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The development of cutting-edge techniques to study specific brain regions and neural circuits that regulate sleep-wake brain states and general anesthesia (GA), has increased our understanding of these states that exhibit similar neurophysiologic traits. This review summarizes current knowledge focusing on cell subtypes and neural circuits that control wakefulness, rapid eye movement (REM) sleep, non-REM sleep, and GA. We also review novel insights into their interactions and raise unresolved questions and challenges in this field. Comparisons of the overlapping neural substrates of sleep-wake and GA regulation will help us to understand sleep-wake transitions and how anesthetics cause reversible loss of consciousness. SIGNIFICANCE STATEMENT: General anesthesia (GA), sharing numerous neurophysiologic traits with the process of natural sleep, is administered to millions of surgical patients annually. In the past decade, studies exploring the neural mechanisms underlying sleep-wake and GA have advanced our understanding of their interactions and how anesthetics cause reversible loss of consciousness. Pharmacotherapies targeting the neural substrates associated with sleep-wake and GA regulations have significance for clinical practice in GA and sleep medicine., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Good sleep quality is essential for maintaining the body's attention during wakefulness, which is easily affected by external factors such as an ambient temperature. However, the mechanism by which an ambient temperature influences sleep-wake behaviors remains unclear. The dorsomedial hypothalamus (DMH) has been reported to be involved in thermoregulation. It also receives projection from the preoptic area, which is an important region for sleep and energy homeostasis and the suprachiasmatic nucleus-a main control area of the clock rhythm. Therefore, we hypothesized that the DMH plays an important role in the regulation of sleep related to ambient temperatures. In this study, we found that cold exposure (24/20/16/12 °C) increased wakefulness and decreased non-rapid eye movement (NREM) sleep, while warm exposure (32/36/40/44 °C) increased NREM sleep and decreased wakefulness compared to 28 °C conditions in wild-type mice. Then, using non-specific and specific apoptosis, we found that lesions of whole DMH neurons and DMH γ-aminobutyric acid (GABA)-ergic neurons induced by caspase-3 virus aggravated the fluctuation of core body temperature after warm exposure and attenuated the change in sleep-wake behaviors during cold and warm exposure. However, chemogenetic activation or inhibition of DMH GABAergic neurons did not affect the sleep-wake cycle. Collectively, our findings reveal an essential role of DMH GABAergic neurons in the regulation of sleep-wake behaviors elicited by a change in ambient temperature.

The olfactory tubercle (OT), an important nucleus in processing sensory information, has been reported to change cortical activity under odor. However, little is known about the physiological role and mechanism of the OT in sleep-wake regulation. The OT expresses abundant adenosine A 2A receptors (A 2A Rs), which are important in sleep regulation. Therefore, we hypothesized that the OT regulates sleep via A 2A Rs. This study examined sleep-wake profiles through electroencephalography and electromyography recordings with pharmacological and chemogenetic manipulations in freely moving rodents. Compared with their controls, activation of OT A 2A Rs pharmacologically and OT A 2A R neurons via chemogenetics increased non-rapid eye movement sleep for 5 and 3 h, respectively, while blockade of A 2A Rs decreased non-rapid eye movement sleep. Tracing and electrophysiological studies showed OT A 2A R neurons projected to the ventral pallidum and lateral hypothalamus, forming inhibitory innervations. Together, these findings indicate that A 2A Rs in the OT play an important role in sleep regulation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2019. Published by Elsevier Ltd.)

Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Because sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining, and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin- and parvalbumin-positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naive mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic.

