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Ventrolateral Preoptic Nucleus
The VLPO is located at the anterior of the Hypothalamus
Anatomical terms of neuroanatomy


The ventrolateral preoptic nucleus (VLPO) is a small cluster of neurons situated in the anterior hypothalamus, lateral to the optic chiasm. The VLPO is a uniform feature of the mammalian brain. The VLPO is active during sleep, primarily during Non-rapid eye movement sleep (NREM sleep), and releases inhibitory neurotransmitters, mainly GABA and Galanin, which inhibit neurons that are involved in wakefulness/the arousal system. The VLPO is in turn innervated by neurons from brain regions involved in the arousal system. The VLPO is activated by somnogens; Serotonin and Adenosine [1], and endosomnogens; Prostaglandin D2[2] , which promotes sleep. The VLPO is inhibited during wakefulness by arousal neurotransmitters; Norepinephrine and Acetylcholine[3] .The role of the VLPO in sleep and wakefulness, and its association with sleep disorders particularly Insomnia and Narcolepsy is a growing area of neuroscience research in the 21st century.

Structure edit

Approximately 80% of neurons in the VLPO are GABAergic (neurons that produce GABA) [4]. In vitro studies in rats have shown that two-thirds of the VLPO consists of homogenous multipolar triangular shaped cells with low threshold spikes [5]. Approximately 68% of these cells are active during sleep. All the triangular multipolar neurons are inhibited by norepinephrine and acetylcholine. However in the past few years it has become clear that these triangular multipolar neurons exist in two sub-populations in the VLPO:

  • Type 1 - inhibited by serotonin.
  • Type 2 - excited by serotonin and adenosine.

Since serotonin and adenosine accumulate during wakefulness [1] it is likely that type 2 play a role in sleep induction, and type 1 play a role in sleep consolidation.

The remaining one-third of neurons in the VLPO are excited by norepinephrine. Their role is unclear.

Function edit

Sleep/Wakefulness edit

In the mid-19th century in vivo studies first in rats and then in cats showed that lesions in the VLPO results in insomnia [6] [7], suggesting the VLPO has a key role in sleep. VLPO innervates cell bodies and proximal dendrites of brain regions that are part of the arousal system; the Tuberomammillary nucleus(TMN), the Raphe Nucleus, the Locus Coeruleus(LC), the Pedunculopontine Tegmental Nuclei(PPT), the Laterodorsal Tegmental Nucleus (LTD), the Substantia Nigra (SN), the Ventral Periaqueductal Grey (vPAG) and the orexinergic neurons; all monaminergic nuclei of Diffuse Modulatory Systems (DMS). The VLPO is activated by serotonin, adenosine and Prostaglandin D2 which accumulate during wakefulness. A majority of VLPO neurons are GABAergic and Galaninergic primarily secreting the inhibitory neurotransmitters GABA and Galanin respectively. The secretion of these inhibitory neurotransmitters supresses the arousal system and results in sleep. The VLPO also receives afferent projections from the DMS nuclei of the arousal system. These afferent projections secrete the arousal neurotransmitters norepinephrine and acetylcholine which inhibit VLPO and result in wakefulness. VLPO firing is inversely proportionate to the activation of the arousal system (as VLPO firing increases, the arousal system firing decreases, and vice versa).

A current theory suggests that VLPO and the arousal system exist in a simple A-B circuit, where A is inhibiting B and B is inhibiting A. This hypothesis, named the flip-flop switch model [8],suggests that the counteracting inhibition between VLPO and the arousal system results in the brain switching between two states, the sleep state and the wake state, so that at any time only one is firing; VLPO or the arousal system. Oxerin neurons in the posterior of the hypothalamus excite brain nuclei in the arousal system and help keep you awake. Oxerin neurons also extend to the VLPO likely inhibiting its activity [8]. Thus oxerin neurons are thought to play an important role in the stabilisation of the flip-flop switch regulating sleep and wakefulness.

 
Schematic representation of the Flip-Flop Switch Hypothesis

Circadian Rhythm edit

It has been suggested in recent years that sleep and circadian rhythms are closely linked in mammals. The “master clock” of circadian rhythms in mammals is the Suprachiasmatic Nucleus (SCN). The SCN has modest projections to the VLPO. These projections are thought to activate GABAergic neurons of the VLPO promoting the onset of sleep [8]. The VLPO in turn has projections to the SCN, suggesting the VLPO may play a role in the control of circadian rhythm in mammals.

