Preoptic Area Modulation of Arousal in Natural and Drug Induced Unconscious States

Abstract

The role of the hypothalamic preoptic area (POA) in arousal state regulation has been studied since Constantin von Economo first recognized its importance in the early twentieth century. Over the intervening decades, the POA has been shown to modulate arousal in both natural (sleep and wake) as well as drug-induced (anesthetic-induced unconsciousness) states. While the POA is well known for its role in sleep promotion, populations of wake-promoting neurons within the region have also been identified. However, the complexity and molecular heterogeneity of the POA has made distinguishing these two populations difficult. Though multiple lines of evidence demonstrate that general anesthetics modulate the activity of the POA, the region’s heterogeneity has also made it challenging to determine whether the same neurons involved in sleep/wake regulation also modulate arousal in response to general anesthetics. While a number of studies show that sleep-promoting POA neurons are activated by various anesthetics, recent work suggests this is not universal to all arousal-regulating POA neurons. Technical innovations are making it increasingly possible to classify and distinguish the molecular identities of neurons involved in sleep/wake regulation as well as anesthetic-induced unconsciousness. Here, we review the current understanding of the POA’s role in arousal state regulation of both natural and drug-induced forms of unconsciousness, including its molecular organization and connectivity to other known sleep and wake promoting regions. Further insights into the molecular identities and connectivity of arousal-regulating POA neurons will be critical in fully understanding how this complex region regulates arousal states.

Divergent Neural Activity in the VLPO During Anesthesia and Sleep

“…Our result is supported by recent work reporting that direct activation of the vLPO GABA neurons fails to modulate anesthetic state transitions [70] and is also consistent with previous studies showing that specific sleep-regulating circuits may not be required for GA. [71][72][73] Together, these studies provide evidence that argues against the shared circuit hypothesis for anesthesia and sleep. [48] Various anesthetics can cause inhibition of global neural activity. [74][75][76] Our results, obtained using fiber photometry recording the population Ca 2+ signal from the vLPO neuronsincluding the GABAergic neurons, glutamatergic neurons, and the sleep-active galanin neurons-clearly support the general inhibition hypothesis of the anesthesia.…”

“…Our result is supported by recent work reporting that direct activation of the vLPO GABA neurons fails to modulate anesthetic state transitions [ 70 ] and is also consistent with previous studies showing that specific sleep‐regulating circuits may not be required for GA. [ 71 , 72 , 73 ] Together, these studies provide evidence that argues against the shared circuit hypothesis for anesthesia and sleep. [ 48 ]…”

“…The vLPO GABA neurons were selected because of their well‐documented role in sleep control. [ 16 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ] We recorded the neural activity of vLPO GABA neurons at the population level using fiber photometry and at the single‐neuron level using micro‐endoscopic imaging when mice were treated with four commonly‐used anesthetics as well as during the natural sleep‐wake cycle. A comparison of the activity modulation in the same group of recorded neurons revealed divergent states of the vLPO circuits during anesthesia and sleep.…”

Nitric Oxide Synthase Neurons in the Preoptic Hypothalamus Are NREM and REM Sleep-Active and Lower Body Temperature

“…Numerous circuits dispersed throughout the brain induce NREM sleep, but the preoptic (PO) hypothalamus, one of the first sleep-promoting centers to be identified ( Nauta, 1946 ), has a major role ( Sherin et al, 1996 ; Zhang et al, 2015 ; Weber and Dan, 2016 ; Chung et al, 2017 ; Kroeger et al, 2018 ; Ma et al, 2019 ; Reichert et al, 2019 ; Reitz and Kelz, 2021 ). The PO area also contains neurons that are required for REM sleep ( Lu et al, 2000 ), including REM-promoting cells in MPO ( Suntsova and Dergacheva, 2004 ; Gvilia et al, 2006 ).…”

Nitric oxide synthase neurons in the preoptic hypothalamus are sleep-active and contribute to regulating NREM and REM sleep and lowering body temperature

“…Numerous circuits dispersed throughout the brain induce NREM sleep, but the preoptic (PO) hypothalamus, one of the first sleep-promoting centres to be identified (Nauta, 1946), has a major role (Sherin et al, 1996;Zhang et al, 2015;Weber and Dan, 2016;Chung et al, 2017;Kroeger et al, 2018;Ma et al, 2019;Reichert et al, 2019;Reitz and Kelz, 2021). The PO area also contains neurons that are required for REM sleep (Lu et al, 2000), including REMpromoting cells in MPO (Suntsova and Dergacheva, 2004;Gvilia et al, 2006).…”