Sleep is regulated by homeostatic process and circadian clock. Light indirectly modulates sleep by entraining the circadian clock to the solar day. Light can also influence sleep independent of photo-entrainment [1]. An acute light exposure could induce sleep, and an acute dark pulse could increase wakefulness in nocturnal animals [1, 2]. The photoreceptors and cell types in the retina that mediate light and dark effects on sleep are well characterized [1-4]. A few studies have explored the brain region involved in acute light induction of sleep. Fos expression and nonspecific lesions suggest that the superior colliculus (SC) may play a role in acute light induction of sleep [2, 5]. In contrast, the brain area and neural circuits mediating acute dark induction of wakefulness are unknown. Here, we demonstrated that retina ganglion cells (RGCs) had direct innervations on the GABAergic neurons in the mouse SC, and the activities of these cells were inhibited by an acute dark pulse, but not influenced by a light pulse. Moreover, ablating SC GABAergic neurons abolished the acute dark induction of wakefulness, but not light induction of sleep. Based on optogenetic and electrophysiological experiments, we found that SC GABAergic neurons formed monosynaptic functional connections with dopaminergic neurons in the ventral tegmental area (VTA). Selective lesions of VTA dopaminergic cells totally abolished acute dark induction of wakefulness without affecting the light induction of sleep. Collectively, our findings uncover a fundamental role for a retinal-SC GABAergic-VTA dopaminergic circuit in acute dark induction of wakefulness and indicate that the dark and light signals affect sleep-wake behaviors through distinct pathways., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The classic endogenous somnogen adenosine promotes sleep via A 1 and A 2A receptors. In this chapter, we present an overview of the current knowledge regarding the regulation of adenosine levels, adenosine receptors, and available pharmacologic and genetic tools to manipulate the adenosine system. This is followed by a summary of current knowledge of the role of adenosine and its receptors in the regulation of sleep and wakefulness. Despite strong data implicating numerous brain areas, including the basal forebrain, the tuberomammillary nucleus, the lateral hypothalamus, and the nucleus accumbens, in the adenosinergic control of sleep, the complete neural circuitry in the brain involved in the sleep-promoting effects of adenosine remains unclear. Moreover, the popular demand for natural sleep aids has led to a search for natural compounds that can promote sleep via adenosine receptor activation. Finally, we discuss the effects of caffeine in man and the possible use of more selective adenosine receptor drugs for the treatment of sleep disorders.

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.

Background: Sleep and epilepsy are mutually related in a complex, bidirectional manner. However, our understanding of this relationship remains unclear., Results: The literatures of the neurobiological basis of the interactions between sleep and epilepsy indicate that non rapid eye movement sleep and idiopathic generalized epilepsy share the same thalamocortical networks. Most of neurotransmitters and neuromodulators such as adenosine, melatonin, prostaglandin D2, serotonin, and histamine are found to regulate the sleep-wake behavior and also considered to have antiepilepsy effects; antiepileptic drugs, in turn, also have effects on sleep. Furthermore, many drugs that regulate the sleep-wake cycle can also serve as potential antiseizure agents. The nonpharmacological management of epilepsy including ketogenic diet, epilepsy surgery, neurostimulation can also influence sleep., Conclusion: In this paper, we address the issues involved in these phenomena and also discuss the various therapies used to modify them., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Dysfunction of the striatum is frequently associated with sleep disturbances. However, its role in sleep-wake regulation has been paid little attention even though the striatum densely expresses adenosine A 2A receptors (A 2A Rs), which are essential for adenosine-induced sleep. Here we showed that chemogenetic activation of A 2A R neurons in specific subregions of the striatum induced a remarkable increase in non-rapid eye movement (NREM) sleep. Anatomical mapping and immunoelectron microscopy revealed that striatal A 2A R neurons innervated the external globus pallidus (GPe) in a topographically organized manner and preferentially formed inhibitory synapses with GPe parvalbumin (PV) neurons. Moreover, lesions of GPe PV neurons abolished the sleep-promoting effect of striatal A 2A R neurons. In addition, chemogenetic inhibition of striatal A 2A R neurons led to a significant decrease of NREM sleep at active period, but not inactive period of mice. These findings reveal a prominent contribution of striatal A 2A R neuron/GPe PV neuron circuit in sleep control.

Sleep control is ascribed to a two-process model, a widely accepted concept that posits homoeostatic drive and a circadian process as the major sleep-regulating factors. Cognitive and emotional factors also influence sleep-wake behaviour; however, the precise circuit mechanisms underlying their effects on sleep control are unknown. Previous studies suggest that adenosine has a role affecting behavioural arousal in the nucleus accumbens (NAc), a brain area critical for reinforcement and reward. Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A 2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound. In addition, motivational stimuli inhibit the activity of ventral pallidum-projecting NAc indirect pathway neurons and suppress sleep. Our findings reveal a prominent contribution of this indirect pathway to sleep control associated with motivation.In addition to circadian and homoeostatic drives, motivational levels influence sleep-wake cycles. Here the authors demonstrate that adenosine receptor-expressing neurons in the nucleus accumbens core that project to the ventral pallidum are inhibited by motivational stimuli and are causally involved in the control of slow-wave sleep.

