Neurobiological Basis of Sleep PDF

Neurobiological Basis of Sleep Julie Ann Kristy L. Torres, MD, FPCP, FPNA Brokenshire College – School of Medicine References  Why do we sleep and wake up? Humans evolved as equatorial animals and our behavior is dominated by a circadian rhythm of daylight activity and noct...

Neurobiological Basis of Sleep Julie Ann Kristy L. Torres, MD, FPCP, FPNA Brokenshire College – School of Medicine References  Why do we sleep and wake up? Humans evolved as equatorial animals and our behavior is dominated by a circadian rhythm of daylight activity and nocturnal sleep  Biological Rhythms Defined as the inherent timing mechanisms that control or initiate various biological processes – Linked to cycles of days and seasons produced by the Earth’s rotation on its axis  Biologic Clock Synchronize the behavior of organisms to the temporal passage of a real day Allows an organism to anticipate events in advance and prepare for them both physiologically and cognitively Regulates feeding times, sleeping times and metabolic activity so that they are appropriate to day-night cycles Regulate gene expression in every cell for homeostasis  Biologic Clock 24 hours – Time required to complete a cycle of activity  Suprachiasmatic Nucleus Main biological clock Located in the hypothalamus – Above the optic chiasm Curt Richter (1965) – First to locate the SCN – Circadian rhythm in rats lost when SCN was ablated by electrical current  Suprachiasmatic Nucleus Neurons in this area have an intrinsically rhythmic pattern of activity that is genetically determined  Suprachiasmatic Nucleus GABA – main neurotransmitter of the SCN neurons – Inhibitory synapses – Allows SCN neurons to act in synchrony  Suprachiasmatic Nucleus 2 parts: 1. Core – non rhythmic, entrains the shell neurons 2. Shell - rhythmic  Suprachiasmatic Nucleus Zeitgebers – Time-givers or cues that entrain the SCN neurons to the solar day – Light as the main zeitgeber – Others: feeding, mobility, arousal, changes in lighting  Suprachiasmatic Nucleus Experiment in rodents: – When a radioactive tracer is injected into rodents, more tracer is found in the SCN after injections given in the light period than after injections given in the dark period of the light–dark cycle – Therefore, suprachiasmatic nucleus neurons are more active during the light period. Suprachiasmatic Nucleus LIGHT ON LIGHT OFF  Suprachiasmatic Nucleus Light entrains the SCN and in turn drives a number of slave oscillators, which are responsible for rhythmic occurrence of one activity  Suprachiasmatic Nucleus The SCN clock entrains slave oscillators through: 1. SCN neurons send axonal connections to nuclei close by in the hypothalamus and thalamus. 2. The SCN connects with pituitary endocrine neurons to control the release of a wide range of hormones. 3. The SCN also sends indirect messages to autonomic neurons in the spinal cord to inhibit the pineal gland from producing the hormone melatonin, which influences daily and seasonal biorhythms.  Suprachiasmatic Nucleus The SCN controls the release of these hormones: 1. Melatonin from the pineal gland circulates during the dark phase of the circadian cycle rest activities 2. Glucocorticoids from the adrenal gland circulate during the light phase of the circadian cycle arousal activities  Melatonin Hormone that induces sleepiness Postganglionic retinal nerve fibers mediate its production and secretion through the retinohypothalamic tract to the SCN then to the superior cervical ganglion and finally to the pineal gland  Melatonin Light inhibits its release Darkness facilitates its release Tryptophan – source of melatonin The daily rhythm of melatonin secretion is also controlled by an endogenous, free-running pacemaker located in the suprachiasmatic nucleus.  Melatonin Production activation of a 1-and b 1-adrenergic receptors in the pineal gland raises cyclic AMP and calcium concentrations activates arylalkylamine N- acetyltransferase, initiating the synthesis and release of melatonin  Biologic Clock Other biological clocks: – Intergeniculate leaflet of thalamus – Pineal gland – Raphe nucleus of brainstem  Damage to Suprachiasmatic Nucleus Animals still eat, drink, exercise, and sleep, but they do these activities at haphazard times. – If all the pathways into and out of the SCN are cut, SCN neurons maintain their rhythmic electrical activity.  