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Neurobiology Of Sleep. By Ahmad Younis Professor of Thoracic Medicine Mansoura Faculty of Medicine. Neurobiology Of Sleep.
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Neurobiology Of Sleep By Ahmad Younis Professor of Thoracic Medicine Mansoura Faculty of Medicine
Neurobiology Of Sleep • Patients with damage to the posterior hypothalamus and rostral midbrain often had excessive sleepiness, whereas those with injury to the anterior hypothalamus had unrelenting insomnia. • Based on these observations, the anterior hypothalamus contained neurons that promoted sleep, whereas neurons near the hypothalamus-midbrain junction helped promote wakefulness.
Neurobiology Of Sleep • The term neurotransmitter is currently applied to situations in which one presynaptic neuron directly influences another postsynaptic neuron. • In neuromodulation, a given neurotransmitter regulates the activity of diverse populations of neurons in the central nervous system. Examples of neurotransmitters that are also neuromodulators include acetylcholine (ACh), serotonin (5HT), dopamine (DA), and histamine (HA). • Neurons are often characterized with respect to sleep by when they are most active. Some neurons are active during wake, during rapid eye movement (REM) only (REM-on), during REM and wake (wake/REM-on), during non–rapid eye movement (NREM) only (NREM-on),or during NREM and REM sleep .
MAJOR BRAIN AREAS IMPORTANT FOR SLEEP AND WAKE • Hypothalamic Areas • 1- Lateral Hypothalamus • Neurons in the lateral and posterior hypothalamus are the sole source of the awake-promoting neuropeptides hypocretin 1 (Hcrt1) and hypocretin 2 (Hcrt2), also known as Orexin A and Orexin B, respectively. • Hcrt1 can attach to both Hcrt1 and 2 receptors, whereas Hcrt2 attaches only to Hcrt2 receptors. • Patients with narcolepsy with cataplexy have loss of 90% or more of Hcrt-producing neurons and have low to undetectable CSF levels of Hcrt1. • Patients with narcolepsy without cataplexy has partial loss of Hcrt neurons.
Orexin (hypocretin) neurons in the lateral hypothalamic area innervate all of the ascending arousal systems, as well as the cerebral cortex. • BF = basal forebrain ; LC = locus coeruleus; LDT = lateral dorsal tegmental; PPT = pedunculo-pontine tegmental; SN = substantia nigra; TMN = tubero-mammillary nucleus; VTA = ventral tegmental area.
MAJOR BRAIN AREAS IMPORTANT FOR SLEEP AND WAKE • Hcrt neurons send abundant excitatory projections to the dorsal raphe (Hrct1 and Hcrt2 receptors) nucleus, the locus coeruleus (Hcrt1 receptors), and the tuberomammillary nucleus (Hcrt2 receptors) . • These areas in turn send inhibitory projections to Hcrt neurons. • Hcrt neurons have a strong excitatory effect on the cholinergic neurons of the basal forebrain that contribute to cortical arousal but have no effect on GABAergic sleep-promoting neurons within the ventrolateral preoptic (VLPO) area.
MAJOR BRAIN AREAS IMPORTANT FOR SLEEP AND WAKE • Hcrt appears to stabilize transitions between wake and sleep. • Hcrt neurons are relatively inactive in quiet waking but are transiently activated during sensory stimulation. • Hcrt cells are silent in slow wave sleep and tonic periods of REM sleep, with occasional burst discharge in phasic REM). • Hcrt cells discharge in active waking and have moderate and approximately equal levels of activity during grooming and eating and maximal activity during exploratory behavior. • Hcrt cells are activated during emotional and sensorimotor conditions similar to those that trigger cataplexy in narcoleptic animals.