Prostaglandin D 2 (PGD 2 ) is one of the most potent endogenous sleep promoting substances. PGD 2 activates the PGD 2 receptor (DPR) and increases the extracellular level of adenosine in wild-type (WT) mice but not DPR knockout (KO) mice, suggesting that PGD 2 -induced sleep is DPR-dependent, and adenosine may be the signaling molecule that mediates the somnogenic effect of PGD 2 . The aim of this study was to determine the involvement of the adenosine A 2A receptor (A 2A R) in PGD 2 -induced sleep. We infused PGD 2 into the lateral ventricle of WT and A 2A R KO mice between 20:00 and 2:00 for 6 h, and electroencephalograms and electromyograms were simultaneously recorded. In WT mice, PGD 2 infusion dose-dependently increased non-rapid eye movement (non-REM, NREM) sleep, which was 139.1%, 145.0% and 202.7% as large as that of vehicle-treated mice at doses of 10, 20 and 50 pmol/min, respectively. PGD 2 infusion at doses of 20 and 50 pmol/min also increased REM sleep during the 6-h PGD 2 infusion and 4-h post-dosing periods in WT mice to 148.9% and 166.7%, respectively. In A 2A R KO mice, however, PGD 2 infusion at 10 pmol/min did not change the sleep profile, whereas higher doses at 20 and 50 pmol/min increased the NREM sleep during the 6-h PGD 2 infusion to 117.5% and 155.6%, respectively, but did not change the sleep in the post-dosing period. Moreover, PGD 2 infusion at 50 pmol/min significantly increased the episode number in both genotypes but only enhanced the episode duration in WT mice. The results demonstrate that PGD 2 -induced sleep in mice is mediated by both adenosine A 2A R-dependent and -independent systems.

Interleukin-1β (IL-1β) and prostaglandin (PG) D 2 are endogenous sleep-promoting substances. Since it was reported that a highly selective cyclooxygenase-2 (COX-2) inhibitor, NS398, completely inhibited IL-1β-induced sleep in rats, IL-1β-induced sleep had been believed to be mediated by prostanoids, most probably PGD 2 . However, in the present study, pretreatment of rats with NS398 (3mg/kg) did not suppress the 64.2% increased non-rapid eye movement (non-REM, NREM) sleep during infusion of IL-1β (10ng) for 6h in the nocturnal (active) period between 23:00 and 5:00 into the subarachnoid space of the PGD 2 -sensitive sleep-promoting zone of the basal forebrain. Meanwhile, IL-1β at doses of 1.7 and 5μg/kg also significantly increased NREM sleep for 6h after intraperitoneal injection at 20:00 (light-off time) by 76.8% and 121.1%, respectively, in wild-type (WT) mice, by 67.7% and 147.3%, respectively, in WT mice pretreated with NS398 (5mg/kg) and by 108.9% and 121.6%, respectively, in PGD 2 receptor (DP 1 R) knockout mice. These results indicate that IL-1β-induced NREM sleep is independent of the PGD 2 /DP 1 R system and other COX-2-derived prostaglandins in rats and mice., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Depression, which is characterized by a pervasive and persistent low mood and anhedonia, greatly impacts patients, their families, and society. The associated and recurring sleep disturbances further reduce patient's quality of life. However, therapeutic sleep deprivation has been regarded as a rapid and robust antidepressant treatment for several decades, which suggests a complicated role of sleep in development of depression. Changes in neural plasticity are observed during physiological sleep, therapeutic sleep deprivation, and depression. This correlation might help us to understand better the mechanism underlying development of depression and the role of sleep. In this review, we first introduce the structure of sleep and the facilitated neural plasticity caused by physiological sleep. Then, we introduce sleep disturbances and changes in plasticity in patients with depression. Finally, the effects and mechanisms of antidepressants and therapeutic sleep deprivation on neural plasticity are discussed.

