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The VLPO and Ascending Arousal System in Sleep

Written by Joe Cohen, BS | Last updated:

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

About the Author

Joe Cohen, BS

Joe Cohen, BS

Joe Cohen flipped the script on conventional and alternative medicine…and it worked. Growing up, he suffered from inflammation, brain fog, fatigue, digestive problems, insomnia, anxiety, and other issues that were poorly understood in traditional healthcare. Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. Through this personalized approach, he discovered his genetic weaknesses and was able to optimize his health 10X better than he ever thought was possible. Based on his own health success, he went on to found SelfDecode, the world’s first direct-to-consumer DNA analyzer & precision health tool that utilizes AI-driven polygenic risk scoring to produce accurate insights and health recommendations. Today, SelfDecode has helped over 100,000 people understand how to get healthier using their DNA and labs.
Joe is a thriving entrepreneur, with a mission of empowering people to take advantage of the precision health revolution and uncover insights from their DNA and biomarkers so that we can all feel great all of the time.


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