The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s situated in the anterior
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, sitting just above and to the side of the
optic chiasm
In neuroanatomy, the optic chiasm, or optic chiasma (; , ), is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrate ...
in the brain of humans and other animals.
The brain's sleep-promoting nuclei (e.g., the VLPO,
parafacial zone
The parafacial zone (PZ) is a brain structure located in the brainstem within the medulla oblongata believed to be heavily responsible for Non-rapid eye movement sleep, non-rapid eye movement (non-REM) sleep regulation, specifically for inducing s ...
,
nucleus accumbens core
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypotha ...
, and
lateral hypothalamic MCH neurons),
together with the
ascending arousal system which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states.
The VLPO is active during
sleep
Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefulness by a de ...
, particularly during
non-rapid eye movement sleep
Non-rapid eye movement sleep (NREM), also known as quiescent sleep, is, collectively, sleep stages 1–3, previously known as stages 1–4. Rapid eye movement sleep (REM) is not included. There are distinct electroencephalographic and other char ...
(NREM sleep),
and releases inhibitory
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s, mainly
GABA and
galanin
Galanin is a neuropeptide encoded by the ''GAL'' gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.
Much of galanin's function ...
, which inhibit neurons of the
ascending arousal system that are involved in
wakefulness
Wakefulness is a daily recurring Human brain, brain state and state of consciousness in which an individual is conscious and engages in coherent cognition, cognitive and behavioral responses to the external world.
Being awake is the opposite of ...
and arousal.
The VLPO is in turn innervated by neurons from several components of the ascending arousal system.
The VLPO is activated by the endogenous sleep-promoting substances
adenosine
Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
and
prostaglandin D2
Prostaglandin D2 (or PGD2) is a prostaglandin that binds to the receptor PTGDR (DP1), as well as CRTH2 (DP2). It is a major prostaglandin produced by mast cells – recruits Th2 cells, eosinophils, and basophils. In mammalian organs, large amou ...
.
[
] The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
and
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
.
The role of the VLPO in sleep and wakefulness, and its association with
sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...
s – particularly
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
and
narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
– is a growing area of neuroscience research.
Structure
At least 80% of neurons in the VLPO that project to the ascending arousal system are GABAergic (neurons that produce GABA).
[
]
''In vitro'' studies in rats have shown that many neurons in the VLPO that are inhibited by norepinephrine or acetylcholine are multipolar triangular shaped cells with low threshold spikes.
These triangular multipolar neurons exist in two sub-populations in the VLPO:
*Type 1 – inhibited by serotonin.
*Type 2 – excited by serotonin and adenosine.
As adenosine accumulates during wakefulness
[
] it is likely that type 2 cells play a role in sleep induction.
The remaining third of neurons in the VLPO are excited by norepinephrine. Their role is unclear.
Function
Sleep/wakefulness
![VLPO Flip-Flop Switch Hypothesis](https://upload.wikimedia.org/wikipedia/commons/5/59/VLPO_Flip-Flop_Switch_Hypothesis.png)
In the early 20th century,
Constantin von Economo
Constantin Freiherr von Economo ( gr, Κωνσταντίνος Οικονόμου; 21 August 1876 – 21 October 1931) was an Austrian psychiatrist and neurologist of Greek descent, born in modern-day Romania (then Ottoman Empire). He is most ...
noted that humans who had encephalitis with lesions in the anterior hypothalamus had insomnia, and proposed a sleep-promoting influence from that area.
Animal studies in the mid-20th century in rats and cats confirmed that very large lesions in the preoptic area and basal forebrain resulted in insomnia
[
][
] but did not identify the cell group that was responsible. In 1996, Sherin and colleagues reported the presence of a cell group in the VLPO that expresses cFos (a protein often found in neurons that have recently been active) during sleep, and that these neurons contain the inhibitory neurotransmitters GABA and galanin.
These same neurons were found to innervate components of the ascending arousal system, including the
tuberomammillary nucleus
The tuberomammillary nucleus (TMN) is a histaminergic nucleus located within the posterior third of the hypothalamus. It consists of, largely, histaminergic neurons (i.e., histamine-releasing neurons) and is involved with the control of arousal, l ...
(TMN) and other components of the lateral hypothalamus; the
raphe nuclei; the
locus coeruleus
The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system.
