The Physiology of Sleep. Basic Functions of Sleep in The Grand Design

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1 The Physiology of Sleep Sleep is a fundamental need for all animals with a nervous system. Even the simplest animals like the ants, box jellyfish and fruit flies require sleep. Each has been shown to hunt during the day and shut down and apparently sleep at night. No one has yet given a clear explanation of what the objective of sleep might be. The function of sleep and the difference between REM and NREM sleep, has never been explained. The lack of sleep of both types is associated with multiple different causes of early death and changes in activity of the various parts of the cortex. (1) A 1996 study by the University of Chicago Medical Center showed that sleep deprivation severely affects the Human body's ability to metabolize glucose, which can lead to earlystage type 2 Diabetes. (2) Sleep deprivation can adversely affect brain function. The study showed that regions of the brain's prefrontal cortex displayed more activity in sleepier subjects. This appeared to be an attempt to compensate for the adverse effects caused by lack of sleep. (3) The temporal lobe, which is a brain region involved in language processing, was unable to activate normally in sleep-deprived subjects. (4) The parietal lobe was more active when the subjects were deprived of sleep. (5) A 2001 Study at Chicago Medical Institute suggested that sleep deprivation may be linked to more serious diseases such as heart disease, and mental illnesses such as psychosis, bipolar and even death. (6) Animal studies suggest that sleep deprivation increases stress hormones (NE and cortisol), which may reduce new cell production in adult brains. Basic Functions of Sleep in The Grand Design (1) Sleep is required to discharge the brain battery each night to allow more input the next day. During daily activities N-acetyl serotonin is created and builds up in the Thalamus. This causes fatigue and demands sleep. (2) Both NE and N-acetyl serotonin must be removed by sleep. NREM sleep is for reduction of N-acetyl serotonin and fatigue. REM sleep is required to reduce norepinephrine induced stress effects. (3) During the first 4 stages of sleep, N-acetyl serotonin is converted to melatonin. Build up of melatonin is required to allow REM to progress without waking the patient. (4) Norepinephrine build-up increases all defenses. Failure to REM keeps NE levels high and the individual in defensive posture the next day. REM sleep provides a system for removal of excess NE.

2 (5) During REM sleep acetylcholine reacts at the nach receptor in the amygdala. Ach opens the receptor and drains the fear (NE) neuron. (6) Then, Ach reacts to provide a methyl group to NE. This partially neutralizes the -/- charge to -/+. This reduces the Redox potential and creates epinephrine. (7) REM sleep serves to sort and solidify important memories. Neuron Firing Rates with Sleep NREM sleep occurs in the thalamus and functions to remove the N-acetyl serotonin left over from the day s activities. Reaction of acetylcholine with N-acetyl serotonin produces melatonin, which is released into the cerebral spinal fluid (CSF) from the pineal gland at the posterior of the thalamus. The CSF carries melatonin as it flows through the 3 rd ventricle and blocks the GABA receptors of the super-chaismic nucleus in the forward portion of the hypothalamus. This suppresses alertness (consciousness) and allows REM sleep to occur. The suprachiasmatic nucleus, or nuclei, (SCN), a tiny region on the brain's midline in a shallow impression of the optic chiasm, is responsible for controlling endogenous circadian rhythms. The neuronal and hormonal activities it generates regulate many different body functions over a 24-hour period. The SCN, pinecone shaped and smaller than a pea, interacts with many other regions of the brain. It contains several cell types and several different peptides (including vasopressin and vasoactive intestinal peptide) and neurotransmitters. The ratio of norepinephrine to dopamine at the suprachiasmic nucleus affects circadian rhythms and release of prolactin, which in turn affects steroid metabolism. REM sleep occurs in the hippocampus in the survival centers. Dreams are apparently only viewed by the thalamus (consciousness) in incomplete snatches as the patient is coming in and out of REM and into consciousness. Neuron firing rates of from rat studies, below, reveal that serotonin, norepinephrine and dopamine neurons are silent during REM, yet acetylcholine neurons continue to fire rapidly. During sleep, acetylcholine-producing neurons from the movement/rem group of the giganto-cellular nucleus fire steadily. They release acetylcholine in the hippocampus that reacts with the negative amine neurotransmitters (DA, NE, SER) from the interstitial tissues of the Hippocampus. State Specific Firing Rates: Brainstem and Cortical Neuron Groups Site Neurotransmitter Wakefulness NREM With REM Basal Forebrain Acetylcholine LateralTegmentum/Pedunculopontine Tegementum Acetylcholine Dorsal and median Raphe Serotonin Loceus coerulus Norepinephrine Tuberomammillary nucleus Histamine Posterolateral hypothalamus Hypocretin/Orexin

