Physiology of Sleep


Physiology of Sleep

Neurotransmitters and brain areas involved in Sleep and Arousal


The reticular formation

       All the characteristics of sleep are functions of different brain activities and circuits. The brain stem  contains an extremely complex web of interconnecting neurons that when electrically stimulated provokes arousal, we call this area the reticular formation. Experimentation shows that stimulation of reticular formation induces arousal and EEG desynchronization. At the same time, destruction of reticular formation produces sleep. Cells from the reticular formation projects into the cortex indirectly and excitation of those cells produce arousal, or wakefulness. This means that one of the functions of the reticular formation is to keep us awake, but at the same time its also involved in REM.


        The reticular formation is also responsible for the production of the main neurotransmitters involved in sleep andwakefulness . One of these is acetylcholine (Ach). Cells that release acetylcholine are called "cholinergic". These cholinergic cells project into the forebrain and cerebral cortex and causes stimulation of these areas, resulting in behavioral arousal. ACh antagonists decrease stimulation of the cortex and ACh agonists increase them. When these cholinergic neurons are sedated by using anesthetics, the arousing effects of electrical stimulation of the reticular formation are eliminated.

       Acetylcholine is released in high levels as a result of wakefulness and alertness. But it is also found in high levels during REM sleep. Its lowest levels have been found in slow wave sleep when there is no cortical arousal, but relaxation. People that have been unfortunate enough to be exposed to organophosphates insecticides, which are ACh agonists, spend more time in REM sleep than individuals who have not been exposed to these toxins. All this evidence suggests that ACh is involved in controlling REM sleep as well as arousal. If we compare the EEG of an awake person vs. EEG of an asleep person we find a great similarity. But how is Ach involved in this process?

Peribrachial area

       Peribrachial area. In the pons there are specific clusters of cholinergic neurons that play a very important role in the activation of REM sleep. This region of the pons responsible for the activation of REM is called the peribrachial area. Cells in this area are quite active during REM sleep. Lesions to this area cause a drastic reduction of REM sleep.

       It is thought that the peribrachial area is involved in initiating REM sleep. Cells in the peribrachial area start firing 80 seconds before the onset of REM sleep. This is why these ACh cells in the peribrachial area are called REM on cells.

       The peribrachial neurons connect directly to brain stem regions that control eye movements. The peribrachial area also has connections with areas of the brain involved in emotion, learning and memory. This suggests that REM on cells could be responsible for the initiation of the fast and scanning eye movements that are characteristic of REM sleep and maybe the emotional aspects of dreaming.


       Another neurotransmitter that has an important role during wakefulness is dopamine, which originates in the cells of the substantia nigra. These cells connect with the frontal cortex, which is involved in thinking, planning, imagining and intellectual capabilities.  Ritalin, cocaine and amphetamines act as dopamine agonists by enhancing its release and by inhibiting dopamine reuptake.  This in turn increases dramatically wakefulness and alterness.

Glutamate and Aspartate

       Other neurochemicals involved in arousal are Glutamate and Aspartate. They are both excitatory, meaning that they trigger an electrical response in neurons. Glutamate is the main excitatory neurotransmitter found in the Nervous system. These neurotransmitters are released the most during wakefulness. They are both found in neurons that project to the cerebral cortex, forebrain and brainstem, thus, important in the activation and arousal of these areas.


       Histamine is also a hormone and a neurotransmitter. It serves an important role outside the nervous system as a by product of inflammation and it also stimulates gastric secretion. Its role in the nervous system is that of keeping us awake and aroused.

       By blocking one of the receptor sites for Histamine (receptor H 1), as in antihistamines to alleviate allergies , causes sleepiness and drowsiness. Histaminergic cells are located in the hypothalamus, specifically in the tuberomammilary nucleus. They project into the cerebral cortex and into areas involved in emotion, memory, temperature and sleep, etc. This indirectly activates Ach REM On cells.


       Serotonin originates mostly in cell of the raphe nuclei in the reticular formation, . Their projections target the same areas as histamine (the thalamus, hypothalamus, hippocampus, basal ganglia and the neocortex). Stimulation of the raphe nuclei produces cortical arousal and automatic motor behavior like chewing and grooming. Serotonin antagonists, like PCPA, greatly reduces cortical activation. Serotonergic cells are activated when we are awake and aroused, during slow wave sleep the firing of serotonin cells decreases and in REM sleep their activity stops and right after REM sleep, their activity slowly increased until the next REM phase.


