The Ascending Arousal system

  • The ascending arousal system has two major branches, which include discrete cell populations and neurotransmitters [1].
  • The first branch supplies nerves into the thalamus, activating neurons and nuclei essential for thalamocortical transmission.
  • The second branch of the ascending arousal system projects into the lateral hypothalamus, basal forebrain and cerebral cortex [2, 3, 4].
  • It comprises a number of cell populations (including noradrenergic, serotoninergic, dopaminergic and histaminergic neurons), lateral hypothalamic peptidergic neurons (orexin/hypocretin) and the basal forebrain (contains acetylcholine or GABA) [5].
  • Neurons in these monoaminergic systems discharge most rapidly during wakefulness, slow down during non-rapid eye movement (NREM) sleep and show a little activity during rapid-eye-movement (REM) sleep [6, 7, 8]. A similar effect is observed with the orexin/hypocretin neurons [9, 10].
  • In contrast, melatonin-concentrating neurons are strongly active during REM sleep [11].
  • In sum, all these systems together discharge in a specific and coordinated manner to promote cortical arousal [1].

The VLPO and the Sleep State

  • Sherin et al determined that a group of ventrolateral preoptic neurons is specifically activated during sleep [12].
  • The ventrolateral preoptic neuron (VLPO) efferents contain inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and galanin, which play a major role in keeping the ascending arousal system quiet during sleep [13, 14].
  • Neurons of the extended VLPO are connected with the various sites in the brain that are involved in REM sleep.
  • While the VLPO cluster provides output to the histaminergic neurons. Histaminergic neurons are active during waking, reduce firing during NREM sleep and stop discharge during REM sleep [15, 16].
  • Afferent neurons of the monoaminergic arousal system also connect with the VLPO [17].
  • Noradrenaline, acetylcholine, and serotonin are all neurotransmitters of wakefulness inhibit VLPO neurons [18]. The reciprocal inhibitory interaction of the VLPO neurons with the noradrenergic, serotoninergic and cholinergic waking systems play a key role in regulating sleep [1].
  • Experiments in different animals showed that injury to the VLPO cluster and the extended VLPO decreased NREM and REM sleep [19, 20].
  • A familial advanced sleep phase syndrome (FASPS) mutation in location 2106 (A-G) of epsilon casein kinase 1 (CK1ε)-binding herp2 gene on chromosome 2 results in translocation of serine in amino-acid 662 with a glycine (56624) [21].
  • Phenotypes are a set of observable characteristics of an individual resulting from the interaction of its genotypes with the environment.
  • De novo synthesis refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids as opposed to recycling after partial degradation.
  • DAT is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into the cytosol, from which other transporters sequester DA into vesicles and storage for later release.
  • Cataplexy is a symptom of narcolepsy in which patients experience abrupt transitions from waking to a state akin to REM sleep, with complete muscle atonia [22].
  • An efferent organ or body part carries impulses from the central nervous system to the effector.
  • Noradrenaline and serotonin inhibit the activity of orexin through the activation of G-protein-regulated inwardly rectifying K+ (GIRK or Kir3) channels via α2-adrenoceptors and 5HT1A-receptors [23].
  • An afferent nerve fiber or organ carries nerve impulses from the sensory organs to the central nervous system (CNS).

Also see: How Brain Health & Neurotransmitters Affect Sleep

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