Ventrolateral preoptic nucleus
|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, to the side of the optic chiasm in 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 and arousal. The VLPO is in turn innervated by neurons from brain regions involved in the arousal system. The VLPO is activated by the sleep-inducing neurotransmitters serotonin and adenosine. and endosomnogens; Prostaglandin D2 The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters norepinephrine and acetylcholine. 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.
Approximately 80% of neurons in the VLPO are GABAergic (neurons that produce GABA). In vitro studies in rats have shown that two-thirds of the VLPO consists of homogeneous multipolar triangular shaped cells with low threshold spikes. Approximately two thirds 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  it is likely that type 2 play a role in sleep induction, and type 1 play a role in sleep consolidation.
The remaining third of neurons in the VLPO are excited by norepinephrine. Their role is unclear.
In the mid-19th century in vivo studies - first in rats and then in cats - showed that lesions in the VLPO result in insomnia 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 (LDT), the substantia nigra (SN), the ventral periaqueductal grey (vPAG) and the orexinergic neurons; all of these are 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 suppresses 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, 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. Orexin neurons in the posterior of the hypothalamus excite brain nuclei in the arousal system and help keep you awake. Orexin neurons also extend to the VLPO likely inhibiting its activity. Thus orexin neurons are thought to play an important role in the stabilisation of the flip-flop switch regulating sleep and wakefulness.
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. The VLPO in turn has projections to the SCN, suggesting the VLPO may play a role in the control of circadian rhythm in mammals.
Lesions in the VLPO in rats results in 50-60% decrease in NREM sleep time and prolonged insomnia. It is hypothesised that 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 orexin neurons, resulting in over-excitation of the arousal system. Orexin-receptor antagonists are currently being developed for the treatment of insomnia.
Narcolepsy is due to a decrease in orexin. It is hypothesised in narcolepsy the reduced level of orexin means that the switch between the VLPO and the arousal system is destabilised  resulting in sudden switches from wakefulness to sleep; the characteristic symptom of narcoleptics.
Deep Brain Stimulation
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. 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.
Studies showed that two anaesthetics, isoflurane and halothane, increase the activity of the VLPO in mice. 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  however the mechanism of action is uncertain.
- Gallopin T (2005). "The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus". Neuroscience 134 (4): 1377–1390. doi:10.1016/j.neuroscience.2005.05.045. PMID 16039802.
- Scammell T (1998). "Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2". PNAS 95: 7754–7759. doi:10.1073/pnas.95.13.7754.
- Chou T (2002). "Afferents to the Ventrolateral Preoptic Nucleus". The Journal of Neuroscience 22: 977–990.
- 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.
- Gallopin T (2000). "Identification of sleep-promoting neurons in vitro". Nature 404: 992–995. doi:10.1038/35010109.
- Nauta W (1946). "Hypothalamic regulation of sleep in rats". Journal of Neurophysiology 9: 285–314.
- McGinty D (1968). "Sleep Suppression after Basal Forebrain Lesions in the Cat". Science 160 (3833): 1253–1255. doi:10.1126/science.160.3833.1253.
- Saper C (2005). "Hypothalamic regulation of sleep and circadian rhythms". Nature 437 (7063): 1257–1263. doi:10.1038/nature04284. PMID 16251950.
- Liu J (2002). "Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep". The Journal of Neuroscience 22: 4568–4576.
- Winrow C (2014). "Discovery and development of orexin receptor antagonists as therapeutics for insomnia". British Journal of Pharmacology 171: 283–293. doi:10.1111/bph.12261.
- Jie F (2013). "A magnetic field projector for deep brain modulation". Neural Engineering: 1214–1217. doi:10.1109/NER.2013.6696158.
- 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.
- Liu Y (2013). "Propofol Facilitates Glutamatergic Transmission to Neurons of the Ventrolateral Preoptic Nucleus". Anesthesiology 111: 1271–1278. doi:10.1097/ALN.0b013e3181bf1d79.
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.