Suprachiasmatic Nucleus The SCN receives information about light through the retinohypothalamic tract – This pathway begins with specialized retinal ganglion cells (RGCs)  Retinohypothalamic Pathway Retinal ganglion cells – Distributed throughout the retina – Contains melanopsin photosensitive pigment – Receive light-related signals from the rods [dim] and cones [light] and send these signals to visual centers in the brain – Can also be activated directly by certain wavelengths of blue light in the absence of rods and cones  Retinohypothalamic Pathway Retinal ganglion cells – Glutamate main neurotransmitter – Other neurotransmitters: substance P pituitary adenylate cyclase-activating polypeptide (PACAP) Retinohypothalamic Pathway Retinohypothalamic Pathway  Molecular Basis of the Biological Clock Step 1: Transcription In the cell nucleus: three Period genes (Per1,* Per2, Per3) two Cryptochrome genes (Cry1, Cry2) Transcribed into Per1, Per2, and Per3 mRNA transcription-translation- Cry1 and Cry2 mRNA inhibition feedback loop  Molecular Basis of the Biological Clock Step 2: Translation In the endoplasmic reticulum, ribosomes translate these mRNAs into the proteins PE R1, PE R2, PE R3 and CRY1, CRY2. transcription-translation- inhibition feedback loop  Molecular Basis of the Biological Clock Step 2: Translation In the intracellular fluid, the proteins then form various dimers, or two protein combinations, such as PERCRY. transcription-translation- inhibition feedback loop  Molecular Basis of the Biological Clock Step 3: Inhibition PERCRY dimers enter the cell nucleus, where they bind to and inhibit the CB dimer (formed by the CLOCK and BMAL proteins). transcription-translation- inhibition feedback loop  Molecular Basis of the Biological Clock Step 3: Inhibition The CB dimer turns ON the Enhancer box (Ebox), a part of the DNA that activates transcription of the Period and Cryptochrome genes. So when the CB dimer is inhibited, the Per and Cry genes are no longer expressed. transcription-translation- inhibition feedback loop  Molecular Basis of the Biological Clock Step 4: Decay After they play their inhibitory role, the PERCRY proteins decay. Then the CB dimer resumes its activity, the Per and Cry genes resume expression, and the 24- hour cycle begins anew. transcription-translation- inhibition feedback loop  Molecular Basis of the Biological Clock This sequence of gene turn-on followed by gene turn-off occurs in an inexorable, daily loop.  Molecular Basis of the Biological Clock Mutations in any circadian gene can lead to circadian alterations, including absence of a biorhythm or an altered biorhythm. – For example, alleles of Period 1 and Period 2 genes determine chronotype. whether an individual will be “early to bed and early to rise” or “late to bed and late to rise” PHYSIOLOGY OF SLEEP  Function of Sleep Not a passive process Biological adaptation – Energy conserving strategy to cope with times when food is scarce – Increases alertness in waking state  Function of Sleep Neural maturation Facilitation of learning and memory Targeted erasure of synapses to “forget” unimportant information that might clutter the synaptic network Cognition Clearance of metabolic waste products generated by neural activity in the awake brain Conservation of metabolic energy  Sleeping Behavior Consists of – Resting – Napping – Long bouts of sleep – Various sleep-related events including snoring, dreaming, thrashing about, and even sleepwalking  Cellular Basis of Sleep Sleep promoting activity – Mediated by GABA through its interactions with the GABA-A receptor GABA released by sleep-promoting neurons in the anterior hypothalamus – Adenosine also promotes sleep inhibits hypocretin/orexin neurons in the basal forebrain, lateral hypothalamus and tuberomammillary nucleus Activates neurons in the preoptic/anterior hypothalamus and ventrolateral preoptic area  Cellular Basis of Sleep Wakefulness promoting activity – Acetylcholine, dopamine, norepinephrine, serotonin, histamine and hypocretin promote wakefulness  Stages of Sleep Sleep is not a unitary state but consists of a number of stages 1. Waking state 2. Non rapid eye movement sleep – N1, N2, N3 3. Rapid eye movement sleep 75% of