The locus coerule ...
(LC); the
pedunculopontine
The pedunculopontine nucleus (PPN) or pedunculopontine tegmental nucleus (PPT or PPTg) is a collection of neurons located in the upper pons in the brainstem. It lies caudal to the substantia nigra and adjacent to the superior cerebellar pedunc ...
(PPT) and
laterodorsal tegmental nuclei (LDT); and the parabrachial nucleus (PB). More recent studies using opto- or chemogenetic activation of VLPO neurons have confirmed that they promote sleep.
The sleep-promoting effects of the VLPO neurons is thought to be due to release of GABA and possibly galanin that suppresses firing of arousal system neurons. As the VLPO is also inhibited by neurotransmitters released by components of the arousal systems, such as acetylcholine and norepinephrine,
a current theory has proposed that the VLPO and the arousal system form a "flip-flop" circuit.
This term from electrical engineering denotes a circuit in which mutual inhibition means that each component of the circuit, as it turns on, turns the other off, resulting in rapid transitions from one state (wake or sleep) to the other, with minimal time in transition states. This theory has been used to create mathematical models that explain much of the wake-sleep behavior in animals, including in pathological states and responses to drugs.
Orexin
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
neurons in the posterior lateral hypothalamus potentiate neurons in the ascending arousal system and help stabilize the brain in the waking state (and consolidated wakefulness, which builds up homeostatic sleep drive, helps stabilize the brain during later sleep). The loss of orexin neurons in the disorder narcolepsy destabilizes the wake-sleep switch, resulting in overwhelming sleep episodes during the waking day, as well as more frequent awakenings from sleep at night.
Circadian rhythm
There is a strong
circadian rhythm of sleep in mammals. The “master clock” for circadian rhythms in mammals is the
suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...
(SCN). The SCN has little if any projection directly to the VLPO neurons. Instead, they project strongly to the adjacent subparaventricular zone, which in turn contains inhibitory GABAergic neurons that innervate the dorsomedial nucleus of the hypothalamus.
Lesions of the dorsomedial nucleus almost completely eliminate the circadian rhythm of sleep. GABAergic neurons in the dorsomedial nucleus innervate the VLPO, and glutamatergic neurons innervate the lateral hypothalamus, suggesting that the dorsomedial nucleus mainly promotes wakefulness during the active period (daytime for humans).
Clinical significance
Insomnia
Elderly human patients with more galanin neurons in their
intermediate nucleus (the human equivalent of the VLPO galanin neurons in rodents) have better, more continuous sleep. A reduced number of VLPO neurons is associated with more fragmented sleep (more awakenings throughout the night).
[
]
Lesions in the VLPO in rats results in 50-60% decrease in NREM sleep time and prolonged
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
. More recent research suggests that stress-induced insomnia could be due to an imbalance of input to arousal system and VLPO neurons.
Sedative/hypnotic drugs
Many sedative/hypnotic drugs act by binding to and potentiating GABA-A receptors. These include older drugs such as ethanol, chloral hydrate and barbiturates, as well as newer benzodiazepines and "non-benzodiazepine" drugs (such as zolpidem, which bind to the same receptor but have a different chemical configuration), and even anesthetics such as propofol and isoflurane. As the VLPO inputs to the arousal system use this same receptor, these drugs at low doses essentially act by potentiating the VLPO, producing a sleepy state. Animal studies show that VLPO neurons show cFos activation after sedative doses of these drugs, and that VLPO lesions produce resistance to their sedative effects. However, at high doses that produce a surgical plane of anesthesia, these drugs have much more widespread inhibitory effects, that do not depend upon the VLPO.
Studies have shown that multiple sedative/hypnotic drugs that act by potentiating GABA-A receptors, including ethanol, chloral hydrate, propofol and gas anesthetics such as
isoflurane
Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia rather than isoflurane, due to airway irritation w ...
, at sedative doses increase the activity of the VLPO neurons in mice.
[
] This finding suggests that at relatively low sedative doses, these medications may have a common mechanism of action, which includes potentiating the firing of VLPO neurons. High doses used in surgical anesthesia, however, reduce activity of neurons throughout the nervous system.
References
External links
*
{{Diencephalon
Hypothalamus