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
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. 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
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
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
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.