       Norepinephrine cells arise from the locus coeruleus a nuclei located in the brain stem.  These cells project their axons to the neocortex, cerebral cortex, areas involved in memory, temperature regulation, hormonal regulation and brainstem areas. Norepinephrine is the main neurotransmitter involved in vigilance and arousal. It's a flight or fight substance. It increases our heart beat, respiratory rate and it makes alert. The rate of firing of norepinephrine cells of the locus coeruleus almost stops during REM sleep and increases radically when awoken.

Medial pontine reticular formation

       Another area that is directly connected to the peribrachial area and that is heavily activated in REM sleep is the medial pontine reticular formation or MPRF. MPRF activates cells in the basal forebrain., which will stimulate cortical activity, which is characteristic during REM sleep. Lesions of the MPRF also cause a great decrease of REM sleep.

Muscle paralysis

       Imagine what would happen if we acted out our dreams every night. Dreaming feels so real but while we experience a dream, we are only lying on our bed deeply asleep. Is there a mechanism that inhibits our bodies from acting out our dreams. Evidence suggests that there is a center for the control of muscular activity during REM sleep. This cellular circuit inhibits muscular activity during REM sleep, basically paralyzing the body. During REM sleep,our muscle tone is low, muscles are relaxed and at the same time we are inhibited from using them. Neurons located in the subcoerulear area (under the locus coeruleus, where norepinephrine is produced in the brainstem) seem to be the responsible ones to initiate atonia. Cells from the subcoerulear region project their axons into the magnocellular nucleus, which in turn synapses with motor neurons of the spinal cord, inhibiting their activity, resulting in atonia or muscle paralysis.

       Some brain stem lesions that disturb this pathway produces a disorder called REM without atonia or REM sleep behavior disorder . People with this disorder act out their dreams during REM sleep and cause great harm to themselves without noticing.

Ventrolateral preoptic area

       This area in the basal forebrain, is essential for the initiation of sleep. When VLPA is damaged, it produces a total insomnia and eventually death. Cells in these areas are highly active during all stages of sleep and innactive during wakefulness. This is also confirmed by the high levels of Fos protein found in VLPA cells.

       Evidence shows that VLPA cells are GABA secreting cells and that they project their axons to areas such as the locus coeruleus, the raphe nuclei and the tuboeromamilary nucleus.These ares are the producers of Norepinephrine, Serotonin and Histamine respectively and these neurotransmitters are associated with cortical activation, wakefulness and vigilance. In other words these neurotransmitters activate areas ivolved in thoughts, imagination, etc while keeping us awake. The VLPA cells by having inhibitory effects on these cell centers abolishes wakefulness and mental activity and stimulates drowsiness and sleep.

PGO waves (Pons Genicualte Occipital waves)

        The first sign of the of REM sleep is the presence of PGO waves, which are phasic electrical bursts of neural activity that start in the Pons and move on to the Lateral genicualte nucleus in the hypothalamus and end in the occipital primary visual cortex. All this areas are responsible for eye movements, visual information and visual processing of that information.  PGO waves occur shortly before the onset of REM sleep, suggesting that dreaming is caused by PGO waves. Further support for this is the activation of the occipital lobe and the lateral geniculate nucleus, areas of whose role is to process (or create,or fill in) visual information. Also the activation of areas involved in the control of eye movements could be a response to the visual scenery created by the Occipital lobe and Lateal geniculate nucleus. This means that the person undegoing PGO waves is having a visual experience which is visually scanned. PGO waves might be responsible for the vivid visual experience of dreams and the rapid eye movements typical of REM stage.  In REM deprived individuals PGO activity can take place in earlier stages of sleep, suggesting that PGO waves have physiological relevance. PGO waves have not been recorded in humans for ethical reasons.

REM sleep and the rebound effect

       When we deprive a person of REM sleep for a night and then the person is permitted to sleep through the next night without interruption, they spend a longer period of time in REM sleep, as if compensating the REM sleep that they missed last night. PGO wave might be associated with REM rebound effect. Deprived animals show PGO activity early stages of sleep (as early as in stage 2). In severely deprived animals PGO activity might even show up in wakefulness producing rare behavior suggesting REM intrusions or hallucinations.

Sleep and Thermoregulation

       In the VLPA area, there seems to be a type of circuitry involved in regulating our temperature, a thermostat of the body. Cells  in the hypothalamus receiveinformation about temperature from skin sensors. When these cells are warmed up they decrease the activity of the arousal areas of the brain (areas that secrete neurotransmitters involved in keeping us awake), causing sleepiness. Sleep deprivation in rats caused them to be uncoordinated, sick, weak and unable to control their body temperature. Their metabolic rate was so high that even though they ate more, they continued to loose weight. Maybe an increase in brain temperature raises metabolic rate and the nervous system has the need for more rest and repair which it gets from slow wave sleep. But if this is true than cold temperatures should do the same by increasing metabolic rate to maintain vital temperature.

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