The sleep-wake cycle: molecular mechanisms, disorders, and therapeutic targets in the context of energy metabolism

Abstract

A close interconnection exists between the sleep-wake cycle and energy metabolism. During non-rapid eye movement (NREM) sleep, the body experiences a significant decline in basal metabolic rate and overall energy expenditure, coupled with a concurrent acceleration in the clearance of cerebral metabolic wastes. Sleep deprivation or insufficiency can disrupt metabolic homeostasis, compromising the clearance of metabolic waste from the brain and thereby elevating the risk for a range of adverse outcomes, including type 2 diabetes, obesity, and dementia. However, the converse relationship, whereby perturbations in energy metabolism disrupt the sleep-wake cycle and lead to sleep disorders, remains an area lacking detailed investigation. Accordingly, this review synthesizes established evidence on the neural substrates and regulatory mechanisms of the sleep-wake cycle. Central to our discussion is the role of energy metabolism in these processes, with special consideration given to the impact of cell type-specific metabolic profiles on sleep-wake regulation, such as their roles in ATP surge during the early stage of sleep. We also summarize the sleep disorders observed in conditions of energy metabolic disruption and those with impaired energy generation. Complementing this, a compelling body of evidence indicates that pharmacological enhancement of metabolism frequently results in improved sleep. In short, this review advances the perspective that rectifying underlying metabolic deficiencies offers a paradigm shift in sleep therapy.

Introduction

Sleep is widespread among homeothermic animals and has important impacts on cognition, memory formation,¹ brain plasticity,² insulin release and response,³ temperature regulation,⁴ and immune maintenance.⁵ However, amid the rapid pace of modern society and the rising trend of an aging population, sleep disorders are increasingly prevalent among a growing number of individuals. Sleep disorders currently affect an estimated one-third of the world’s population, representing a significant and growing public health concern.⁶ A Korean retrospective cohort study revealed that the prevalence of sleep disorders increased from 7.62% in 2011 to 14.41% in 2020, nearly doubling over the decade.⁷ Long-term sleep disorders can increase the risk of obesity,⁸ diabetes,⁹ cardiovascular and cerebrovascular diseases,¹⁰ dementia,¹¹ and other diseases. Sleep disorders not only significantly diminish the quality of life for individuals but also place a substantial societal burden. Therefore, sleep science has become one of the hot topics in contemporary research.

Sleep is a natural, cyclical physiological state characterized by the disappearance of various conscious voluntary behaviors for a period, as well as decreased responsiveness to external stimuli. One important feature is the ability of the brain to transition rapidly from a state of sleep to wakefulness.¹² The two-process model¹³ is currently the most widely accepted theory in sleep-wake regulation. This model proposes that sleep is the result of the interaction and integration of sleep-wake homeostasis (Process S) and the circadian rhythm system (Process C). Electroencephalogram (EEG) signals are the sum of synchronized excitatory and inhibitory postsynaptic potentials of cortical neurons, which are fundamental in sleep research. In EEG studies, the spectral features of wakefulness span alpha (8–12 Hz), beta (12–35 Hz), and gamma (>35 Hz) bands, with beta and gamma dominating during active cognition and alpha dominating during a relaxed state¹⁴ (Fig. 1). Based on different manifestations in EEG and electromyograms (EMG), sleep can be divided into nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.^15,16 In NREM sleep, the delta band (0.5–4 Hz) is the predominant oscillation, especially during the slow-wave sleep (SWS)/NREM stage, whereas the theta band (4–8 Hz) is the characteristic rhythm during REM sleep.^15,16 Organisms acquire nutrients from their surroundings, converting them through digestion, absorption, and metabolism processes into usable energy for tissues and cells, thereby sustaining vital life functions. Energy metabolism encompasses the coordinated processes of energy production, allocation, storage, and utilization. The primary role of cellular energy metabolism lies in synthesizing adenosine triphosphate (ATP), the universal currency of biological energy. This process mainly occurs in the mitochondria through oxidative phosphorylation (OXPHOS).^17,18 Additionally, it contributes to cell signaling,^19,20 neural signal transmission,^21,22 hormone synthesis and secretion,²³ maintenance of body temperature,²⁴ and normal functioning of the immune system.²⁵ The energy metabolism of the brain is exceptionally active; despite representing just 2% of body weight, it consumes 20% of the body’s total energy.²² This high energy consumption is predominantly dedicated to powering neuronal signaling and maintaining ionic gradients across cell membranes, underscoring the profound interdependence between neural function and metabolic support.

Fig. 1.

Features of the five basic spectra of brain waves. The gamma band (>35 Hz) appears in higher-level cognitive processes. The beta band (12–35] Hz occurs during active brain states. The alpha band (8–12] Hz is observed during relaxed wakefulness. The theta band (4-8] Hz is linked to deep relaxation. The delta band [0.5–4] Hz is most prominent during NREM sleep and is associated with reduced consciousness. (a, b] indicates all numbers greater than “a” and less than or equal to “b”, where “(“ is exclusive while “]” is inclusive

There is a bidirectional relationship between sleep and energy metabolism. Different species require different amounts of sleep. In fact, sleep duration is not influenced by brain size or cognitive abilities. Instead, it is related to the ecological niche and feeding requirements of the species,²⁶ indicating that the balance of sleep-wakefulness plays a role in food acquisition and energy expenditure. NREM sleep, particularly SWS, represents a fundamental state of energy conservation and restoration. This function is directly driven by the brain’s dominant electrophysiological pattern: synchronized, low-frequency, high-amplitude oscillations in the delta band (0.5–4 Hz).²⁷ These slow waves reflect a highly coordinated, oscillating pattern of neuronal silence and activity, which lowers the brain’s metabolic demand. Concurrently, this period is marked by a significant decline in both cerebral and core body temperatures, a result of reduced thermoregulatory set-point.²⁸ This systemic cooling further contributes to a substantial reduction in the overall metabolic rate and energy expenditure, allowing for the replenishment of energy stores and critical cellular repair processes. In contrast, REM sleep is a period of active energy consumption and redistribution.²⁹ Despite a state of muscle atonia that paralyzes the body, the brain’s metabolic rate surges to levels matching wakefulness. This high energy cost is directed toward functions essential for higher-order cognition, particularly the reactivation and consolidation of memories and the intricate processing of emotions.³⁰ To fuel this intense cerebral activity, energy is strategically diverted away from nonessential somatic functions.³⁰

Synaptic homeostasis also provides a strong link between energy metabolism and sleep regulation. Synaptic transmission is one of the most energy-costly processes in the brain.³¹ The current study indicates that sleep-dependent synaptic downscaling occurs,³² a phenomenon that helps to explain the energy conservation observed during this period. In addition, a key piece of evidence is that the potentiation of excitatory synapses within the prefrontal cortex (PFC) has been demonstrated to promote longer NREM sleep duration and higher delta wave power, which are hallmarks of deep sleep.³³ Consequently, a drop in cellular energy metabolism disrupts the precise modulation of synaptic strength, a mechanism that supports both learning during wakefulness and restorative processes during sleep.

In this review, we explore the role of energy metabolism in the initiation of the sleep-wake cycle, as well as the interplay between specific brain nuclei and neurotransmitters; examine how energy metabolism influences the sleep-wake cycle through sleep-wake homeostasis, the circadian rhythm system and the different types of cells; analyze the connection between energy dysmetabolism-related diseases and the increased risk of sleep disorders; summarize medications that simultaneously enhance energy metabolism and improve sleep; and propose the potential of using drugs that enhance energy metabolism as a novel therapeutic approach for sleep disorder intervention.

The initiation of the sleep-wake cycle

Traditionally, sleep was misconceived as a passive state of neural quiescence; however, extensive experimental evidence has firmly established it as a complex, actively regulated process orchestrated by the central nervous system.^12,34 The seamless progression of the sleep-wake cycle depends on a dynamic balance, maintained by complex interactions and mutual inhibition among numerous neural nuclei and neurotransmitters/neuropeptides in the brain, which influence the initiation and maintenance of sleep and wakefulness.

Homeostatic regulation of sleep-wake nuclei in the sleep-wake cycle

The sleep-wake cycle is governed by a complex interplay of specialized neuronal circuits (Fig. 2). The classical ascending reticular activating system (ARAS) consists of dorsal and ventral pathways driving arousal. The dorsal pathway originating from pedunculopontine tegmental nuclei (PPT)/laterodorsal tegmental nuclei (LDT) cholinergic neurons activates thalamocortical circuits for sensory integration, while the ventral pathway integrates inputs from locus coeruleus (LC) norepinephrinergic, dorsal raphe nucleus (DRN) serotonergic, ventral tegmental area (VTA) dopaminergic, tuberomammillary nucleus (TMN) histaminergic, and lateral hypothalamus (LH) orexinergic nuclei to sustain prolonged wakefulness. Modern optogenetic/chemogenetic studies have expanded this framework by identifying novel arousal-promoting populations, including glutamatergic neurons in the paraventricular thalamus (PVT), medial parabrachial nucleus (MPB), and basal forebrain (BF), as well as GABAergic interneurons across midbrain and forebrain regions. These systems counterbalance sleep-active nuclei such as the ventrolateral preoptic area (VLPO) hypothalamic region, whose inhibitory projections to ARAS components are critical for transitioning into NREM sleep via GABA/galanin release. Thalamic networks further regulate this equilibrium through the centromedial thalamus (CMT) nuclei mediating sleep recovery and the thalamic reticular nuclei (TRN) circuits generating sleep spindles. REM sleep is regulated by a specialized subnetwork involving neurons in the sublaterodorsal tegmentum nucleus (SLD) that drive state transitions while being constrained by GABAergic gatekeepers in the ventrolateral periaqueductal gray (vlPAG) and dorsal deep mesencephalic nucleus (dDpMe). This multilayered system achieves homeostatic regulation through reciprocal interactions between wake-promoting, NREM sleep-promoting, and REM sleep-promoting circuits.