The basal forebrain (BF) cholinergic neurons have long been thought to be involved in behavioral wakefulness and cortical activation. However, owing to the heterogeneity of BF neurons and poor selectivity of traditional methods, the precise role of BF cholinergic neurons in regulating the sleep-wake cycle remains unclear. We investigated the effects of cell-selective manipulation of BF cholinergic neurons on the sleep-wake behavior and electroencephalogram (EEG) power spectrum using the pharmacogenetic technique, the 'designer receptors exclusively activated by designer drugs (DREADD)' approach, and ChAT-IRES-Cre mice. Our results showed that activation of BF cholinergic neurons expressing hM3Dq receptors significantly and lastingly decreased the EEG delta power spectrum, produced low-delta non-rapid eye movement sleep, and slightly increased wakefulness in both light and dark phases, whereas inhibition of BF cholinergic neurons expressing hM4Di receptors significantly increased EEG delta power spectrum and slightly decreased wakefulness. Next, the projections of BF cholinergic neurons were traced by humanized Renilla green fluorescent protein (hrGFP). Abundant and highly dense hrGFP-positive fibers were observed in the secondary motor cortex and cingulate cortex, and sparse hrGFP-positive fibers were observed in the ventrolateral preoptic nucleus, a known sleep-related structure. Finally, we found that activation of BF cholinergic neurons significantly increased c-Fos expression in the secondary motor cortex and cingulate cortex, but decreased c-Fos expression in the ventrolateral preoptic nucleus. Taken together, these findings reveal that the primary function of BF cholinergic neurons is to inhibit EEG delta activity through the activation of cerebral cortex, rather than to induce behavioral wakefulness.

Paeoniflorin (PF, C23H28O11), one of the principal active ingredients of Paeonia Radix, exerts depressant effects on the central nervous system. We determined whether PF could modulate sleep behaviors and the mechanisms involved. Electroencephalogram and electromyogram recordings in mice showed that intraperitoneal PF administered at a dose of 25 or 50 mg/kg significantly shortened the sleep latency and increased the amount of non-rapid eye movement (NREM). Immunohistochemical study revealed that PF decreased c-fos expression in the histaminergic tuberomammillary nucleus (TMN). The sleep-promoting effects and changes in c-fos induced by PF were reversed by 8-cyclopentyl-1,3-dimethylxanthine (CPT), an adenosine A1 receptor antagonist, and PF-induced sleep was not observed in adenosine A1 receptor knockout mice. Whole-cell patch clamping in mouse brain slices showed that PF significantly decreased the firing frequency of histaminergic neurons in TMN, which could be completely blocked by CPT. These results indicate that PF increased NREM sleep by inhibiting the histaminergic system via A1 receptors., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Histaminergic neurons have been reported to play an important role in the regulation of sleep-wake behavior through the histamine H1 receptor (R, H1R). First generation H1R antagonists, such as doxepin and diphenhydramine, produce drowsiness in humans, and are occasionally used to treat insomnia. However, if H1R antagonists function via physically blocking the H1R remains unclear. In the current study, we used H1R knockout (KO) mice to investigate if the sleep-promoting effects of doxepin and diphenhydramine are dependent on blockade of the H1R. When doxepin was administered, non-rapid eye movement (NREM) sleep in wild type (WT) mice increased for 4h, with an increase in the numbers of NREM sleep bouts of 256-512 s and 512-1024 s. These effects were not observed in the H1R KO mice. Furthermore, diphenhydramine increased NREM sleep for 6h in WT, and not in the H1R KO mice after the injection. These results indicate that both doxepin at 15 mg/kg and diphenhydramine at 10 mg/kg induce NREM sleep through blockade of H1R., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Rationale: In psychopharmacology, researchers have been interested in the hypnotic effects of terrestrial plant polyphenols and their synthetic derivatives. Phlorotannins, a marine plant polyphenol, could have potential as a source of novel hypnotic drugs., Objectives: The effects of phlorotannins and major phlorotannin constituent eckstolonol on sleep-wake profiles in mice were evaluated in comparison with diazepam, and their hypnotic mechanism was also investigated., Methods: The effects of phlorotannin preparation (PRT) and eckstolonol orally given on sleep-wake profiles were measured by recording electroencephalograms (EEG) and electromyograms in C57BL/6N mice. Flumazenil, a GABAA-benzodiazepine (BZD) receptor antagonist, was injected 15 min before PRT and eckstolonol to reveal its hypnotic mechanism., Results: PRT administration (>250 mg/kg) produced a significant decrease in sleep latency and an increase in the amount of non-rapid eye movement sleep (NREMS). Eckstolonol significantly decreased sleep latency (>12.5 mg/kg) and increased the amount of NREMS (50 mg/kg). PRT and eckstolonol had no effect on EEG power density of NREMS. The hypnotic effects of PRT or eckstolonol were completely abolished by pretreatment with flumazenil., Conclusions: We demonstrated that phlorotannins promote NREMS by modulating the BZD site of the GABAA receptor. These results suggest that phlorotannins can be potentially used as an herbal medicine for insomnia and as a promising structure for developing novel sedative-hypnotics.