sleep is spent in NREM stage (N2)  Stages of Sleep The body cycles through all stages of sleep approximately 4 to 6 times each night – From N1 to N2 to N3 to N2 then REM A complete cycle takes about 90 to 110 minutes First REM period is short and as night progresses, longer period of REM and decreases time in deep sleep (NREM) occur  Rapid Eye Movement vs Non-REM Sleep REM Sleep Non-REM Sleep Fast wave activity Delta rhythm or slow wave sleep Eyes flickering back and forth (REM) Atonia [no muscle tone]  Stages of Sleep Awake – EEG: beta rhythm – open eye awake state alpha rhythm – if relaxed and drowsy, eyes closed  Stages of Sleep N1 Stage – 5% of total sleep time – Lasts for 1 to 5 minutes – EEG: theta rhythm – low voltage – Lightest stage of sleep – Begins when more than 50% of alpha rhythm are replaced by low amplitude mixed frequency activity – Muscle tone is present, breathing is regular  Stages of Sleep N2 Stage – 45% of total sleep time – Lasts for 25 minutes in the 1st cycle and lengthens with each successive cycle – EEG: sleep spindles and K complexes – Deeper stage of sleep – Heart rate and body temperature drop – Bruxism may occur  Stages of Sleep N3 Stage – 25% of total sleep time – Slow wave sleep (SWS) – Deepest stage of sleep – EEG: delta rhythm – lowest frequency, highest amplitude – Difficult to awaken from; if awoken, may have sleep inertia (mental fogginess) – As people age, they spend less time in this stage and more time in N2 – Body repair, builds bone and muscle, strengthen immune system – Sleepwalking, night terrors and bedwetting may occur  Stages of Sleep REM Stage – 25% of total sleep time – Lasts for 90 minutes after sleep onset – 1st REM cycle lasts 10 minutes and final cycle lasts for 1 hour – EEG: beta rhythm – similar to wakefulness – Associated with dreaming – Atonic skeletal muscles except for eye and diaphragm movement – Breathing is erratic and irregular – Dreams, nightmares, penile or clitoral tumescence may occur  Stages of Sleep REM Stage – Important characteristics: People tend to awaken spontaneously in the morning during an episode of REM sleep Loss of motor tone, increased brain O2 use, increased and variable pulse and blood pressure Increased levels of ACh The brain is highly active throughout REM sleep, increasing brain metabolism by up to 20%  Evolution of Sleep through Aging Newborns and Infants (birth to 1 year) – Sleep timing in newborns is distributed evenly across day and night for the first few weeks of life, with irregular sleeping and waking patterns. – Newborns sleep approximately 16 to 18 hours per day discontinuously, with the longest continuous sleep episode typically lasting 2.5 to 4 hours.  Evolution of Sleep through Aging Newborns and Infants (birth to 1 year) – Newborns have 3 different types of sleep: quiet sleep (similar to NREM), active sleep (similar to REM), and indeterminate sleep. – In contrast to children and adults, newborn sleep onset occurs through REM, not NREM, with each sleep episode consisting of only 1 or 2 cycles.  Evolution of Sleep through Aging Newborns and Infants (birth to 1 year) – Circadian rhythms develop around 2 to 3 months of age – At 2 months of age, the progression of nocturnal sleeping begins. – At 3 months of age, the cycling of melatonin and cortisol in a circadian rhythm occurs, and sleep onset begins with NREM. REM sleep decreases and shifts to the later part of the sleep cycle. The total NREM and REM sleep cycle is typically 50 minutes instead of the adult 90-minute cycle.  Evolution of Sleep through Aging Newborns and Infants (birth to 1 year) – At 6 months of age, the longest continuous sleep episode lengthens to 6 hours. – At 12 months, infants typically sleep 14 to 15 hours daily, with most sleep occurring in the evening and only 1 to 2 naps needed during the day.  Evolution of Sleep through Aging Toddlers (1 to 3) and Children (3 to 9) – Around 2 to 5 years of age, the total sleep time needed each day decreases by 2 hours, from 13 to 11 hours. – By 6 years of age, children manifest circadian sleep phase preferences and tend toward being night owls or early risers.  