions of a dream. The midbrain acts as an arousal system.
The hypothalamus contains a group of nerve cells that act as a control center affecting sleep and arousal. Within the hypothalamus are a specialized group of neurons, called the suprachiasmatic nucleus, or SCN. These neurons are responsible for translating information about the kinds of light we see and relaying this to the kinds of neurotransmitters we should be synthesizing. People with damage to their SCN experience erratic behaviors in their circadian rhythm.
When it is dark, the pineal gland receives information from the SCN to increase production of melatonin. That helps to initiate sleep. People who have defective SCNs or who cannot see are encouraged to take melatonin regularly, because peaks and valleys of melatonin concentration in the brain is believed to be central to maintaining circadian rhythms.
The thalamus acts as a relay for information from the external senses to the cerebral cortex. During most stages of sleep, the thalamus stops being as active to allow a person to rest and “tune out” the external environment. During REM sleep, the thalamus begins becoming active again, sending the cortex sensations that become dreams, like images, sounds, and feelings.
Glia, sometimes referred to as glial cells, are non-neuronal cells that that make up the central and peripheral nervous systems. Neurons are thought to be the primary source of cells in the brain and nervous system, but these support cells actually outnumber the neurons by a factor of 10. Their primary role within the brain is to provide support and protection, form myelin, and maintain homeostasis. Homeostasis is a range of parameters that allow the body to function regularly, the optimal conditions under which the brain can function, like temperature, toxicity levels, and ion levels. Glia are a large class of cells, including oligodendrocytes, astrocytes, ependymal cells, microglia, and, in the peripheral nervous system, schwann cells. Glial cells are thought to play a role in sleep by detoxifying the brain, regulating natural metabolism, and promoting synaptic plasticity.
Astrocytes provide nutritional support to neurons by connecting them to a blood supply, typically a capillary. They’re responsible for regulating the concentrations of ions and chemicals in extracellular fluid, the fluid surrounding neurons. They also provide structural support. Because they are the gateway from the blood supply to the neuron, they form the blood brain barrier, a selective barrier that protects the brain from toxins that may be present in the blood.
The ependymal cells are cells that line fluid-filled ventricles in the brain and the central canal of the spinal cord. They’re involved in the production of cerebrospinal fluid, cushion for the brain and spinal cord, and move fluid between the spinal cord and the brain.
Microglia are one of the only kinds of brain cell that can move locations. They seek out and break down dead cells and other debris and also protect the brain from foreign antigens that are able to cross the blood brain barrier.
Schwann cells compromise the myelin on longer neurons in the peripheral nervous system. Because of the logn nature of peripheral nervous system nerves, they require special insulation so that changes can move along the whole axon body, and the signal isn't lost to surrounding tissue. Schwann cells are not found within the central nervous system, so they do not play a large role in sleep.
Neurons are nerve cells that make up the entire nervous system and the brain. These cells are significantly different than most of the cells in the body because their function is to receive sensory input from the external world, cognition and memory recall and storage, send motor commands to muscles, and transform and relay electrical signals in between these steps.
A neuron, generally speaking, has dendrites, a cell body (soma), a nucleus, axons, and axon terminals. On the surface of dendrites are receptors that collect chemical inputs called neurotransmitters from neighboring axon terminals. Common neurotransmitters include dopamine, serotonin, and GABA, but there are many more. These chemical signals can cause changes to the electrical properties of the surface of the cell.
The resting potential of the membrane is -70 mV due to the salt concentrations internal and external to the cell. There are more sodium ions (Na+) outside of the cell and more potassium ions (K+) inside the cell. Even though these two ions are both positive, the overwhelming prevalence of sodium over potassium produces an overall effect of a negative membrane potential. When stimulated, the potential can become more positive or negative, depending on the transmitters released from the efferent neuron. The following is a description of what happens during an action potential, the change in electrical potential associated with the passage of an impulse along the membrane of a neuron. When the membrane reaches a potential of about -55 mV, it signals to sodium voltage-gated channels to open, causing sodium ions to rush into the cell, causing a depolarizing effect. Once the cell membrane potential reaches around +40 mV, the sodium channels close and the potassium channels open, causing an outflux of potassium, while sodium-potassium pumps also work to pump sodium out in exchange for potassium going in. Because of the the combination of pumps and potassium outflux, the cell repolarizes, and then hyperpolarizes. Eventually, the potassium is pumped back in and the potential reaches the resting potential of the cell.
This electrical stimulus causes the neuron to release neurotransmitters from the axon terminals. These stimuli may act to stimulate another action potential in the neighboring neuron if the amount of signal is enough to surpass the -55 mV potential.
This video from Harvard Extension School explains the process of an action potential.
A synaptic cleft is the space between an exon terminus and a dendrite. In the presynapse, there are pockets, called vesicles, that contain a number of neurotransmitters. These neurotransmitters are forced out of the axon terminal after an action potential stimulates a process called exocytosis, where the vesicle is released and the neurotransmitters can flow freely into the synaptic cleft.