Clinical Significance edit

Insomnia edit

Lesions in the VLPO in rat’s results in 50-60% decrease in NREM sleep time and prolonged insomnia [9]. It is hypothesised disruption of the VLPO results in reduced and irregular inhibition of the arousal system by VLPO meaning patients with insomnia wake up several times during the night. More recent research suggests insomnia could be due to an overabundance of oxerin neurons, resulting in over-excitation of the arousal system. Orexin-receptor antagonists are currently being developed for the treatment of insomnia [10].

Narcolepsy edit

Narcolepsy is due to a decrease in oxerin. It is hypothesised in narcolepsy the reduced level of oxerin means that the switch between the VLPO and the arousal system is destabilised [8] resulting in sudden switches from wakefulness to sleep; the characteristic symptom of narcoleptics.

Deep Brain Stimulation edit

In 2013 a novel method of deep brain stimulation, the Magnetic Field Projector (MFP), which magnetically induces deep brain stimulation, was tested in rats and was shown to successfully modulate the firing activity of neurons in the VLPO, inducing sleep [11] . This new method of deep brain stimulation which avoids surgical operation and is much cheaper than current methods could lead to new therapies for Insomnia and Narcolepsy in humans.

Anaesthetics edit

Studies showed that two anaesthetics, isoflurane and halothane, increase the activity of the VLPO in mice [12] . This proved anaesthetics are capable of directly affecting sleep/wake networks, and indicates the potential of anaesthetics in the treatment of insomnia and narcolepsy. Propofol has been shown to increase activity in the VLPO [13] however the mechanism of action is uncertain.

References edit

  1. ^ a b Gallopin T (2005). "The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus". Neuroscience. 134: 1377–1390. doi:10.1016/j.neuroscience.2005.05.045.
  2. ^ Scammell T (1998). "Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2". PNAS. 95: 7754–7759. doi:10.1073/pnas.95.13.7754.
  3. ^ Chou T (2002). "Afferents to the Ventrolateral Preoptic Nucleus". The Journal of Neuroscience. 22: 977–990.
  4. ^ Sherin J (1998). "Innervation of Histaminergic Tuberomammillary Neurons by GABAergic and Galaninergic Neurons in the Ventrolateral Preoptic Nucleus of the Rat". The Journal of Neuroscience. 18(12): 4705–4721.
  5. ^ Gallopin T (2000). "Identification of sleep-promoting neurons in vitro". Nature. 404: 992–995. doi:10.1038/35010109.
  6. ^ Nauta W (1946). "Hypothalamic regulation of sleep in rats". Journal of Neurophysiology. 9: 285–314.
  7. ^ McGinty D (1968). "Sleep Suppression after Basal Forebrain Lesions in the Cat". Science. 160: 1253–1255. doi:10.1126/science.160.3833.1253.
  8. ^ a b c d Saper C (2005). "Hypothalamic regulation of sleep and circadian rhythms". Nature. 437: 1257–1263. doi:10.1038/nature04284.
  9. ^ Liu J (2002). "Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep". The Journal of Neuroscience. 22: 4568–4576.
  10. ^ Winrow C (2014). "Discovery and development of orexin receptor antagonists as therapeutics for insomnia". Britich Journal of Pharmocology. 171: 283–293. doi:10.1111/bph.12261.
  11. ^ Jie F (2013). "A magnetic field projector for deep brain modulation". Neural Engineering: 1214–1217. doi:10.1109/NER.2013.6696158.
  12. ^ Moore J (2012). "Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis". Current Biology. 22: 2008–2016. doi:10.1016/j.cub.2012.08.042.
  13. ^ Liu Y (2013). "Propofol Facilitates Glutamatergic Transmission to Neurons of the Ventrolateral Preoptic Nucleus". Anesthesiology. 111: 1271–1278. doi:10.1097/ALN.0b013e3181bf1d79.

External links edit

Gallopin T, Luppi PH, Cauli B, Urade Y, Rossier J, Hayaishi O, Lambolez B, Fort P. (2005). "The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus". Neuroscience. 134 (4): 1377–90. doi:10.1016/j.neuroscience.2005.05.045. PMID 16039802.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Category:Cerebrum

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