3 Ventrolateral preoptic area GABA The Goals of REM Sleep It appears that the there are several goals of REM sleep. These include: REM sleep is important for removal of excess norepinephrine, which reduces irritability, hyper-vigilance and its over-all survival effects. REM sleep functions as a switching device to reduce the individual s survival status from stressed to relaxed. REM sleep includes a coincidence detector that allows memories to be added to previous memories in series. REM sleep includes a system that appears to determine which memories are important and should be saved, based on survival criteria. REM system blesses these neuron-connection-sets and causes a system of solidification of important memories. REM sleep is required for survival based long-term memory Other Effects of REM REM sleep can be dissociated into its different components, including (1) muscle atonia, (2) EEG de-synchronization, (3) PGO waves, and (4) random eye movements. Each of these clinical manifestations of REM sleep is under the control of discrete cell groups within the pontine reticular formation and the midbrain reticular formation, i.e. the sublateral dorsal area (SLD), also known as the sub-coeruleus area. PGO (PontoGeniculoOccipital) waves are named for the sites where they can be easily recorded-the pons (where they originate), the lateral geniculate nucleus, and the occipital (visual) cortex. They are important for two major reasons. These PGO waves are important for two reasons. They indicate that prior to the cortical EEG signs of REM profound changes in the neural activity are taking place within the brain and, secondly, they represent a powerful example of how other brain regions are influenced by activity

4 emanating from the pontine brainstem. The cell groups of the PGO system are the effector neurons. These cell groups are silent during NREM sleep. They begin to depolarize 30 to 60 seconds before the first sign of REM sleep occurs, producing PGO waves. The pontine-midbrain reticular formation then undergoes further neuronal depolarization, leading to the development of action potentials in these cell groups. The action potentials increase as REM sleep starts and this high rate of firing of acetylcholine neurons is maintained throughout the REM sleep episode. The Flip-Flop Switch Saper and colleagues have been at the forefront of research into the mechanisms of the sleep-wake cycle. Clifford B. Saper, MD, PhD James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School Professor, Department of Neurology, Beth Israel Deaconess Medical Center They identified inhibitory and excitatory neuron nuclei in the hypothalamus that work a so-called flip-flop switch. Saper and his team have discovered that inhibitory neurotransmitters from neurons making up the ventrolateral pre-optic nucleus (VLPO) in the hypothalamus are responsible for turning the switch on and off. The VLPO, which is made of both GABAnergic (γ-aminobutyric acid) and galaninergic neurons, sends inhibitory outputs to the components of the ascending arousal system (locus ceruleus) and these nuclei primarily fire only during sleep states. By inhibiting the arousal system, neurons of the VLPO allow rapid transition from wake to sleep. This so-called flip-flop switch loses its 50% of efficiency in the course of normal aging because of neuron loss. Removal of VLPO neurons compromised the ability to sleep and the experimental animals lost three-fourths of slow wave sleep. Another crucial, but opposite, component of the sleep-wake mechanism is the activity of peptonergic, orexin neurons within the lateral hypothalamus. These neurons send excitatory outputs to the ascending arousal system, evoking the opposite effect of neurotransmissions from the VLPO. Orexin neurons add weight to the 'on' side of the flip-flop switch and create stability. They allow a person to maintain a waking state for a 16-hour day. At the appropriate time, VLPO neurons turn off orexin and

5 allow consolidated sleep to occur. Adenosine had been identified as a possible mediator of the homeostatic sleep process. It is an endogenous sleep-producing substance [10,18,22 24]. A breakdown product of adenosine triphosphate (ATP), adenosine is believed to be a homeostatic sleep factor that mediates the transition from prolonged wakeful-ness to NREM sleep. Adenosine mediates this transition by inhibiting arousal-promoting neurons of the basal forebrain. Caffeine is believed to promote Wakefulness by blocking adenosine receptors. ATP is an important energy reserve in neurons. Adenosine accumulates in certain areas of the brain when neurons consume energy in the form of ATP during prolonged wakefulness. Single Neuron Activity in Cat Gigantocellular Tegmental Field: Selectivity of Discharge in Desynchronized Sleep Robert W. McCarley 1 and J. Allan Hobson 1 1 Department of Psychiatry, Harvard Medical School, Boston, Massachusetts Science 17 December 1971: Vol no. 4015, pp DOI: /science Ratios of discharge rates in desynchronized sleep to those in waking and synchronized sleep of gigantocellular neurons are five to ten times higher than are those of neurons in adjacent tegmental fields and 25 to 30 times higher than in other brain sites. This marked concentration of activity in desynchronized sleep is compatible with an active role of gigantocellular neurons in the generation of this sleep phase Proposed Chemistry of Sleep Stages I to IV During the day s activities, non-emotional stimuli generate serotonin in the reticular system. This is sent to the limbic system where it must be taken up by neurons to power non-emotional activities. Activity from serotonin neurons motivates work and responsible behaviors. Serotonin is the most active amine transmitter and is used for all the mundane non-emotional stimuli. During conscious thought, the acetyl group from acetylcholine reacts to form N-acetylserotonin in the CM during the day, releasing low-level energy. Excess serotonin remains stored primarily in the interstitial tissues in the cingulate gyrus. N-acetyl serotonin, produced during consciousness and the days activities, causes fatigue and absolute need for sleep. During sleep, melatonin is formed in a two-stage process. As sleep begins, the NAS reacts with one of the methyl groups from acetylcholine, which is produced by the neurons of the low pontine tegementum (movement/rem neurons of the gigantocellular nucleus). This reacts to form melatonin, which blocks the suprachiasmic nucleus and inhibits NE release from the locus ceruleus. Thus, melatonin calms fear and allows deeper sleep. The reaction releases the acetyl group, which is then free to react with serotonin to produce more N-acetyl serotonin. The system appears to feed backward because the methyl group from acetylcholine must come off first. After reacting with NAS, the acetyl group is left and can react with serotonin to make more NAS. Both parts of the acetylcholine must be used. This would explain why it takes a slow decent to reach stage IV sleep.