This article, published in the journal Cell Discovery, explores the role of leptin receptor neurons in the ventral premammillary nucleus (PMv) in modulating emotion-induced insomnia. The study found that exposure to emotional stimuli, such as urine or TMT (a component of fox odor), significantly delayed non-rapid eye movement (NREM) sleep onset and increased wakefulness in mice. The researchers also discovered that PMvLepR neurons were activated by emotional stimuli and that their activation led to prolonged wakefulness, mimicking insomnia-like behavior. Inhibition of PMvLepR neurons abolished the increase in sleep latency and wakefulness following emotional stimuli. These findings suggest that PMvLepR neurons may be an important therapeutic target for managing emotion-induced insomnia. [Extracted from the article]

Elevated glucocorticoid levels triggered by stress potentially contribute to sleep disturbances in stress-induced depression. However, sleep changes in response to elevated corticosterone (CORT), the major glucocorticoid in rodents, remain unclear. Here, we investigated the effects of acute or chronic CORT administration on sleep using electroencephalogram (EEG) and electromyography (EMG) recordings in freely moving mice. Acute CORT exposure rapidly promoted wakefulness, marked by increased episodes and enhanced EEG delta power, while simultaneously suppressing rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, with the latter marked by decreased mean duration and reduced delta power. Prolonged 28-day CORT exposure led to excessive wakefulness and REM sleep, characterized by higher episodes, and decreased NREM sleep, characterized by higher episodes and reduced mean duration. EEG theta activity during REM sleep and delta activity during NREM sleep were attenuated following 28-day CORT exposure. These effects persisted, except for REM sleep amounts, even 7 days after the drug withdrawal. Elevated plasma CORT levels and depressive phenotypes were identified and correlated with observed sleep changes during and after administration. Fos expression significantly increased in the lateral habenula, lateral hypothalamus, and ventral tegmental area following acute or chronic CORT treatment. Our findings demonstrate that CORT exposure enhanced wakefulness, suppressed and fragmented NREM sleep, and altered EEG activity across all stages. This study illuminates sleep alterations during short or extended periods of heightened CORT levels in mice, providing a neural link connecting insomnia and depression. [ABSTRACT FROM AUTHOR]

Sleep and wakefulness are basic behavioral states that require coordination between several brain regions, and they involve multiple neurochemical systems, including neuropeptides. Neuropeptides are a group of peptides produced by neurons and neuroendocrine cells of the central nervous system. Like traditional neurotransmitters, neuropeptides can bind to specific surface receptors and subsequently regulate neuronal activities. For example, orexin is a crucial component for the maintenance of wakefulness and the suppression of rapid eye movement (REM) sleep. In addition to orexin, melanin-concentrating hormone, and galanin may promote REM sleep. These results suggest that neuropeptides play an important role in sleep–wake regulation. These neuropeptides can be divided into three categories according to their effects on sleep–wake behaviors in rodents and humans. (i) Galanin, melanin-concentrating hormone, and vasoactive intestinal polypeptide are sleep-promoting peptides. It is also noticeable that vasoactive intestinal polypeptide particularly increases REM sleep. (ii) Orexin and neuropeptide S have been shown to induce wakefulness. (iii) Neuropeptide Y and substance P may have a bidirectional function as they can produce both arousal and sleep-inducing effects. This review will introduce the distribution of various neuropeptides in the brain and summarize the roles of different neuropeptides in sleep–wake regulation. We aim to lay the foundation for future studies to uncover the mechanisms that underlie the initiation, maintenance, and end of sleep–wake states. [ABSTRACT FROM AUTHOR]