Fig. 2.

Neural nuclei and neurotransmitters/neuropeptides in the neural circuits regulating the sleep-wake cycle. The ventral and dorsal pathways of the ascending reticular activating system are illustrated by red and yellow nuclei with corresponding arrows, respectively. Green nuclei are involved in the regulation of NREM sleep, and blue nuclei are involved in the regulation of REM sleep. VLPO ventrolateral preoptic area, GABA γ-aminobutyric acid, Gal galanin, NAc nucleus accumbens, A_2AR adenosine A_2A receptor, LH lateral hypothalamus, ORX orexin, MCH melanin-concentrating hormone, BF basal forebrain, Ach acetylcholine, TMN tuberomammillary nucleus, His histamine, VTA ventral tegmental area, DRN dorsal raphe nucleus, LC locus coeruleus, NA noradrenaline, LDT laterodorsal tegmental nuclei, PPT pedunculopontine tegmental nuclei, dDpMe dorsal deep mesencephalic nucleus, vlPAG ventrolateral periaqueductal gray, SLD sublaterodorsal tegmentum nucleus. Orx (orexin) and Hcrt (hypocretin) are synonymous terms representing the same neuropeptide system

Wakefulness-promoting nuclei

In 1949, Moruzzi and Magoun found that damaging the reticular formation in the brainstem causes cats to remain in a “sleep” state, while electrical stimulation of the brainstem reticular formation can cause desynchronization and activation of the EEG in anesthetized cats,³⁵ leading them to believe that wakefulness is driven by the ARAS located within the brainstem.^35,36 Later studies confirmed the existence of two major pathways in ARAS.³⁷ The dorsal pathway originates from PPT/LDT cholinergic neurons, which transmit excitatory neural signals to the nonspecific nuclei of the thalamus, activating the thalamocortical pathway and thus exciting the cortex.³⁸ The ventral pathway originates from LC norepinephrinergic neurons, DRN serotonergic neurons, midbrain dopaminergic neurons, and TMN histaminergic neurons.^37,39 It passes through LH orexinergic neurons and BF cholinergic or GABAergic neurons, ultimately projecting extensively to the cortex, causing cortical excitation and resulting in arousal^37,39 (Fig. 2). The dorsal pathway allows the thalamus to process signals related to sensation, motor responses, and cognition, with minimal impact on wakefulness duration.⁴⁰ However, an impaired ventral pathway can significantly reduce wakefulness duration.⁴¹

With the advent of technologies such as calcium imaging, optogenetics, and chemogenetics, it has become possible to monitor and modulate specific neuronal populations. An increasing number of nuclei have been identified as contributors to arousal, including glutamatergic neurons in the VTA,⁴² BF,^43,44 PVT,⁴⁵ and MPB,⁴⁶ as well as GABAergic neurons in the BF,⁴³ LH,⁴⁷ SC,⁴⁸ and VP.⁴⁹ In addition, the ventromedial thalamic nucleus (VM),⁵⁰ dorsal medial thalamus (DMT),⁵¹ and posterior parietal cortex (PtA)⁵² have also been shown to promote arousal. Ren et al. recently revealed that GABAergic neurons expressing GAD2 in the midbrain dorsal raphe nucleus (DRN^2GAD) are activated during wakefulness and can inhibit excessive arousal under both physiological and stress conditions.⁵³ This means that the state of wakefulness is finely controlled by the balanced activity of wake-promoting neurons and wake-limiting neurons (Table 1).

Table 1.

Regulation of the sleep-wake cycle by specific types of neurons in different brain regions

Region	Types of neurons	Regulation of the sleep-wake cycle	Reference
PPT/LDT	Cholinergic	Promote wakefulness/REM sleep	38,95,121,122
	many GABAergic and glutamatergic	Promote wakefulness/REM sleep	83
LC	Noradrenergic	Promote wakefulness	37,110
DRN	Serotonergic	Promote wakefulness	140,141,143
	Dopaminergic	Promote wakefulness	160
	GAD2+ GABAergic	Suppress hyperarousal	53
VTA	Dopaminergic	Promote wakefulness/REM sleep	94,161
	Glutamatergic/nitrergic (NOS1)	Promote wakefulness	42
	GABAergic	Promote NREM sleep
TMN	Histaminergic	Promote wakefulness	179,185,186
	Adenosine A1 receptor (+)	Promote NREM sleep	266
LH	Hypocretin/orexinergic	Promote wakefulness/REM sleep	86,210,213
	GABAergic	Promote wakefulness/REM sleep	47,89
	MCH	Promote NREM and REM sleep	67,69,91,92
	Adenosine A1 receptor (+)	Promote NREM sleep	267
NAc	Dopamine D1 receptors (+)	Promote wakefulness	109
	Adenosine A2A receptor (+)	Promote NREM sleep	73,74
BF	Cholinergic	Promote wakefulness	43,44
	Glutamatergic	Promote wakefulness
	PV+ GABAergic	Promote wakefulness
	SOM+ GABAergic	Promote NREM sleep
	Adenosine A1 receptors (+)	Promote NREM sleep	265,268
PVT	Glutamatergic	Promote wakefulness	45
	MT1/MT2 receptors (+)	Promote NREM sleep	339
MPB	Glutamatergic	Promote wakefulness	46
SC	GABAergic	Promote wakefulness	48
VP	GABAergic	Promote wakefulness	49
VM	Calbindin1-positive matrix cells	Promote wakefulness	50
DMT	Calretinin (CR)-containing	Promote wakefulness	51
PtA	Not mentioned	Promote wakefulness	52
VLPO	GABAergic	Promote NREM sleep	57,59
	Galaninergic	Promote NREM sleep
	Adenosine A2A receptor (+)	Promote NREM sleep	271
	Adenosine A1 receptor (+)	Promote wakefulness	269
CMT	Not mentioned	Induce NREM-wake transitions/ Promote sleep recovery	62
TRN	GABAergic	Promote NREM sleep	47
	Cholinergic	Promote NREM sleep	65
Posterior thalamic	Neurotensinergic	Promote NREM sleep	66
CeA	Neurotensinergic	Promote NREM sleep
cortex	nNOS/NK1	Promote NREM sleep	70
	SOM+ interneurons	Promote NREM sleep	71
Striatum	Dopamine D1 receptors (+)	Promote wakefulness	164
	Adenosine A2A receptor (+)	Promote NREM sleep	72
OT	Adenosine A2A receptor (+)	Promote NREM sleep	75
PZ	GABAergic/glycinergic	Promote NREM sleep	76–78
vlPAG	NTS-expressing glutamatergic	Promote NREM sleep	79
	GABAergic	Suppress REM sleep	96
SLD	Neurotensinergic	Promote NREM sleep	80
	Glutamatergic	Promote REM sleep	83–85
	GABAergic	Promote REM sleep
	Cholinergic	Promote REM sleep
Ventral medulla	GABAergic	Promote REM sleep	87
dmM	GABAergic	Promote REM sleep	88
ZI	GABAergic	Promote REM sleep	90
RSC	Not mentioned	Promote REM sleep	93
BLA	Dopamine D2 receptor (+)	Promote REM sleep	94
dDpMe	GABAergic	Suppress REM sleep	97

NREM sleep-promoting nuclei

In the late 1990s, the first group of sleep-active neurons was discovered in the VLPO of the hypothalamus.⁵⁴ The VLPO sends inhibitory projections to several arousal-promoting neuronal populations,⁵⁵ including PPT/LDT cholinergic neurons,⁵⁵ LC norepinephrinergic neurons,⁵⁶ DRN serotonergic neurons,⁵⁶ midbrain dopaminergic neurons,⁵⁶ TMN histaminergic neurons,⁵⁷ and LH orexinergic neurons.⁵⁸ By inhibiting these arousal-related neurons, the VLPO promotes sleep. In the VLPO, neurons release inhibitory neurotransmitters such as galanin and GABA and are mainly active during sleep.^57,59 The activation of the VLPO is positively correlated with sleep duration, and its destruction leads to a reduction in NREM sleep time.^54,60 Notably, glucose can activate VLPO neurons to induce slow-wave sleep, suggesting a link between energy metabolism and sleep,⁶¹ which in part explains the phenomenon of postprandial sleepiness.