Orexin (hypocretin) neurons are active during wake and quiet NREM sleep with some activity only during phasic REM sleep. •
MAJOR BRAIN AREAS IMPORTANT FOR SLEEP AND WAKE 2- Ventrolateral Preoptic Nucleus • The VLPO is an area in the hypothalamus containing neurons active during sleep. Most sleep-active neurons in the VLPO are believed to be active during both NREM and REM sleep • Many of the VLPO neurons are activated by sleep-inducing factors including adenosine and prostaglandinD2. These neurons are sensitive to warmth, and heating this area of the brain increases their activity and decreases wake. • A compact group of VLPO neurons (VLPO cluster) projects to the tuberomammillary nucleus (TMN) and inhibits the neuronal activity of that area.
MAJOR BRAIN AREAS IMPORTANT FOR SLEEP AND WAKE • A second group of VLPO neurons is located dorsal and medial to the VLPO cluster neurons and the group is called the extended VLPO (eVLPO) by some authors. • The eVLPO neurons make up the majority of the projections to the dorsal raphe nucleus (DRN) and locus coeruleus (LC) as well as to the interneurons of the lateral dorsal tegmental/pedunculopontine tegmental (LDT/PPT) region. • Most VLPO neurons appear to be active during both NREM and REM. The neurons in the VLPO contain the neurotransmitters gammaaminobutyric acid and galanin. • The VLPO neuronal projections to the DRN, LC, and TMN are inhibitory , • The neurons in the VLPO receive inhibitory projections from the DRN, LC and TMN.
Inhibitory projections from the ventrolateral preoptic area (VLPO;gamma-aminobutyric acid, galanine) during non–rapid eye movement (NREM) sleep to the tuberomamillary (TMN), the raphe area, locus coeruleus (LC), and pendunculopontine lateral/dorsal tegmentum (PPT/LDT) area, substantia nigra (SN), and ventral tegmental area (VTA).
MAJOR BRAIN AREAS IMPORTANT FOR SLEEP AND WAKE 3-Tuberomammillary Nucleus • Histaminergic neurons are confined to the posterior hypothalamus in the area called the tuberomammillary nucleus.. • TMN neurons project to the cerebral cortex, amygdala, substantia nigra (SN), DRN, LC, and nucleus of the solitary tract. • HA acting at H1 receptors is associated with wakefulness, and antihistamines (H1 receptor blockers) cause drowsiness or sleep. • Conversely, H3 receptor agonists cause sleepiness possibly by stimulating autoregulatory receptors that decrease HA release.
MAJOR BRAIN AREAS IMPORTANT FOR SLEEP AND WAKE • The TMN receives stimulatory input from the lateral hypothalamus (Hcrt). • The TMN firing rate is high during wake, lower during NREM, and absent during REM . • In contrast to REM sleep, during attacks of cataplexy, TMN neurons have a high firing rate associated with preservation of consciousness. • Low CSF HA has been found in patients with narcolepsy with and without low Hcrt. • The low HA may be a marker rather than a cause of sleepiness because lesions of the TMN have minimal effecton wakefulness. • This mean that HA is not essential for wakefulness in general. HA may be important at the onset of wakefulness.
Brainstem Regions 1-Dopamine Regions • Neurons producing dopamine (DA) are abundant in the SN and ventral tegmental area (VTA). Previously, studies suggested that DA neurons do not change their firing rates substantially across sleep stages. However, extracellular DA levels are high in several brain regions during wakefulness. • DA agonists acting at D1, D2, and D3 receptors increase waking and decrease NREM and REM sleep. • DA blockers of D1 and D2 receptors can promote sleep. In patients with low DA activity such as in Parkinson’s disease, low doses of DA agonists (pramipexole, ropinirole) that bind D2/D3 autoreceptors on DA neurons can actually cause sleepiness by reducing DA signaling. • Amphetamines promote wakefulness by increasing DA signaling.
Brainstem Regions 2- Reticular Formation • The reticular formation is a loose collection of neurons extending from the caudal medulla to the core of the midbrain. • Wakefulness depends on the activity of the ascending reticular activating system (ARAS). • This system projects to higher brain centers. One pathway ascends dorsally to the thalamus, and the second ascends ventrally through the lateral hypothalamus and forebrain .