Simply put, a neurotransmitter is a chemical that stimulates or inhibits an action potential to a neuron. They are released from the axon terminal of a neuron and bind to receptors on the surface of dendrites. A neurotransmitter can only be excitatory or inhibitory. Often, excitatory and inhibitory neurotransmitters are released to the same neuron at the same time. Whether an action potential happens depends on if the combinatory effect of the two kinds of neurotransmitters is enough to surpass the threshold (-55 mV) necessary to do so. There are many different kinds of neurotransmitters, and new ones are being discovered almost daily. In this section, we’ll cover some of the most commonly found neurotransmitters and the most active neurotransmitters during sleep cycles. Because of the large number of neurotransmitters, only ones lined with sleep or wakefulness will be discussed in the following section.
Neurotransmitters Associated with Wakefulness
Acetylcholine is a confusing neurotransmitter for wakefulness, because it’s activated in both wakefulness and REM sleep. However, it is more closely associated with wakefulness, because it is more commonly found when transitioning from a deeper sleep state to a more wakeful sleep state. Acetylcholine levels in sleep are highest in the forebrain during REM sleep, lower during quiet wakefulness, and lowest during non-REM sleep. In the cortex, acetylcholine is highest during wakefulness and REM sleep compared to non-REM sleep.
Antihistamines like benadryl have long been known to cause drowsiness. Decreasing histamine levels through inhibition of synthesis significantly decreases wakefulness and increases non-REM sleep in rats and cat models. These neurotransmitters are most commonly active in the hypothalamus, but there are diffuse projections throughout the brain.
The following monoamines, Dopamine, norepinephrine, and serotonin, have long been understood to play a critical role in wakefulness. They are found in highest quantities during periods of wakefulness, slow their firing in non-REM sleep, and completely stop firing in REM sleep. They resume their activity in wakefulness.
Stimulants like amphetamine, cocaine, and methylphenidate increase wakefulness and stop hypersomnia by increasing levels of dopamine in the synaptic cleft between the axon terminals.
Administration of norepinephrine, better known as adrenaline, in the brain increases wakefulness of the animal models this has been tested in.
Serotonin release is higher during wakefulness and electrical stimulation of the area of the brain that is known to release the most serotonin. This neurotransmitter is thought to decrease REM sleep in humans and rodents. Selective serotonin reuptake inhibitors are thought to have an insomnia side effect because of these wakefulness effects.
Orexin, also referred to as hypocretin, is known to be involved in the sleep/wakefulness cycle because of its association with narcolepsy. Narcolepsy, a sleep disorder where a person will be completely alert and awake and suddenly fall asleep, is In patients with narcolepsy, there’s a deficiency in this neurotransmitter. Several scientific studies have found that orexin-specific neurons are heavily influenced by the presence of monoamines, suggesting that orexin is associated with wakefulness.
Neurotransmitters Associated with Sleep
Adenosine receptors are thought to be important in sleep because of caffeine. Caffeine binds to a kind of adenosine receptor and produces an alert and awake feeling. When caffeine binds, there are less receptors for adenosine to bind to. Activation the most common adenosine receptor by binding adenosine to the receptor causes neural inhibition, which means neurons are communicating less with each other. Adenosine also indirectly inhibits wakefulness-promoting neurons in the basal forebrain, hypothalamus.
The main inhibitory neurotransmitter in the brain, γ-aminobutryic acid (GABA), plays a large role in sleep health. GABA receptors are the main target of sedative and anesthetic drugs. GABA is also a common additive for sleep aids, although its efficacy is highly debated as a sleep inducer because GABA is unable to pass the blood brain barrier. Neurons with lots of GABA receptors have been inhibited in animal models, and this inhibition leads to increasing sleep. Decreasing levels of GABA in the extracellular fluid increases wakefulness, which is another signal that GABA is a sleep inducing neurotransmitter.
N-acetyl-5-methoxytryptamine, more commonly referred to as Melatonin, is commonly used as an active ingredient in sleep products, and its role as an active ingredient is listed in the active ingredient section below. Melatonin is derived from the neurotransmitter serotonin, which is derived from the amino acid/neurotransmitter tryptophan. Here we will only discuss its role as an endogenous neurotransmitter. Melatonin is produced primarily by the pineal gland in a circadian rhythm, with production happening only in the absence of light. There are a few other areas of the body that produce melatonin, like the gastrointestinal tract.
Two internal mechanisms work together to control whether we are awake or asleep. These are called circadian rhythms and sleep-wake homeostasis.
The circadian rhythm is responsible for directing a wide variety of functions that maintain a steady fluctuation of temperature, metabolism, and hormone release. Human beings must be kept in a strict limit of all of these components to maintain functional capacity. The body’s biological clock controls most circadian rhythms. These sync with environmental cues like light and temperature.
Sleep-wake homeostasis keeps track of the body’s need for sleep, aka the “sleep drive.” It is also responsible for regulation of sleep intensity. This sleep drive gets stronger the longer a person is awake and causes a person to sleep longer and more intensely after a period of sleep deprivation. Sleep-wake needs are impacted by many things: medical conditions, medications, stress, sleep environment, and diet. A huge influence to sleep-wake homeostasis is light. Specialized neurons in the eyes communicate the different wave patterns of light a person sees. These wave patterns can signal to the brain to produce more/less melatonin and other hormones that regulate sleep. Exposure to any light can make it difficult to fall asleep and return to sleep when awakened.