The thalamus has a dual role in the regulation of sleep and wakefulness. It has been mentioned above that thalamic nuclei such as PVT, VM, and DMT are involved in the regulation of wakefulness. CMT neurons in the thalamus can not only induce NREM-wake transitions but also promote sleep recovery.⁶² By using simultaneous functional MRI (fMRI) and EEG, Song et al. demonstrated that the thalamus has an important function in the initiation and maintenance of sleep.⁶³ In addition, sleep spindles (bursts of activity at 7–15 Hz during NREM sleep) are generated by the interaction between thalamic reticular nuclei (TRN) and thalamocortical neurons.⁶⁴ Recent studies have shown that GABAergic neurons⁴⁷ and cholinergic neurons⁶⁵ in the TRN, as well as neurotensinergic neurons within a thalamo-amygdala circuit involving the posterior thalamus and the central nucleus of the amygdala (CeA),⁶⁶ can promote NREM sleep.

Combining optogenetic activation, optrode recording, and in vitro physiology, Xu et al. found that activation of somatostatin-positive (SOM⁺) GABAergic neurons in the BF can promote NREM sleep.⁴³ Melanin-concentrating hormone (MCH) neurons in the LH are also involved in the regulation of NREM sleep. Selective ablation of MCH neurons in the LH resulted in decreased NREM sleep and unchanged REM sleep.⁶⁷ Interestingly, prolonged inhibition of LH elicits a unique NREM sleep state with enhanced slow-wave activity and REM sleep suppression, an effect not observed following selective orexin or MCH neuron inactivation, pointing to the existence of additional sleepregulatory neurons in this region.⁶⁸ Chronic optogenetic activation of MCH neurons (over 24 hours) can increase both NREM and REM sleep.⁶⁹ Furthermore, multiple other neuronal populations have been implicated in the regulation of NREM sleep. These include cortical nNOS/NK1 neurons⁷⁰; somatostatin-positive cortical interneurons⁷¹; adenosine A_2A receptor neurons in the striatum,⁷² NAc,^73,74 and olfactory tubercle (OT)⁷⁵; parafacial zone (PZ) GABAergic neurons^76–78; neurotensin (NTS)-expressing glutamatergic neurons in the vlPAG^79; and neurotensinergic neurons in the SLD of the pontine.⁸⁰

REM sleep nuclei

REM sleep nuclei contain two types of mutually antagonistic neurons.⁸¹ One type of neuron can inhibit wakefulness and NREM sleep and promote the initiation and maintenance of REM sleep. The SLD is a key nucleus for REM sleep.^81,82 The SLD contains glutamatergic, GABAergic, and possibly cholinergic neurons, which are strongly activated during REM sleep and wakefulness.^83,84 Pharmacologic activation or disinhibition of SLD can increase REM sleep duration.⁸⁵ LH orexin neurons can also play a role in stabilizing REM sleep by modulating the SLD.⁸⁶ GABAergic neurons in the ventral medulla,⁸⁷ dorsomedial medulla (dmM),⁸⁸ LH,⁸⁹ and zona incerta (ZI),⁹⁰ MCH neurons in the LH,^91,92 and neurons in the retrosplenial cortex (RSC)⁹³ have all been shown to promote REM sleep. Recently, Hasegawa et al. found that basolateral amygdala (BLA) dopamine signaling from the VTA is significant for the initiation of REM sleep.⁹⁴ The cholinergic neurons of the PPT/LDT, along with the majority of glutamatergic and GABAergic neurons, are also believed to be involved in the initiation and maintenance of REM sleep.^83,95

Another group of neurons acts as gatekeepers for REM sleep and is primarily located in the vlPAG⁹⁶ and dDpMe,⁹⁷ consisting mainly of GABAergic neurons. The majority of vlPAG/dDpMe_GABA neurons exhibit the highest activity during wakefulness, decrease their activity during NREM sleep and are almost inactive during REM sleep, while a small subset of neurons show the greatest activity during REM sleep.⁹⁶ Activation of vlPAG/dDpMe_GABA neurons using optogenetic or chemogenetic approaches can significantly inhibit REM sleep.^96,98

Under normal conditions, the neural circuits of wakefulness-promoting and sleep-promoting nuclei, along with their neurotransmitters/neuropeptides, interact to maintain homeostasis between wakefulness and sleep (Fig. 3a). Impairment of any one of these associated nuclei results in sleep-wake disturbances. The “flip-flop switch” theory^37,99 provides a good explanation for the rapid transition between sleep and wakefulness cycles. The LH orexinergic neurons serve as a critical “switch button” for the transition.^37,99 When their excitability increases, they promote the excitation of almost all wakefulness-promoting nuclei, which in turn inhibit the VLPO, thereby terminating sleep and inducing wakefulness.^99,100 Conversely, when their excitability decreases, the inhibitory effect of these wake-promoting nuclei on the VLPO is reduced, which terminates wakefulness and initiates sleep.^37,99 If the activity of LH orexin neurons is reduced or absent, it severely affects the initiation of wakefulness, leading to narcolepsy (which is discussed in detail below)^101,102 (Fig. 3b). Fatal familial insomnia (FFI) also serves as a model disease in sleep physiopathology, characterized by the loss of sleep spindles and K-complexes.¹⁰³ The D178N mutation of the prion protein-encoding gene (PRNP) causes the normal prion protein to misfold into a pathogenic form, leading to abnormal accumulation of pathogenic protein in the thalamus, particularly in the anterior (A) and dorsomedian (DM) thalamic nuclei, and inferior olivary nuclei^104,105 (Fig. 3c). The TRN is essential for the generation of sleep spindles^,64 and the DM receives afferents from the oral pole of the TRN.¹⁰⁶ Therefore, degeneration of the DM may underlie the loss of spindling activity in FFI.¹⁰³

Fig. 3.

The wakefulness and sleep initiation systems coordinate and constrain each other. a In the normal sleep-wake cycle, the wakefulness and sleep systems counteract each other to maintain homeostasis. b In narcolepsy, the reduced or absent activity of orexin neurons in the arousal system of the LH weakens its excitatory effects, leading to a more stable inhibitory effect from the sleep system. c Fatal familial insomnia is pathologically characterized by the abnormal deposition of prion proteins in the thalamus, leading to neuronal degeneration, vacuole formation, and gliosis in that region. This results in a weakened inhibitory effect of the sleep system and, correspondingly, an enhanced excitatory effect of the wakefulness system. LC locus coeruleus, DRN dorsal raphe nucleus, PPT pedunculopontine tegmental, LDT laterodorsal tegmental, TMN tuberomammillary nucleus, LH lateral hypothalamus, BF basal forebrain, VLPO ventrolateral preoptic area, NAc nucleus accumbens

Sleep-wake neurotransmitters/neuropeptides in the sleep-wake cycle

The sleep-wake cycle is a complex physiologic process orchestrated by multiple neurotransmitters and neuropeptides. Central cholinergic systems play pivotal roles in maintaining wakefulness through acetylcholine-mediated activation of nicotinic and muscarinic receptors, with marked increases during both REM sleep and waking states (Table 2). Wakefulness represents a distinct behavioral state characterized by low-voltage high-frequency EEG patterns (α-γ bands) and postural stability, maintained via cholinergic projections from the basal forebrain to neocortical regions and the brainstem reticular activating system.¹⁰⁷ Serotonergic projections from the dorsal raphe nucleus (DRN) exhibit a dual role: while 5-HT neuronal activity peaks during active waking and may suppress REM sleep via G_i/G_s coupled receptor signaling, recent studies highlight its bidirectional modulation of sleep regulation through tonic/burst firing patterns in distinct brain regions.¹⁰⁸ Dopaminergic pathways contribute to arousal by activating D1-type receptors, with dysregulation linked to altered NREM/REM architecture. Arousal is a broad neurophysiological concept encompassing sustained cortical network activation, primarily regulated by the dopaminergic pathway in the ventral tegmental area and substantia nigra and the histaminergic pathway in the hypothalamus circuits^,54,109, Noradrenergic output from the locus coeruleus (LC) exhibits phasic activity during waking via α₁/α₂ receptor signaling,¹¹⁰ while histaminergic neurons maintain sustained alertness through H₁ receptor-mediated cortical excitation.⁵⁴ Alertness denotes an optimized sensory processing threshold reflecting heightened vigilance, primarily mediated by histaminergic neurons in the tuberomammillary nucleus of the hypothalamus. These neurons directly excite corticothalamic circuits through H₁ receptor activation.¹¹¹ Simultaneously, orexin neurons in the LH are active during wakefulness and essential for stabilizing the wake state and sustaining alertness by inhibiting sleep-active regions, such as the ventrolateral preoptic area (VLPO), and activating monoaminergic nuclei. Loss of orexin-producing neurons in humans results in narcolepsy, a disorder characterized by excessive daytime sleepiness and sudden transitions between wakefulness and sleep. Inhibitory GABAergic signaling via GABA_A receptors provides counterbalancing mechanisms to modulate excitatory drives. Emerging evidence underscores the interdependence between these systems and mitochondrial energetics, as ATP-dependent vesicular uptake and release of neurotransmitters rely on axonal mitochondrial trafficking, a process whose dysfunction disrupts neurochemical homeostasis and sleep regulation equilibrium.

