Sleep and wakefulness Domina Petric, MD

Average healthy sleep time is 7,5 hours a day

Sleep across the lifespan Decreases with age.

Circadian cycles sleep body temperature growth hormone cortisol

Nocturnal body temperature is lower than daytime body temperature. Circadian cycles Body temperature decreases in the bedtime and rises in the time when we awake. Nocturnal body temperature is lower than daytime body temperature. Growth hormone levels rise in the bedtime, whilst cortisol hormone levels rise in the time of awakening.

Retino-hypothalamic projection Suprachiasmatic hypothalamic nucleus contains a molecular clock responsible for generating circadian rhythm. Retino-hypothalamic projection connects the molecular clock with signals from environment.

Retino-hypothalamic projection Photosensitive retinal ganglion cells contain the pigment MELANOPSIN. Photosensitive RGC are important for sensing the overall level of illumination in the environment. Projections from photosensitive RGC go into the suprachiasmatic hypothalamic nucleus.

Molecular mechanisms When light strikes photosensitive RGC and they send signals into the cells of suprachiasmatic hypothalamic nucleus, certain genes are activated. Those genes produce proteins CLOCK and BMAL1. CLOCK and BMAL1 associate as dimers and enter the nucleus of the hypothalamic cell. Dimers bind to regulatory elements called E-boxes.

Molecular mechanisms Another set of genes is then activated with production of protein CCG and proteins from the PER family (PER 2 and PER3). These proteins form their own dimers that enter the nucleus of the cell. CCG, PER2 and PER3 proteins dimers prevent BMAL1 and CLOCK dimers to bind to the E-boxes. This is form of negative feedback.

Molecular mechanisms This cycle with a negative feedback endures a little bit more than 24 hours (24 and a half hours) and represents our circadian rhythm.

Melatonin It is produced by PINEAL GLAND (EPYPHISIS). Melatonin begins to promote a transition from wakefulness towards drowsiness and sleep. Levels of melatonin start to rise in the later afternoon and are high during the night sleep and then begin to fall before awakening. During the day melatonin levels are low.

Normal activity: high frequency, low amplitude, irregular. EEG Normal activity: high frequency, low amplitude, irregular. Seizure: highly synchronous, high amplitude, low frequency.

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Normal brain waves Delta waves are characterised with very large amplitude, very slow waves, frequency 1-4 Hz: deepest stage of sleep. Theta waves are characterised with frequency of 4-7 Hz: drowsiness. Alpha waves are characterised with frequency of 8-13 Hz: deactivation of sensory cortical areas (state of quiet rest). Beta waves are characterised with frequency above 12 Hz. Gamma waves are characterised with frequency of 40-60 Hz. Both beta and gamma waves are high frequency and low amplitude waves: high degree of irregular activity and desynchronization, information processing.

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There are four stages of non-REM sleep and there is the REM sleep. Sleep stages There are four stages of non-REM sleep and there is the REM sleep.

Non-REM stages of sleep Stage I: drowsiness, modest increase in amplitude of brain waves and increase in synchronicity. Stage II: sleep spindles (very brief high frequency high amplitude activity in clusters), lasts 15-20 minutes. Stage III: larger incrase in amplitude of brain waves and slower frequencies (moderate levels of sleep). Stage IV: large amplitudes, slow delta waves (cerebral cortex is dissociated from its environment). Stage IV is hypersynchronous slow rhythm of thalamocortical oscillation.

REM sleep Rapid eye movement or paradoxical sleep. Low amplitude, high frequency pattern. Cerebral cortex is in the desynchronised state. Medial parts of the forebrain are activated in REM sleep: anterior cingulate cortex, parahippocampal gyrus and amygdala. Dorsolateral prefrontal cortex and posterior cingulate cortex are inactivated during the REM sleep. Most of the dreams occure in REM sleep fase.

Body states As night progresses we spend more time in REM sleep than in stage IV of non-REM sleep. There is active supression of sceletal muscle activity during REM sleep. In deep fases of non-REM sleep there is decrease in heart frequency and respiration frequency. During REM sleep there is increase in heart and respiration frequency. Men can experience penile erection during REM sleep.

Functions of dreams in REM fase Maintenance: going through intense emotional states, aggression. Unlearning: erasing non-adaptive memories. Learning: consolidation of learning and memory (synaptic plasticity).

Wakefulness cellular mechanisms Brainstem nuclei Neurotransmitter Activity state of brainstem neurons Cholinergic nuclei of pons-midbrain junction Acetylcholine Active Locus coeruleus Norepinephrine Raphe nuclei Serotonin Tuberomammillary nuclei Histamine Lateral hypothalamus Orexin

Non-REM sleep cellular mechanisms Brainstem nuclei Neurotransmitter Activity state of brainstem neurons Cholinergic nuclei of pons-midbrain junction Acetylcholine Decreased Locus coeruleus Norepinephrine Raphe nuclei Serotonin

REM sleep cellular mechanisms Brainstem nuclei Neurotransmitter Activity state of brainstem neurons Cholinergic nuclei of pons-midbrain junction Acetylcholine Active (PGO waves) Raphe nuclei Serotonin Inactive Locus coeruleus Norepinephrine

PGO waves Ponto-geniculo-occipital waves propagate from the pons into the lateral geniculate nucleus of the thalamus, and then into the occipital cortex. PGO waves are present in REM sleep.

Hypothalamic nuclei Ventrolateral preoptic nucleus (VLPN) has antagonising effect on the orexin neurons from the lateral hypothalamic area. Orexin neurons promote wakefulness. Ventrolateral preoptic neurons promote drowsiness. Tuberomammillary nucleus promotes wakefulness.

Tuberomammillary nucleus To cerebral cortex, basal forebrain VLPN Tuberomammillary nucleus Orexin neurons Cholinergic brainstem nuclei Locus coeruleus (brainstem) Raphe nuclei (brainstem)

Adenosine ADENOSINE activates VLPN (ventrolateral preoptic nucleus) to promote sleep. Adenosine is energy thermostat in the basal forebrain region that is indicating the energy levels. Adenosine accumulates when it is time to go to sleep, when the energy level is low. Caffeine and theophylline block adenosine receptors promoting wakefulness.

Thalamocortical neurons Oscillatory state in sleep: hyperpolarisation. Active, tonic state in wakefulness: depolarisation.

Literature https://www.coursera.org/learn/medical-neuroscience: Leonard E. White, PhD, Duke University http://www.med.nyu.edu Medicalook.com