The role of the brain and neurotransmitters in the sleep-wake cycle.
Written by: Shriya
The brain is undoubtedly the most complex part of the human body. It is the source of all the qualities that define our humanity. This three-pound organ is responsible for your intelligence, interpreting senses, initiating body movement and even controlling behavior. From a virtually never ending list, one important control the brain expresses is that over sleep. The brain’s influence over sleep and wake is not completely understood. However, through extensive research, scientists have identified several neurotransmitters and structures in the brain that are involved with sleep.
Every night we spend several hours asleep and every morning we awaken to go about our lives. Our sleep is divided into two phases, non-rapid eye movement (NREM) sleep, and REM (or paradoxical) sleep during which most of our dreaming occurs. These phases, which can be further characterized into 4 stages, were discovered through experiments using electroencephalography (EEG) to examine human brain waves. An EEG is a test that detects electrical activity in your brain using small, metal discs, known as electrodes, attached to your scalp. Your brain cells communicate via electrical impulses and are active all the time, even when you're asleep (1).
When we fall asleep, the EEG reveals that our brains generate rhythmic oscillations called "slow waves." These waves are important for keeping us asleep and for recovering after a full day of mental and physical activity.
In general, when the alerting areas of the brain are most active, they send arousal signals to the cerebral cortex (the outer layer of the brain that is responsible for learning, thinking, and organizing information), while at the same time inhibiting activity in other areas of the brain that are responsible for promoting sleep, resulting in a period of stable wakefulness (2). When the sleep-promoting areas of the brain are most active, they inhibit activity in areas of the brain responsible for promoting wakefulness. This results in a period of stable sleep.
What parts of the brain control the sleep/wake cycle?
Until recently, it was thought that only two areas in the brain were required to control sleep and wakefulness. However, more recent research has indicated that the situation is actually substantially more complicated than that: wakefulness actually appears to be regulated by a whole network of redundant structures and is not centred in any one part of the brain. (2)
When it is time to sleep, the normal signals of wakefulness are interrupted at the thalamus. The thalamus serves as the “gatekeeper” or relay system to the cerebral cortex (which is the outer layer of the brain where conscious activity occurs). During this period before sleep, it effectively disconnects the cortex from most internal and external signals. It is largely the thalamus that imparts the regular brain waves of deep slow-wave sleep to the cortex.
The hypothalamus contains nerve cells that act as control centers affecting sleep and arousal. It also contains the suprachiasmatic nucleus which has clusters of thousands of cells. These cells receive information about light exposure directly from the eyes thus aiding in creating a light-dark cycle which is matched to the circadian rhythm. The suprachiasmatic nucleus sends messages to the pineal gland, which then increases production of the melatonin, a hormone important in the sleep wake cycle.
The ventrolateral preoptic nucleus (VLPO) of the hypothalamus is one area of the brain that is particularly involved in the switch between wakefulness and sleep, which scientists refer to as “mutual inhibition” (3). Neurons in this small area help to promote sleep by inhibiting activity in areas of the brainstem that maintain wakefulness. Similarly, during waking hours, those areas of the brain that are active in maintaining wakefulness by stimulating the cerebral cortex also work to inhibit the neurons of the VLPO. For this reason, the VLPO is often referred to as the “sleep switch.”
The brain stem communicates with the hypothalamus to control the transitions between wake and sleep. Sleep-promoting cells within the hypothalamus and the brain stem produce a brain chemical called GABA, which reduces the activity of arousal centers. The brain stem also plays a special role in REM sleep by sending signals to relax muscles essential for body posture and limb movements. (4)
The basal forebrain also promotes sleep and wakefulness, while part of the midbrain acts as an arousal system. They allow for the release of adenosine which supports sleep drive. The amygdala, a structure involved in processing emotions, becomes increasingly active during REM sleep. This supports the idea of dreaming during this stage of sleep.
How are neurotransmitters involved?
The sleep wake cycle is also driven by the release of a variety of different neurotransmitters, which are the body’s chemical messengers and transmit messages between neurons, or from neurons to muscles.
The Neurochemistry of Sleepiness
Gamma-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter that has a critical role in coordinating the actual process of falling asleep. It lowers the activity of neural cells in the brain and central nervous system, having the effect of moving the brain and the body into lower gear. By inhibiting neural activity, GABA facilitates sleep, reduces mental and physical stress, lowers anxiety, and creates a calmness of mood (5).
Adenosine is a byproduct of metabolic and electrical activity within your neurons. This means that the level of adenosine in particular regions of your brain is an indication of the amount of time you have spent awake that day. It directly inhibits regions which are tasked with keeping the brain awake, in particular specialized cells in the hypothalamus which contain the chemical orexin/hypocretin, as well as cholinergic cells (containing the neurotransmitter acetylcholine) in the brain stem (6). Furthermore, adenosine is also able to send excitatory messages to the preoptic region, which in turn inhibits wake-promoting regions.
Nitric oxide promotes sleep through a variety of mechanisms by promoting the release of adenosine and therefore initiating the kind of sleep-promoting effects described above. It is involved in NREM sleep and sleep homeostasis.
Melatonin is often referred to as the sleep hormone and is converted from serotonin in the pineal gland. It is released during the night under the regulation of your suprachiasmatic nucleus. Melatonin release is therefore sensitive to light signals from the retina and works to entrain your internal sleep-wake cycle to an external clock.
The Neurochemistry of NREM Sleep
GABA / Galanin are chemical messengers that are used by the ventrolateral preoptic nucleus to activate sleep. NREM sleep is therefore predominantly associated with these two neurochemicals.
Serotonin functions during NREM sleep to inhibit acetylcholine signals which predominantly support REM sleep. In this sense, serotonin helps to regulate the onset of REM sleep during the night (6).
The Neurochemistry of REM Sleep
Acetylcholine is the main neurochemical which is released from these “REM-on” cells in the pons, which generate REM sleep. Activation of these acetylcholine cells creates an oscillating pattern of electrical activity. These waves pass from the pons to areas of the brain which are involved in visual processing (your occipital cortex) and help to create the vivid imaginary world which plays out inside your dreams (6).
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