Table 2.

Neurotransmitters/neuropeptides and their receptors related to the sleep-wake cycle

Neurotransmitters/neuropeptide	Receptor types		Type of major coupled G protein	Reference
Acetylcholine	Nicotine	N1; N2	Ligand-gated ion channels	115
	Muscarine	M1; M3; M5	Gq	117,118
		M2; M4	Gi
5-HT/Serotonin	5-HT3		Ligand-gated ion channels	136–138
	5-HT1; 5-HT5		Gi
	5-HT4; 5-HT6; 5-HT7		Gs
	5-HT2		Gq
Dopamine	D1 - like	D1; D5	Gs	156–158
	D2 - like	D2; D3; D4	Gi
Noradrenaline	α1		Gq	171
	α2		Gi
	β	β1	Gs
		β2	Gs; Gi	171,172
		β3	Gs; Gi	171,173
Histamine	H1		Gq	187,190,193,199
	H2		Gs
	H3		Gi
	H4		Gq
Orexin	OX1R; OX2R		Gq	205
Glutamate	NMDA; AMPA; kainite; GluD		Ligand-gated ion channels	226
	mGluR1, mGluR5		Gq	227
	mGluR2, mGluR3		Gi
	mGluR4, mGluR6, mGluR7, mGluR8		Gi
GABA	GABAA		Ligand-gated ion channels	235
	GABAB		Gi	236
Adenosine	A1; A3		Gi	264
	A2A; A2B		Gs
Melatonin	MT1		Gi; Gs	326,327
	MT2		Gi	326
	MT3		Nqo2	341

ACh maintains wakefulness and induces REM sleep during sleep

Acetylcholine (ACh) is synthesized from choline and acetyl coenzyme A in axon terminals under the catalysis of choline acetyltransferase (ChAT).¹¹² The generated acetylcholine is transported into vesicles under the action of vesicular acetylcholine transporter (VAChT),¹¹³ and this process depends on ATP.¹¹⁴ When an action potential occurs, acetylcholine within a vesicle is released into the synaptic cleft, where it binds to nicotinic or muscarinic receptors to exert its effects. Nicotinic receptors are ligand-gated ion channel receptors, and there are two subtypes: the muscle type (N₁) and the neuronal type (N₂).¹¹⁵ Neuronal nicotinic receptors can modulate neuronal excitability via presynaptic or postsynaptic mechanisms in the brain.¹¹⁶ Muscarinic receptors have five subtypes, M₁-M₅, and they are all G protein-coupled receptors (GPCRs).¹¹⁷ Among them, the M₁, M₃, and M₅ subtypes are coupled with G_q proteins and increase the activity of phospholipase C (PLC), promoting the release of Ca²⁺ from the endoplasmic reticulum calcium stores dependent on inositol trisphosphate (IP3), ultimately leading to an increase in intracellular Ca²⁺ levels and a subsequent increase in excitability. In contrast, the M₂ and M₄ subtypes are coupled with G_i proteins and inhibit adenylate cyclase (AC) activity, preventing the conversion of ATP to cAMP.¹¹⁸ The central nervous system contains all five subtypes.¹¹⁹ After acetylcholine in the synaptic cleft dissociates from its receptors, it is broken down by acetylcholinesterase (AChE) into choline and acetate. Free choline is then reabsorbed back into the presynaptic neuron by the choline transporter (CHT) to participate again in the synthesis and metabolic cycle of acetylcholine.¹²⁰

The pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) contain aggregations of cholinergic neurons.¹²¹ Acetylcholine binding to muscarinic receptors causes rapid cortical activity and blocks slow-wave activity.¹²² Acetylcholine release rises during wakefulness and REM sleep but drops significantly during NREM sleep.¹²³ In the basal forebrain (BF), cholinergic neurons show heightened activity during wakefulness and REM sleep than during NREM sleep, and activating these neurons can rapidly induce wakefulness.⁴³ Interestingly, an older study found that enhancing synaptic acetylcholine during REM sleep can trigger awakening, while the same manipulation during NREM sleep promotes transition into REM sleep,¹²⁴ suggesting a context-dependent role for acetylcholine in sleep regulation. More strikingly, long-term knockout of muscarinic acetylcholine receptors M1 and M3 nearly eliminates REM sleep, leaving it at barely detectable levels.¹²⁵ Furthermore, brain-wide functional ultrasonic imaging and cell-type-specific calcium imaging combined with optogenetics have shown that during NREM sleep, cortical ignition (a brain process related to conscious awareness in humans and nonhuman primates) is strongly suppressed due to reduced cholinergic modulation and rapid inhibition of cortical responses.¹²⁶

Serotonin/5-hydroxytryptamine exhibits bidirectional regulation of the sleep-wake cycle

Serotonin/5-hydroxytryptamine (5-HT) was initially thought to be a vasoconstrictor. Subsequent research has confirmed that serotonin (5-HT) is also distributed in the brain.¹²⁷ Serotonin (5-HT) neurons are mainly distributed in the DRN of the brainstem¹²⁸ and are involved in the regulation of physiological functions such as sleep,^108,129 mood,¹³⁰ learning and memory,¹³¹ pain,¹³² and movement.¹³³ As a monoamine neurotransmitter, serotonin (5-HT) is derived from tryptophan through the action of tryptophan hydroxylase (TPH) and aromatic L-amino acid decarboxylase (AADC).¹³⁴ Serotonin (5-HT) synthesized within neurons is transported from the cytoplasm into synaptic vesicles via vesicular monoamine transporter 2 (VMAT2), and it is subsequently released into the synaptic cleft upon neuronal activation. Concurrently, the serotonin (5-HT) reuptake transporter (SERT), located in the presynaptic membrane, facilitates the reuptake of serotonin (5-HT) from the synaptic cleft back into the neuron,¹³⁵ where it is subsequently metabolized by monoamine oxidase (MAO) located on the outer membrane of mitochondria. Seven 5-HT receptors have been previously identified. The 5-HT₃ receptor is the only receptor that functions as a ligand-gated ion channel receptor, while all other types of 5-HT receptors are G protein-coupled receptors.¹³⁶ The 5-HT₁ and 5-HT₅ receptors primarily couple with G_i proteins, leading to the inhibition of AC activity.¹³⁷ In contrast, the 5-HT₄, 5-HT₆, and 5-HT₇ receptors predominantly couple with G_s proteins, resulting in the activation of AC activity.¹³⁷ Additionally, 5-HT₂ receptors mainly couple with G_q proteins, which activate the activity of PLC.¹³⁸

Serotonin (5-HT) has a complex bidirectional role in the regulation of the sleep-wake cycle. Earlier studies have found that impairments or reductions in the production of the 5-HT pathway lead to decreased sleep in rats or cats,¹³⁹ suggesting that 5-HT has sleep-promoting effects. However, several subsequent studies have reported that 5-HT neurons in the DRN are most active during active waking, significantly less active during NREM sleep, and cease firing during REM sleep.^140–142 Reducing the activity of these neurons can induce sleep.¹⁴³ Consequently, the paradigm of 5-HT shifts toward its arousal function.¹⁴⁴ In recent years, an increasing number of studies have provided evidence supporting the notion that 5-HT also plays a role in promoting sleep. Tryptophan hydroxylase 2 (Tph2) deficiency affects the synthesis of 5-HT in the brain. EEG recordings have shown that Tph2 knockout mice exhibit reduced sleep.¹⁴⁵ Using genetic mutagenesis and optogenetic techniques, Prober and colleagues demonstrated that tonic stimulation of the DRN promotes sleep in both zebrafish and mice, but burst stimulation induces wakefulness.¹⁰⁸

Dopamine contributes to arousal

Dopamine is also a monoamine neurotransmitter that plays a crucial role in both central and peripheral signal transduction.¹⁴⁶ It is involved in various physiological processes, including the regulation of sleep and arousal,^147,148 movement,¹⁴⁹ cognition,¹⁵⁰ reward,¹⁵¹ behavior, and emotion.¹⁵² Dopamine is primarily synthesized from tyrosine,¹⁵³ with tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC) playing crucial functions in this process.¹⁵⁴ Similar to 5-HT, synthetic dopamine can enter synaptic vesicles via VMAT2 and be released into the synaptic cleft upon neuronal activation.¹⁵⁴ The dopamine transporter, located in the presynaptic membrane, facilitates the reuptake of dopamine from the synaptic cleft back into the neurons, thereby regulating dopamine signaling.¹⁵⁵ To date, five dopamine receptors have been identified, namely, D₁, D₂, D₃, D_4, and D₅.^156,157 As G protein-coupled receptors, they are categorized into two classes.¹⁵⁸ Specifically, D₁ and D₅ receptors are classified as D1-type dopamine receptors, which primarily couple with G_s proteins to activate AC activity and promote cAMP production.^157,158 In contrast, D₂, D₃, and D₄ receptors are classified as D2-type dopamine receptors, which mainly couple with G_i proteins and exert an inhibitory effect on AC activity.^157,158