Evolution of Sleep through Aging Adolescents (10 to 18) – The total sleep time required for adolescents is 9 to 10 hours each night. – Due to various pubertal and hormonal changes accompanying puberty's onset, slow-wave-sleep and sleep latency time declines, and time in stage N2 increases. – Around mid-puberty, daytime sleepiness occurs more frequently than at earlier puberty stages.  Evolution of Sleep through Aging Adults (19 years and beyond) – Adults tend to demonstrate earlier sleep time, wake time, and reduced sleep consolidation. – Adults aged 65 and older awaken approximately 1.5 hours earlier and sleep an hour earlier than adults aged 20 to 30. Most people sleep less as they grow older  Evolution of Sleep through Aging Gender differences – Men tend to spend a greater amount of time in stage N1 sleep and experience more nighttime awakenings, so there is a greater propensity for daytime sleepiness. – Women maintain slow-wave sleep longer than men and tend to complain more often of difficulty falling asleep. Additionally, daytime sleepiness increases during pregnancy and the first few months postpartum.  Neural Basis of Sleep Reticular activating system – Proposed by Moruzzi and Magoun – Sensory pathways entering the brainstem have collateral axons that synapse with neurons in the RAS.  Neural Basis of Sleep Reticular activating system – They proposed that sensory stimulation is conveyed to RAS neurons by these collaterals then RAS neurons produce the desynchronized EEG via axons that project to the cortex.  Neural Basis of Sleep Stimulation of RAS – Waking EEG Damage to RAS – Slow-wave, sleep-like EEG  Neural Basis of Sleep Basal forebrain – contains large cholinergic cells which secrete acetylcholine (ACh) from their terminals onto neocortical neurons to stimulate a waking EEG (beta rhythm). – Waking associated with being still yet alert  Neural Basis of Sleep Median raphe – Located in the midbrain – Contains serotonin (5-HT) neurons whose axons also project diffusely to the neocortex, where they also stimulate neocortical cells to produce a beta rhythm, recorded as a waking EEG. – Waking associated with movement  Neural Basis of REM Sleep Peribrachial area – Responsible for REM sleep – Dorsal part of brainstem anterior to cerebellum – Extends to the medial pontine reticular formation – Damage to this area reduces or abolishes REM sleep  Neural Basis of REM Sleep SLD/subcoerulear nucleus Clinical Correlates  SLEEP APNEA Individuals with sleep apnea experience airway collapse in deeper sleep states, causing them to experience reduced time in stage N3 and REM sleep. This leads to excessive daytime drowsiness as proper, efficient sleep is not obtained throughout the night. Treatment: – CPAP or BiPaP machine during sleep  SLEEP APNEA 2 types: – Central sleep apnea occurs when the brain fails to signal respiratory muscles during sleep. – Obstructive sleep apnea is a mechanical problem in which there is a partial or complete blockage of the upper airway.  REM SLEEP DISORDER If the temporary atonia of REM sleep is disturbed, it may be possible to physically act out (often unpleasant) dreams with vocalizations and sudden limb movements. The cause of this disorder is not entirely known but may be associated with degenerative neurological conditions such as Parkinson disease or Lewy body dementia.  NARCOLEPSY Narcolepsy is a sleep cycle disorder in which individuals present with persistent daytime sleepiness and brief episodes of muscle weakness (cataplexy). Sleep regulation is disturbed, and individuals tend to skip the initial phases of sleep and fall directly into REM sleep. – These individuals can enter the REM phase and have dreams during short naps. This limits their amount of sleep in the N3 deep-sleep stage and thus causes an irregular sleep pattern. – May experience a sudden loss of muscle strength as body muscles are atonic and paralyzed in the REM-sleep phase. – These lapses into REM sleep can happen anytime during the day and usually last seconds to minutes.  SOMNAMBULISM Sleepwalking Common occurrence in school-aged children – These individuals tend to make purposeful movements, but they are not acting out their dreams. – Typically associated with common behaviors, such as dressing, eating, and urinating. Occurs in the non-rapid eye movement phases, usually in N3 Sleepwalking occurs because the sleep cycle is still in the maturing phase, and proper sleep/wake cycles are not yet regulated. Thank You