6 Melatonin is released into the CSF from the pineal gland. CSF flows to the anterior 3 rd ventricle before exiting through the hypothalamus then out through fenestrations in the pituitary capsule. Melatonin calms the GABA receptors of the supra-chaismic nucleus and ventro-lateral pre-optic area. As the melatonin levels increase, the patient descends through the 4 stages of sleep. Melatonin production increases steadily but slowly because of the backward chemistry during the first 4 stages of sleep, until an attempt to dream is made. GABAnergic flip-flop switch neurons are stimulated by melatonin in the cerebral spinal fluid coming from the pineal gland. They inhibit dopamine ß Hydroxylase release in the locus ceruleus. This inhibits norepinephrine production and calms fear. The individual must feel safe to sleep and very safe, to dream. REM Sleep Classically for Humans, the sleep pattern is described as cycling through the first four stages of sleep, over approximately 90 minutes, after which there is an attempt at REM sleep. As can be seen from the graph, the pattern is more complicated and variable than that, and is defined by stress, environment, age, and a host of emotional and situational factors. However, the sleep of a young healthy adult has more deep stage IV sleep, far more REM and fewer awakenings than that of the stressed or aged patient. After the patient slips slowly into deep stage IV sleep, an attempt at REM sleep is made. If the patient s dreams are disturbing or the level of threat is too high, the patient will wake. The patient will also wake if there is insufficient melatonin to suppress fear and maintain sleep.

7 Chemistry of REM Sleep During REM sleep, acetylcholine neurons of the brainstem gigantocellular nucleus (movement/rem neurons) are firing rapidly. These impulses course through the cerebral cortex and then download their energy to norepinephrine in the hippocampus. The acetylcholine produced at the synaptic tip reacts in the hippocampus (not the thalamus) with norepinephrine that has been stored in the neurons of the limbic system. The NE is discharged passively though the nicotinic-ach receptor and not from active firing neurons. During the reaction, acetylcholine opens the nachr, which allows Na + to flood into the neuron and NE -2 to pour out. Acetylcholine reacts with the NE and delivers a methyl group to norepinephrine to form epinephrine in the interstitial tissue. The energy released in the hippocampus is perceived as a dream by the thalamus only in brief flashes, as we come out of sleep.

8 Psychiatric Significance of NREM and REM Sleep

9 Anxiety, fear and anger are driven by norepinephrine and removed by REM sleep. Yet the high level of norepinephrine (fear) must be subdued, temporarily, to allow REM to occur. This catch 22 is reduced by melatonin produced from serotonin and N-acetyl serotonin during NREM sleep. Remember, serotonin is not a happiness transmitter. It is a neurotransmitter for control and inhibition of energy release in all of its reactions. Tricyclic anti-depressants and SSRIs block the uptake of serotonin and norepinephrine into the neurons. This relieves the oppressive symptoms of depression from serotonin. By blocking serotonin, the heavy depressive inhibitory symptoms are lessened and greater proportion to of serotonin can be removed during NREM sleep to produce melatonin. If sufficient melatonin is produced in progressive stage I to stage IV sleep, then REM sleep can occur without waking the individual. During REM sleep, norepinephrine neurons in the locus ceruleus must be held completely silent. They re in charge of the survival instincts, and if they re firing, the individual will be wakeful and worrying at 2:00 a.m. The dreaming process requires that the survival instincts must be turned off. The subject is also in a state of dream paralysis, and memory and consciousness are supposed to be disconnected. If the patient does not dream, then norepinephrine levels will continue to be high the next day. When serotonin and N-acetyl serotonin are used up, further attempts at dreaming cannot continue. Fatigue is relieved, but irritability and defensive posture continue and build each day as norepinephrine levels increase. The dreams we perceive, are most likely just sound bites of dreaming that occur only during the moments of waking for most individuals. Some patients, however, appear to experience prolonged vivid dreams ( like going to the movies ) with REM stimulators. Hallucinations, meditation, self-hypnosis or drug induced states may all be variations of dreaming without being asleep. It takes approximately 90 minutes to cycle through the 4 stages of sleep and attempt to dream. Therefore the patient gets only a few attempts to dream each night. If a patient is waking two or three times per night just to pee, this frequently represents failed REM attempts, and the patient may not be getting effective REM sleep. Individuals who do not get REM sleep will continue to have high levels of norepinephrine the next day. This sets the level of the survival instinct higher each day that the individual cannot achieve REM sleep. The patient becomes increasingly irritable and hypervigilant.