The dopaminergic neurons involved in regulating sleep and wakefulness are primarily located in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc).¹⁴⁷ Dopamine deficiency can impair wakefulness and reduce REM sleep in mice.¹⁵⁹ Dopaminergic neurons in the VTA and DRN significantly contribute to arousal.^160–162 Systemic administration of selective D₁ receptor agonists can induce arousal and suppress REM sleep in rats.¹⁶³ Similarly, selective activation of D₁-expressing neurons in the striatum or nucleus accumbens (NAc) using optogenetics can induce a rapid transition from NREM sleep to wakefulness, while the inhibition of these neurons significantly reduces the duration of wakefulness in mice.^109,164 Dopamine D₂ receptor agonists have biphasic effects on sleep and wakefulness in rats, with low doses decreasing wakefulness and increasing SWS and REM sleep, whereas high doses induce the opposite effects.¹⁶⁵ Compared with wild-type mice, dopamine D₂ receptor knockout mice exhibited a significant decrease in wakefulness and increased NREM and REM sleep but decreased EEG delta power during NREM sleep, especially during the early stage of the active phase.¹⁶⁶

Noradrenaline promotes wakefulness

Noradrenaline (NA) is synthesized from dopamine through the action of dopamine-β-hydroxylase (DBH). In the brain, NA primarily originates from the locus coeruleus (LC) in the pons. As a monoamine neurotransmitter, NA synthesized within neurons is also transported into vesicles by VMAT2 and is released upon the triggering of an action potential.¹⁶⁷ The norepinephrine transporter (NET) located in the presynaptic membrane can also regulate NA release and reuptake.^168,169 NA in neurons is mainly metabolized by the MAO pathway.¹⁷⁰ NA receptors are all G protein-coupled receptors, including three pharmacological receptor types, α₁, α_2, and β, each of which can be further divided into three subtypes according to their structure and function.¹⁷¹ The α₁ receptors are primarily coupled with G_q protein to promote the activation of PLC; the α₂ receptors are mainly coupled to G_i protein, which inhibits AC; the β receptors are predominantly coupled to G_s proteins and play an activating role in AC¹⁷¹; β₂¹⁷² and β₃¹⁷³ receptors are also coupled to G_i.

The noradrenergic neurons in the LC fire most actively during wakefulness, discharge is reduced during SWS, and they are nearly silent during REM sleep.¹¹⁰ Pharmacological experiments found that α₁ receptor antagonists can increase the duration of sleep in a rat model of posttraumatic stress disorder (PTSD).¹⁷⁴ α₂ receptor agonists can inhibit the release of NA, reduce arousal, and exert sedative effects.¹⁷⁵ In addition, a rare and less stable mutant of the β₁ subtype receptor can increase arousal and reduce sleep duration in humans and mice.¹⁷⁶ Recent findings indicate that sleep deprivation boosts growth hormone secretion, which in turn enhances the activity of locus coeruleus neurons, contributing to increased wakefulness.¹⁷⁷

Histamine facilitates alertness

Histamine is a monoamine signaling molecule that is widely present in both central¹¹¹ and peripheral tissues.¹⁷⁸ The only source of histamine in the brain is the tuberomammillary nucleus (TMN).¹⁷⁹ Histaminergic neurons in the TMN can project to various brain regions, regulating the sleep-wake cycle,¹⁸⁰ feeding,¹⁸¹ and learning.¹⁸² Histamine is synthesized from histidine under the catalysis of histidine decarboxylase (HDC).¹⁸³ Recent studies have found that HDC is anchored to synaptic vesicles by interacting with the vesicle membrane protein NSF1 (N-ethylmaleimide-sensitive fusion protein 1) to achieve the coupling of histamine synthesis and synaptic vesicle transport, which avoids the cytotoxicity of histamine.¹⁸⁴ By using the in vitro microdialysis technique, Chu et al. discovered a positive correlation between extracellular histamine levels in the rat frontal cortex and the degree of wakefulness.¹⁸⁵ In recent years, using histamine probes, it has been further discovered that the histamine levels in the preoptic area of the hypothalamus and the prefrontal cortex of mice increase during the transition from NREM or REM sleep to wakefulness and decrease during the transition from wakefulness to NREM sleep.¹⁸⁶

To date, four histamine receptors have been identified: H₁, H₂, H_3, and H₄, which are all G protein-coupled receptors.¹⁸⁷ Among them, H₁ and H₂ receptors are widely expressed in both the brain and peripheral tissues¹⁸⁷; the H₃ receptor is primarily expressed in the brain,¹⁸⁸ while the H₄ receptor is mainly expressed in peripheral tissues.¹⁸⁹ The downstream signaling pathway of the H₁ receptor couples to the G_q protein-coupled pathway,¹⁹⁰ which can activate the activity of PLC, thereby increasing cellular excitability. Under baseline conditions, H₁ receptor knockout mice exhibited similar sleep-wake cycles to WT mice but with fewer brief awakenings (<16 s), longer NREM sleep episodes, and fewer transitions between NREM sleep and wakefulness.¹⁹¹ In addition, H₁ receptors within the hypothalamus play a crucial role in regulating feeding behavior and obesity.¹⁹² The H₂ receptor primarily couples with G_s proteins, which can activate AC and increase intracellular cAMP levels.^193,194 H₂ receptors are involved in the regulation of pain sensation,¹⁹⁵ gastrointestinal,¹⁹⁶ and immune functions.¹⁹⁷ Currently, selective antagonists of the H₂ receptor are widely used to treat digestive system diseases.¹⁹⁶ H₃ receptors are located on the presynaptic membrane and, through coupling with G_i proteins, negatively regulate calcium channels¹⁹⁸ and the AC/PKA pathway.¹⁹⁹ When acting as autoreceptors, H₃ receptors inhibit the synthesis of histamine¹⁹⁹; when acting as heteroreceptors, they can inhibit the release of excitatory neurotransmitters such as norepinephrine²⁰⁰ and acetylcholine.²⁰¹ Therefore, H₃ receptor antagonists/inverse agonists are used clinically to treat narcolepsy.^202,203 The H₄ receptor shares molecular homology with the H₃ receptor²⁰⁴ and is mainly coupled to G_q proteins. However, it is rarely expressed in the brain and primarily functions in peripheral tissues to regulate immune responses.¹⁸⁹

Orexin (hypocretin) is a critical homeostatic regulator of the sleep–wake cycle

In 1998, the research teams of Yanagisawa²⁰⁵ and Sutcliffe²⁰⁶ simultaneously discovered orexin (hypocretin) neuropeptides. Orexin consists of two types, orexin-A and orexin-B, which are derived from a common precursor peptide, prepro-orexin (PPO).²⁰⁵ Orexin is primarily synthesized by neurons in the lateral hypothalamus (LH), which can modulate the level of arousal to suit behavioral needs and regulate energy balance.²⁰⁷ For example, the orexin system is activated in response to stress and emotion,^208,209 and it is suppressed in response to high glucose levels.²¹⁰ Orexin has two receptors, the orexin-1 receptor (OX₁R) and the orexin-2 receptor (OX₂R), which are mainly coupled to the G_q protein.²⁰⁵ When orexin receptors are activated, they can promote the activity of PLC.²¹¹ Orexin-A binds to OX₁R and OX₂R with similar affinity, whereas orexin-B binds OX₂R with higher affinity than OX₁R.²⁰⁵ It is worth noting that orexin functions not merely as a wakefulness-promoting neuropeptide but also as a critical homeostatic regulator of the sleep-wake cycle. Through gating state transitions, reinforcing sustained arousal, and preventing pathological intrusions of NREM or REM sleep into wakefulness, orexin ensures the coherence and stability of vigilance states rather than simply triggering transient arousal.²¹² Orexinergic neurons in the LH exert excitatory modulation of ascending arousal systems via projections to wake-promoting nuclei, including the noradrenergic LC, histaminergic TMN, and cholinergic BF.¹⁰⁰ Concurrently, orexin exerts an inhibitory influence over sleep-promoting nuclei, particularly the VLPO, thus consolidating the stability of vigilance states and impeding aberrant state transitions.²¹³ Orexin activity gradually decreases as sleep depth increases, promoting the transition of NREM sleep to its deeper stages and reducing abnormal arousal during NREM sleep.^99,214 In the later phase of NREM sleep, orexin activity decreases further, coordinating the transition from NREM sleep to REM sleep.²¹⁵

The stabilizing function of orexin is exemplified by narcolepsy type 1, characterized by autoimmune-mediated or sporadic degeneration of orexin neurons.²¹⁶ Narcolepsy is classified into two primary subtypes. Type 1 narcolepsy is defined by excessive daytime sleepiness accompanied by cataplexy, which distinguishes it from type 2 narcolepsy, where typical cataplexy is absent.²¹⁷ Notably, it has been established that the occurrence of type 1 narcolepsy in humans is caused by the loss of orexin neurons.^101,218 Given that loss of muscle tone is a defining feature of REM sleep, this points to an essential role for orexin in the regulation and stability of REM sleep. Although orexin neurons are silent during REM sleep, they provide robust excitatory drive to REM-off neurons during wakefulness.²¹⁹ This arrangement ensures that when the orexin system is intact, REM sleep is effectively prevented from intruding into the awake state. In the absence of orexin, the excitatory drive to REM-off neurons that normally stabilizes wakefulness is lost, blurring the boundary between arousal and REM sleep and giving rise to the characteristic episodes of cataplexy.