Dorsal RAS • Lateral Dorsal Tegmentum/PedunculopontineTegmentum. Neurons in the LDT and PPT areas that are located in the dorsal midbrain and ponsmake up the majority of the dorsal RAS pathway through the pons and are cholinergic. • Some of the neurons are active during wake and REM sleep (wake/ REM-on), whereas others are active mainly during REM sleep (REM-on). • Acetylcholine (ACh) release in the thalamus is high during wake and REM sleep. The cholinergic neurons from the LDT/PPT densely innervate the thalamus (especially the medial and intralaminar thalamic nuclei),lateral hypothalamus, and midbrain. • During REM sleep but not wake or NREM sleep. Wake/REM-on neurons are active during wake and REM sleep . • Other cholinergic neurons in the basal forebrain (BF) project to the cortex, hippocampus, and amygdala. The firing rate of these neurons is high during wake and REM and low during NREM.
Reticular activating system (RAS). The ventral RAS includes neurons from the locus coeruleus, dorsal raphe nuclei, tuberomammillary nucleus (TMN), and lateral hypothalamus (LH). The dorsal RAS includes projections from the lateral dorsal tegmental (LDT) and pedunculopontinetegmental (PPT) areas.
Ventral RAS • The ventral RAS projects through the lateral hypothalamus terminating on magnocellular neurons in the substantia innominata, medial septum, and diagonal band . These regions contain neurons that project to the cortex. • The ascending projections of this branch are joined by input from the TMN and lateral hypothalamus. • The ventral RAS is composed of projections from the DRN (5HT) and LC (norepinephrine [NE]).
Dorsal Raphe Nucleus DRN serotonergic neurons are active during wake, less active during NREM, and minimally active during REM sleep. • The influences of DRN neurons are mainly stimulatory. They are part of the RAS network • Locus Coeruleus Neurons in the LC utilize NE as the neurotransmitter and innervate wide areas of the brain with chiefly stimulatory effects. • LC firing rates are high during wake, lower during NREM, and absent during REM sleep . • Basal Forebrain Cholinergic neurons in the BF excite cortical pyramidal cells. • GABA BF neurons disinhibit cortical neurons. • Lesions that destroy BF ACh and GABA neurons increase delta power.
CONTROL OF NREM SLEEP • During NREM sleep, the VLPO neurons are active and inhibit the firing of neurons in the TMN, DRN, and LC . • The Orexin neurons do not innervate the VLPO but stimulate the TMN, DRN, or LC more or less depending on the sleep state. Orexin neurons are active during wake. • This mutually inhibitory system functions as a flip-flop switch transitioning between the two states .
NREM flip-flop switch. During NREM, the ventrolateral preoptic area (VLPO) inhibits hypocretin neurons as well as the locus coeruleus (LC), tuberomammilary nucleus (TMN), dorsal raphe nucleus (DRN) areas promoting sleep. During wake, the hypocretin neurons stimulate the LC, TMN, and DRN areas, which are active and inhibit the VLPO neurons. eVLPO = extended ventrolateral preoptic area; ORX = Orexin (hypocretin).
FEATURES OF REM SLEEP • The tonic features include EEG desynchronization (reduction in cortical EEG amplitude),theta rhythm generation by the hippocampus (saw tooth wave in the EEG), suppression of muscle tone (atonia) , absent thermoregulation, penile erections in males, and constriction of pupils. • The phasic features of REM sleep include ponto-geniculo-occipital (PGO) waves that precede and occur during REM sleep, irregular respiration and heart rate (sympathetic bursts), and REMs.
FEATURES OF REM SLEEP • The PGO waves start in the pons and transit to the lateral geniculate nucleus (LGN) of the thalamus and from there to the occipital area. • PGO waves are believed to be an integral part of REM sleep but are not seen in the cortical EEG. Recording requires electrodes placed into the appropriate brain areas. • The density of the PGO waves correlates with the amount of eye movement measured in REM sleep.