Summary: Insomnia is one of the most prevalent sleep disorders, which imparts tremendous societal and economic impact. However, the present pharmacotherapy is greatly limited by adverse effects, so it is necessary to explore new drugs for the treatment of insomnia. Radix Bupleuri (RB) has been widely used in traditional Chinese medicine for >2000 years; it has many pharmacological effects, including sedation and anticonvulsant properties. The present study investigated the effects of saikosaponin a (SSa), an active component of RB, on sleep and locomotion. Male C57BL/6j mice received intraperitoneal injections of SSa at three different dosages (0.625, 1.25, and 2.5 mg/kg). Sleep parameters were analysed by electroencephalography and electromyography. The open‐field test was used to measure locomotor activities. Our present results showed that SSa treatment significantly increased the duration of non‐rapid eye movement sleep and shortened sleep latency in a dose‐dependent manner. A high dose of SSa (2.5 mg/kg) also decreased locomotor activities. Moreover, by measuring c‐Fos expression and the calcium signal in the lateral hypothalamus (LH), we found that SSa treatment decreased neuronal activity in the LH. In conclusion, SSa might be the sleep‐promoting component in RB and its mechanism may be related to the modulation of neuronal activity in the LH. [ABSTRACT FROM AUTHOR]

Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain. After nerve injury, ACC PNs displayed spontaneous hyperactivity selectively in periods of insomnia. We then show that ACC PNs were both necessary for developing chronic-pain-induced insomnia and sufficient to mimic sleep loss in naive mice. Importantly, combining optogenetics and electrophysiological recordings, we found that the ACC projection to the dorsal medial striatum (DMS) underlies chronic-pain-induced insomnia through enhanced activity and plasticity of ACC-DMS dopamine D1R neuron synapses. Our findings shed light on the pivotal role of ACC PNs in developing chronic-pain-induced sleep disorders. [Display omitted] • ACC pyramidal neurons (PNs) are selectively activated during chronic-pain-induced insomnia • Lesion of ACC PNs abolishes chronic-pain-induced insomnia • Hyperactive ACC PNs control chronic-pain-induced insomnia via the DMS pathway • Enhanced plasticity of ACC PNs to DMS D1R-MSNs mediates insomnia Over 50% of chronic pain patients experience insomnia. Li et al. reveal that heightened activity of anterior cingulate cortex excitatory neurons precisely governs chronic-pain-induced insomnia via the dorsal medial striatum pathway. This effect relies on enhanced plasticity in dopamine D1-receptor-positive medium spiny neurons. [ABSTRACT FROM AUTHOR]

Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Because sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining, and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin- and parvalbumin-positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naive mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic. [ABSTRACT FROM AUTHOR]

Glutamate is the major excitatory neurotransmitter in the brain and plays an essential role in regulating wakefulness. Histaminergic neurons, which are exclusively localized in the tuberomammillary nucleus (TMN) of the hypothalamus, have a pivotal role in the regulation of sleep–wake patterns by sending widespread projections into many brain areas implicated in sleep–wake control. The role of glutamate in histaminergic neurons within the TMN and the resulting sleep–wake profile remains unknown. We found that glutamate, NMDA, AMPA or dihydrokainate, a glutamate-uptake inhibitor, dose-dependently increased wakefulness when microinjected into the rat TMN. Glutamate, NMDA, and AMPA also increased the firing rate of action potentials in TMN histaminergic neurons. The arousal-promoting effect of glutamate was inhibited by NMDA and histamine H 1 receptor antagonists. Furthermore, MK-801, an NMDA receptor antagonist, inhibited the firing rate of histaminergic neurons and increased non-rapid eye movement sleep after microinjection into rat TMN. Taken together, these findings demonstrated that glutamate activated histaminergic neurons in the TMN and increased wakefulness in rats, possibly via the action of NMDA and histamine H 1 receptors. • Glutamate and its receptor agonist NMDA and AMPA increase wakefulness in rats. • Glutamate, NMDA and AMPA activate the histaminergic neurons in TMN. • The effect of glutamate was inhibited by NMDAR and histamine H 1 R antagonists. [ABSTRACT FROM AUTHOR]