Glutamate and its role in the sleep-wake cycle

Glutamate (Glu) is the most abundant nonessential amino acid in humans. It serves not only as a key building block for protein synthesis but also as the primary excitatory neurotransmitter in the central nervous system (CNS)²²⁰ while simultaneously participating in a variety of metabolic pathways.²²¹ Within neurons, α-ketoglutarate (α-KG) generated via the tricarboxylic acid (TCA) cycle can be used to produce glutamate, enabling a rapid response to the demands of synaptic transmission.²²² Approximately 90% of the glutamate released by neurons into the synaptic cleft is taken up by excitatory amino acid transporters (EAATs) located on the membrane of astrocytes.^223,224 This glutamate is then converted into glutamine under the catalysis of glutamine synthetase (GS), enabling the “storage and regeneration” of glutamate in the brain through the glutamate-glutamine cycle.

Glutamate receptors are classified into two major categories: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs).²²⁵ Different functional subgroups make up the family of iGluRs, including N-methyl-d-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainate receptors, and GluD receptors.²²⁶ These receptors can directly regulate the opening of ion channels and rapidly mediate excitatory synaptic transmission. Based on amino acid sequence homology and signaling pathways, mGluRs are classified into 3 groups, which consist of 8 subtypes: mGluR1 to mGluR8.²²⁷ Group I mGluRs (mGluR1, mGluR5) couple to Gq proteins and exert an excitatory effect on downstream signaling pathways. Group II mGluRs (mGluR2, mGluR3) and Group III mGluRs (mGluR4, mGluR6, mGluR7, mGluR8) both couple to Gi proteins; they inhibit the presynaptic release of glutamate and thereby participate in negative feedback regulation.²²⁷ Glutamatergic signaling is involved in the regulation of the sleep-wake cycle,²²⁸ and human studies have revealed that this signaling dynamically changes throughout the sleep-wake cycle.^229,230 Glutamatergic neurons located in the brainstem reticular formation exhibit notably higher activity during wakefulness and REM sleep.^46,83,84

γ-Aminobutyric acid and its role in sleep

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter and has a significant role in promoting sleep.^231,232 GABA is synthesized by glutamate in the cytoplasm of presynaptic neurons through glutamate decarboxylase (GAD).²³³ GABA is widely distributed in the brain, and when it binds to receptors, it can inhibit the response of neurons to excitatory neurotransmitters such as norepinephrine, serotonin, acetylcholine, histamine, and dopamine.²³⁴ GABA has two receptor types in the central nervous system: GABA_A and GABA_B. The GABA_A receptor is a ligand-gated chloride channel located at the synapse that mediates rapid inhibition.²³⁵ The GABA_B receptor is a G_i protein-coupled metabolic receptor that reduces neuronal Ca²⁺ influx and K⁺ efflux by inhibiting cAMP signaling, resulting in slower inhibitory transmission.²³⁶ The GABA_A receptor is composed of five subunits. Currently, humans have 19 different GABA_A receptor subunits (α_1-6, β_1-3, γ_1-3, δ, ε, π, θ, and ρ_1-3), which can randomly combine to form GABA_A subtypes with different physiological characteristics.²³⁵ However, most GABA_A receptors are composed of two α subunits, two β subunits, and one γ subunit.²³⁵ Different subunit types have different effects. For instance, the α₁ subunit of the GABA_A receptor is associated with sedation and hypnosis,²³⁷ the α₂ and α₃ subunits are associated with antianxiety effects and muscle relaxation,²³⁸ and the α₅ subunits are associated with pain relief and learning processes.²³⁸ The GABA_B receptor is also involved in the regulation of neural networks²³⁹ and has an important role in the pathogenesis of epilepsy, anxiety and depression.²⁴⁰ In addition to its role as a neurotransmitter in the central nervous system, GABA also plays a significant role in metabolism.²⁴¹ The administration of GABA can ameliorate glucose tolerance in rodent models of type 2 diabetes,²⁴² reduce insulin resistance,²⁴³ and decrease the risk of insulin resistance in their offspring.²⁴⁴

Additionally, neurotensin (NTS),^66,79 neuropeptide S (NPS),²⁴⁵ adenosine, and melatonin (which are discussed in detail below) also have significant impacts on the regulation of the sleep-wake cycle. In addition, studies on individuals with familial natural short sleep (FNSS) have identified mutations in the GRM1 gene²⁴⁶ or the NPSR1 gene.²⁴⁷ The former encodes metabotropic glutamate receptor 1, while the latter encodes neuropeptide S receptor 1. These mutations are associated with reduced total sleep time, while learning and memory abilities remain unaffected.^246,247

The synthesis, storage, and release of neurotransmitters and neuropeptides require a large amount of energy,²⁴⁸ which is mainly derived from ATP produced by mitochondria.²⁴⁹ Dynamic mitochondria within neurons can be transported to the axonal region to meet high metabolic demands.²⁵⁰ In addition, mitochondrial depolarization in astrocytes also impacts neurotransmitter homeostasis.²⁵¹ Thus, energy metabolism serves as a fundamental determinant in maintaining physiological neurotransmitter dynamics.

Energy metabolism affects the regulation of the sleep-wake cycle

The two-process model¹³ of sleep regulation is a key theoretical framework in sleep research that explains the regulatory mechanisms underlying the sleep-wake cycle. This model postulates that the balance between sleep and wakefulness is governed by two interrelated yet distinct physiological processes: Process S (the homeostatic sleep process) and Process C (the circadian process). Process S represents an intrinsic sleep-drive mechanism whose intensity increases proportionally with the duration of prior wakefulness. It is characterized by the accumulation of sleep pressure during extended wake periods and its subsequent dissipation during sleep, reflecting a dynamic “use-dependent” recovery system. Process C, primarily regulated by the suprachiasmatic nucleus, also known as the central circadian pacemaker, is synchronized with the 24-hour earth rotation cycle. This process establishes a stable temporal framework for sleep-wake patterning, thereby preventing sleep from occurring at inappropriate times, such as during the day, and avoiding sustained wakefulness at night.

Energy metabolism in the homeostasis of the sleep-wake cycle

Sleep-wake homeostasis reflects the balance between sleep and wakefulness, involving the accumulation and release of sleep pressure. As the duration of wakefulness extends, sleep pressure gradually increases, leading to sleep debt. To adjust the state of sleep debt, the organism actively enters sleep. After undergoing sleep deprivation, subsequent sleep is often deeper or longer to compensate for missed sleep. During the transition between wakefulness and sleep, there are significant changes in brain energy metabolic activities and endogenous sleep-wake related substances. Previous studies have suggested that endogenous sleep-related substances, such as adenosine, mediate the increase in sleep pressure during wakefulness. Recent reports have found that the phosphorylation of some proteins is also involved in this process.^252,253

Adenosine signaling couples energy metabolism with the sleep-wake cycle

Adenosine, formed by the hydrolysis of adenosine monophosphate (AMP) or S-adenosylhomocysteine,²⁵⁴ is widely recognized as an endogenous sleep regulator. Injecting adenosine into the brains of animals can induce sleep behavior^,255 and different adenosine analogs dose-dependently increase the duration of NREM and REM sleep.²⁵⁶ The extracellular adenosine levels in the BF of cats tend to rise during wakefulness and decline during sleep, with a particularly noticeable increase after prolonged wakefulness.²⁵⁷ Selective activation of astrocytes or neurons in the NAc can remarkably increase extracellular adenosine levels and induce slow-wave sleep.⁷⁴ Therefore, adenosine can be considered a regulator reflecting sleep pressure. Additionally, adenosine can integrate light and sleep signals to regulate the circadian rhythms of mice.²⁵⁸

Due to the lack of a visual detection method for adenosine in the past, the exact source of extracellular adenosine remained controversial. Recently, employing a newly optimized extracellular adenosine fluorescent probe based on the G protein-coupled receptor activation principle (GRAB-Ado), neurons have been revealed as the primary source of extracellular adenosine in the hippocampus.²⁵⁹ Nucleoside homeostasis in humans is regulated by two protein families: the SLC28 family of Na⁺-coupled concentrative nucleoside transporters (CNTs) and the SLC29 family of equilibrative nucleoside transporters (ENTs).²⁶⁰ ENTs passively transport adenosine across the cell membrane in both directions according to the concentration gradient. Under normal physiological conditions in the brain, the intracellular adenosine concentration in neurons is generally higher than the extracellular concentration via the pivotal roles of CNTs in maintaining intracellular adenosine levels by mediating its uptake from the extracellular space.²⁶¹ Hippocampal neuronal adenosine release is largely dependent on the coordinated action of concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs), which mediate intracellular-to-extracellular transport driven by a concentration gradient. This pathway significantly surpasses the contribution from vesicular release and ATP degradation via CD39/CD73.²⁵⁹ During hypoxia, local potassium infusion, and ischemia, the extracellular adenosine concentration increases,²⁶² which is likely mediated by increasing the intracellular adenosine concentration or/and decreasing the activity of CNTs. Furthermore, using fiber-optic recording methods, Peng et al.²⁶³ discovered that Ca²⁺ activity in BF astrocytes and the levels of extracellular ATP change during the sleep-wake cycle. Additionally, these changes are related to the Ca²⁺ activity of local glutamatergic and GABAergic neurons. The Ca²⁺ activity of BF astrocytes and extracellular ATP levels are higher during wakefulness and REM sleep, and both are lower during NREM sleep.²⁶³ The trend in extracellular adenosine levels is similar, but the extracellular ATP levels significantly decrease after inhibiting the Ca²⁺ activity of BF astrocytes, while the extracellular adenosine levels show no significant change.²⁶³ Moreover, in CD73 (a key enzyme involved in the hydrolysis of extracellular ATP to adenosine) knockout mice, the extracellular adenosine levels in the BF region are not different from those in normal mice.²⁶³ These results all suggest that the increase in BF extracellular adenosine during waking and REM is mainly caused by ATP metabolism in neurons instead of extracellular ATP hydrolysis (Fig. 4a).

