The Sleep-Promoting Ventrolateral Preoptic Nucleus: What Have We Learned over the Past 25 Years?

Abstract

For over a century, the role of the preoptic hypothalamus and adjacent basal forebrain in sleep–wake regulation has been recognized. However, for years, the identity and location of sleep- and wake-promoting neurons in this region remained largely unresolved. Twenty-five years ago, Saper and colleagues uncovered a small collection of sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) of the preoptic hypothalamus, and since this seminal discovery the VLPO has been intensively investigated by labs around the world, including our own. Herein, we first review the history of the preoptic area, with an emphasis on the VLPO in sleep–wake control. We then attempt to synthesize our current understanding of the circuit, cellular and synaptic bases by which the VLPO both regulates and is itself regulated, in order to exert a powerful control over behavioral state, as well as examining data suggesting an involvement of the VLPO in other physiological processes.

Clinical Neurobiology of Sleep and Wakefulness

“…Two galanin-expressing populations are present in the VLPO nucleus: the VLPO “core” or “cluster,” thought to promote non–rapid eye movement (non-REM) sleep, and the “extended” VLPO nucleus linked to the regulation of REM sleep 11 . The precise location of a human homologue of the rodent VLPO nucleus remains uncertain.…”

“…10 Two galanin-expressing populations are present in the VLPO nucleus: the VLPO "core" or "cluster," thought to promote non-rapid eye movement (non-REM) sleep, and the "extended" VLPO nucleus linked to the regulation of REM sleep. 11 The precise location of a human homologue of the rodent VLPO nucleus remains uncertain. Neurons in the hypothalamic intermediate nucleus have similarities to the rodent VLPO nucleus, including their location in the chiasmatic region and the expression of galanin.…”

NE contribution to rebooting unconsciousness caused by midazolam

“…As a key arousal node, the LC receives inputs from arousal-related neurons and provides widespread NEergic innervation to the cerebral cortex and other forebrain structures related to anesthesia and sleep, such as the VLPO. The VLPO is important for sleep generation and contains multiple neuronal populations including GABAergic and galaninergic neurons, which are thought to be sleep-active neurons 28 .…”

“…As a key arousal node, the LC receives inputs from arousal-related neurons and provides widespread NEergic innervation to the cerebral cortex and other forebrain structures related to anesthesia and sleep, such as the VLPO. The VLPO is important for sleep generation and contains multiple neuronal populations including GABAergic and galaninergic neurons, which are thought to be sleep-active neurons 28 . Previous studies revealed the effect of the LC to VLPO pathway regulation of arousal and found that LC NE neurons synergistically promote arousal by activating wake-active neurons and inhibiting sleep-active neurons in the VLPO simultaneously 21 .…”

Epstein–Barr virus encephalitis with excessive daytime sleepiness as the main manifestation: Two case reports

“…In addition, cholinergic neurons in the pedunculopontine nucleus, laterodorsal tegmental nucleus, and glutamatergic neurons in the parabrachial nucleus promote wakefulness. [8] The structures that promote sleep mainly include the ventrolateral preoptic nucleus [9] and the middle preoptic nucleus [10] of the hypothalamus, which are excited during sleep and the pineal gland that produces melatonin. [11] Therefore, the main neurons that regulate sleep arousal are located in the brainstem and hypothalamus.…”