Fig. 4.

Source of extracellular adenosine in cortical neurons and its regulation of sleep-wakefulness. a Intracellular adenosine is formed by the hydrolysis of AMP or SAH. Extracellular adenosine is primarily released from intracellular adenosine through ENTs under the coordinated action of CNTs and ENTs, which mediate intracellular-to-extracellular transport driven by a concentration gradient. b Extracellular adenosine exerts its regulatory effects on sleep-wakefulness through adenosine A₁ and A_2A receptors in different brain regions. The inhibitory adenosine A₁ receptor has region-specific effects on sleep. Adenosine A₁ receptors distributed in arousal systems such as BF, TMN, and LH promote sleep when activated, whereas adenosine A₁ receptors located in VLPO or PZ of the sleep system promote wakefulness upon activation. The excitatory adenosine A_2A receptors, primarily located in brain regions that promote sleep, such as the NAc and VLPO, increase NREM sleep when activated. AMP adenosine monophosphate, SAH S-adenosylhomocysteine, ENT equilibrative nucleoside transporter, CNT concentrative nucleoside transporter, BF basal forebrain, TMN tuberomammillary nucleus, LH lateral hypothalamus, VLPO ventrolateral preoptic nucleus, NAc nucleus accumbens, PZ parafacial zone

Adenosine, a neuromodulator, needs to bind to receptors to exert its effects. The currently discovered adenosine receptors include the A₁, A_2A, A_2B, and A₃ subtypes, all of which are G protein-coupled receptors. Among them, A₁ and A_2A receptors are related to sleep.²⁶⁴ The effects of inhibitory adenosine A₁ receptors on sleep are region specific. Activation of adenosine A₁ receptors distributed in the BF,²⁶⁵ TMN,²⁶⁶ and LH²⁶⁷ regions can inhibit cholinergic, histaminergic, and hypocretin/orexinergic arousal neurons, respectively, and thus promote sleep.²⁶⁸ Activation of adenosine A₁ receptors in VLPO²⁶⁹ or PZ²⁷⁰ inhibits sleep-promoting GABAergic neurons, thereby promoting arousal. Excitatory adenosine A_2A receptors are primarily distributed in brain regions such as the VLPO,²⁷¹ NAc,^73,74 striatum⁷² and olfactory tubercle.⁷⁵ Their activation leads to an increase in the activity of GABAergic output neurons, thereby inhibiting the arousal systems in the thalamus, hypothalamus, brainstem, and cerebral cortex,²⁷² which ultimately promotes NREM sleep (Fig. 4b). Constitutive adenosine A₁ receptor knockout mice exhibit normal sleep patterns and homeostatic regulation.²⁷³ While conditional A₁ receptor knockout mice in the central nervous system exhibit a reduction in the SWA response following sleep restriction, sleep duration remains unchanged.²⁷⁴ The lack of an abnormal sleep phenotype in constitutive A₁ receptor knockout mice may be due to functional compensation inherent in such a constitutive model.²⁷⁵ Both genetic deficiency and pharmacological antagonism of A_2A receptors disrupt sleep-wake regulation. Genetic deletion of A_2A receptors attenuates the somnogenic effect of prostaglandin D2, a key endogenous sleep-inducing factor,²⁷⁶ whereas pharmacological blockade of A_2A receptors with novel selective antagonists such as compound 38 enhances arousal.²⁷⁷

Caffeine, as a central nervous stimulant, is widely used in daily life. Caffeine can nonselectively antagonize the binding of adenosine to A₁ and A_2A receptors.²⁷⁸ Adenosine has a high affinity for the A₁ receptor, with an inhibition constant (Ki) that can reach a pM level, and the Ki for the A_2A receptor is approximately 10 nM.²⁷⁹ Caffeine has a similar dissociation Ki for A₁ and A_2A receptors, at 55 µM and 50 µM, respectively.²⁸⁰ Therefore, although caffeine has an antagonistic effect on adenosine A₁ receptors, it is difficult to compete with adenosine. It has been shown that the arousal effect of caffeine depends on the adenosine A_2A receptor²⁸¹ and acts on the NAc shell.²⁸² In addition, caffeine typically reduces slow-wave sleep and EEG slow-wave activity, which are key markers of deep sleep.²⁸³ These results show that the NAc shell plays a significant role in NREM sleep. In addition to brain tissue, adenosine A₁ and A_2A receptors are also distributed in the heart, blood vessels, and other tissues, contributing to a slow heart rate and dilated blood vessels.²⁸⁴ Given these cardiovascular responses, adenosine A₁ and A_2A receptor agonists are not currently used in the clinical treatment of sleep disorders. In the future, the development of receptor-biased agonists may provide possibilities for their clinical application.

Protein phosphorylation reflects sleep need

Through forward genetic analysis of sleep in randomly mutated mice, Funato et al. discovered a sleepy mutant (sleepy mice) in which a splicing mutation in the salt-inducible kinase 3 (SIK3) protein kinase gene led to a significant increase in sleep time and a marked decrease in wakefulness.²⁸⁵ It has been reported that the phosphorylation of threonine 221 (T221) in SIK3 in the mouse brain increases after wakefulness and sleep deprivation but decreases after sleep. In cases of loss-of-function (LOF) mutations of SIK3 and an alanine mutation at T221 (T221A), sleep time is reduced.²⁵³ Therefore, the phosphorylation level of SIK3 T221 can reflect sleep need. In addition, the dephosphorylation of SIK3 T469 and S551 can promote sleep via calcineurin (CaN) without affecting the phosphorylation of SIK3 T221.²⁸⁶ Consequently, knocking down the regulatory subunit of CaN reduces mouse sleep time by over 5 hours daily.²⁸⁶ Competitive regulation of the sleep-wake cycle by calcineurin and protein kinase A (PKA) has also been identified at excitatory postsynapses, where PKA serves as a wakefulness-promoting kinase, whereas calcineurin acts as a sleep-promoting phosphatase.²⁸⁷ Additionally, quantitative phosphoproteomic analysis of sleep-deprived mice and sleepy mice suggests that sleep deprivation can induce the accumulation of phosphorylation in the brain proteome, and these accumulations can dissipate during sleep.²⁵² The brain proteome of sleepy mice exhibits hyperphosphorylation, similar to the situation in the brains of sleep-deprived mice. After comparison, a total of 80 phosphoproteins were identified, designated Sleep Need Index Phosphorylated Proteins (SNIPPs), of which 69 (86%) SNIPPs are associated with synapses.²⁵² Subsequent studies have also found that synaptic potentiation is associated with wakefulness (activity) and downscaling with sleep (rest).²⁸⁸

In recent years, a study utilizing adeno-associated virus (AAV)-mediated somatic genetics has characterized the LKB1-SIK3-HDAC4 signaling pathway, which plays a key role in the transcriptional regulation of sleep amount in mice.²⁸⁹ Kim et al.’s concurrent study also found that this pathway is involved in regulating sleep quantity and depth.²⁹⁰ As an upstream kinase in this pathway, LKB1 is involved in regulating the cellular response to changes in energy supply, particularly when the AMP/ATP ratio increases. LKB1 can maintain energy balance by activating AMPK. As an AMPK-related kinase, SIK3 exhibits activation characteristics similar to those of AMPK, meaning it is activated in a phosphorylation-dependent manner mediated by LKB1.²⁹¹

Circadian rhythm affects the sleep-wake cycle mainly via mitochondria and melatonin

The circadian rhythm is a naturally occurring physiological and behavioral pattern in organisms with a period of approximately 24 h. This rhythmic pattern is controlled by the internal clock system of organisms, enabling them to anticipate and adapt to environmental changes brought about by the Earth’s rotation, such as periodic variations in light and temperature.²⁹² Circadian rhythm is evident in animals, plants, fungi, and bacteria, influencing various physiological processes, such as the sleep-wake cycle,²⁹³ feeding behavior,²⁹⁴ temperature regulation,²⁹⁵ hormone secretion,²⁹⁶ and cellular metabolic activities.²⁹⁷ In mammals, the regulation of circadian rhythm is governed by cell-autonomous transcription-translation feedback loops (TTFLs). Specifically, the transcription factors CLOCK and BMAL1 stimulate the expression of period (PER) and cryptochrome (CRY).²⁹⁸ The resulting PER and CRY proteins then provide negative feedback to inhibit the activity of CLOCK and BMAL1²⁹⁸ (Fig. 4a). Normal circadian rhythm is established by a hierarchical network of central and peripheral clocks working together. The central biological clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, is primarily synchronized with the light-dark cycle through photic inputs. Peripheral clocks, on the other hand, are widely distributed in various tissues and organs throughout the body and are synchronized under the pacemaker function of the SCN.²⁹⁹ The circadian rhythm system generates a sleep-wake cycle, and the synchronization between the intrinsic period and behavioral timing is crucial for consolidating sleep and wakefulness.³⁰⁰ Changes in the circadian timing system, its entrainment mechanisms, or a misalignment between the internal circadian rhythm and the external environment can lead to circadian rhythm sleep-wake disorders (CRSWDs).³⁰¹

Mitochondria and circadian rhythm exhibit bidirectional regulation. On the one hand, circadian rhythm influences multiple physiological processes of mitochondria, including biogenesis and dynamics. Factors involved in mitochondrial biogenesis, such as PGC-1α, mitochondrial redox proteins, and dynamin-related protein 1 (DRP1), exhibit circadian rhythmic oscillations in their expression.^302–304 During the active phase, mitochondria tend to undergo more fission, producing more individual units to meet the high energy demands; conversely, during the rest phase, mitochondria are more inclined to fuse, forming larger structures to store energy and undergo repair.^302,305 On the other hand, mitochondria can influence the expression of core circadian rhythm proteins through byproducts of energy metabolism and various metabolites, thereby exerting regulatory effects on the circadian rhythm. For example, the reduced form of the redox cofactor NADH increases the activity of CLOCK/BMAL1, while the oxidized form (NAD⁺) inhibits their activity.³⁰⁵ AMPK is another highly conserved cellular nutrient sensor. After being activated by exercise or fasting,³⁰⁶ AMPK can phosphorylate CRY1 and thus lead to its degradation³⁰⁷ (Fig. 5a). A high-fat diet has been shown to disrupt behavioral and molecular circadian rhythms in mice.³⁰⁸ Additionally, circadian rhythmic activity and sleep-wake cycle regulation are impaired in genetically obese leptin-deficient (ob/ob) and leptin-resistant (db/db) mice.^309,310

Fig. 5.

Production of melatonin and its regulation of circadian rhythms and sleep-wakefulness. a The regulation of circadian rhythm is governed by cell-autonomous transcription-translation feedback loops (TTFLs). Specifically, the transcription factors CLOCK and BMAL1 stimulate the expression of PER and CRY. The resulting PER and CRY proteins then provide negative feedback to inhibit the activity of CLOCK and BMAL1. b Upon receiving light signals, neural impulses form a cascade from the retina to the SCN, PVN of the hypothalamus, spinal cord, and SCG, ultimately reaching the pineal gland, where melatonin is synthesized in this area. Melatonin can act on MT₂ receptors to promote the intrinsic neural activity rhythm of the SCN, thereby altering the expression of the clock gene Per. c Melatonin is synthesized from tryptophan via serotonin, and tryptophan can be metabolized through the kynurenine pathway. In metabolic disorders such as IR, MS, NDDs, and tumors, the kynurenine metabolic pathway of tryptophan is enhanced. d Melatonin can act on the MT₁ and MT₂ receptors in the PVT, inhibiting the excitability of PVT neurons that promote wakefulness. In addition, it can also bind to the MT₃ receptor to promote the retraction of neuronal dendritic spines. PER period, CRY cryptochrome, SCN suprachiasmatic nucleus, PVN paraventricular nucleus, SCG superior cervical ganglion, IR insulin resistance, MS metabolic syndrome, NDDs neurodegenerative diseases, PVT paraventricular thalamus

Melatonin is a natural hormone that is widely present in plants and animals,^311,312 and its secretion is regulated by light exposure. Upon receiving light signals, neural impulses form a cascade from the retina to the SCN, paraventricular nucleus of the hypothalamus (PVN), spinal cord, and superior cervical ganglion (SCG), ultimately reaching the pineal gland, where melatonin is synthesized in the mitochondria of this area^313,314 (Fig. 5b). For humans, melatonin levels rise as light diminishes before darkness, reaching a peak in the dark to promote sleep, while the level of melatonin decreases when exposed to light to facilitate wakefulness.³¹⁵ When endogenous melatonin secretion is insufficient, sleep disorders may occur. In this case, supplementation with exogenous melatonin can improve sleep.^316,317 Melatonin is produced from tryptophan through serotonin, a process that involves the participation of key enzymes such as tryptophan hydroxylase (TPH).³¹⁸ A prospective cohort study from China indicated that there is a positive correlation between dietary tryptophan intake and sleep duration.³¹⁹ Tryptophan, in addition to being converted into serotonin and melatonin, can also be metabolized through the kynurenine pathway under the action of enzymes such as indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO).³²⁰ The kynurenine pathway of tryptophan is enhanced in insulin resistance, metabolic syndrome, neurodegenerative diseases, and cancer^320–323 (Fig. 5c). The production of serotonin and melatonin is correspondingly reduced in these cases.

Melatonin can regulate circadian rhythm and sleep.³²⁴ MT₁ and MT₂ are receptors for melatonin, and both are classified as G protein-coupled receptors.³²⁵ Typically, these receptors are associated with G_i proteins, which leads to the inhibition of AC activity and consequently reduces cAMP accumulation.³²⁶ The MT₁ receptor can also couple with G_s proteins, achieving bidirectional regulation of AC.³²⁷ These two receptors are widely distributed throughout the body. In addition to the brain^328,329 and retina,³³⁰ they are also found in organs such as the heart,³³¹ blood vessels,³³² liver,³³³ and intestines³³⁴ and exhibit tissue specificity.^335,336 Melatonin acts on the MT₁ and MT₂ receptors to modulate the intrinsic neural activity rhythms of the SCN, thereby regulating circadian rhythms. The activation of the MT₁ receptor can inhibit the firing rate of SCN neurons, while the activation of the MT₂ receptor induces phase shifts in circadian rhythms.³³⁷ Experiments with receptor knockout mice have shown that the absence of MT₁ receptors can reduce REM sleep, while the absence of MT₂ receptors can reduce NREM sleep.³³⁸ The specific mechanisms by which melatonin promotes sleep were unclear in the past. Wang et al. demonstrated that melatonin can act on the MT₁ and MT₂ receptors in the paraventricular nucleus of the thalamus (PVT), inhibiting the excitability of PVT arousal neurons and thereby increasing NREM sleep.³³⁹ The MT₃ receptor is an important reductase in the electron transport chain, known as quinone oxidoreductase 2 (Nqo2), and is classified as a cytoplasmic receptor.³⁴⁰ During sleep, melatonin acting on the MT₃ receptor can promote the retraction of neuronal dendritic spines, thereby improving sleep quality and memory capacity³⁴¹ (Fig. 5d).

The interaction between sleep homeostasis and the circadian rhythm

Sleep homeostasis (Process S) and the circadian rhythm (Process C) do not operate independently; instead, they function in a coordinated manner to collectively and precisely regulate sleep timing (when to sleep and how long to sleep), architecture, and quality. This synergistic interaction constitutes the classical two-process model, which serves as the cornerstone for understanding the stability and flexibility of the sleep-wake cycle. As the “command center”, Process C sets critical time windows for the accumulation and release of Process S; from another perspective, Process S acts as a “feedback signal”, which can calibrate and fine-tune the precision and intensity of Process C.

First, by setting the rhythmic fluctuations of the “wake drive”, Process C defines the time window in which Process S can be expressed. The suprachiasmatic nucleus (SCN), the core pacemaker of Process C, acts as a precise biological clock, whose primary function is to ensure the synchronization of bodily activities with the light-dark cycle of the external environment. During the light or active phase, the SCN activates wake-promoting brain areas such as the LC³⁴² and TMN,³⁴³ enhancing the wake drive. This strong wake-promoting pressure can effectively suppress the sleep need accumulated by Process S, enabling individuals to maintain high alertness and activity capacity even after hours of wakefulness. In contrast, during the dark or rest phase, the activity pattern of the SCN undergoes a shift. By activating sleep-promoting centers such as the VLPO, it indirectly inhibits the activity of the aforementioned wake-promoting brain regions.³⁴⁴ At this point, the wake drive is significantly weakened, clearing the way for the release of sleep needs. Therefore, Process S pressure, which has accumulated to a high level, can rapidly trigger sleep onset and effectively maintain the stability of the sleep state, preventing mid-sleep awakenings. This mechanism ensures that sleep is scheduled during specific time periods when energy consumption is at its lowest and the risk of predation is potentially highest, thereby holding significant adaptive and evolutionary importance.

While Process S does not passively accept the regulation of Process C, it also calibrates the amplitude and stability of Process C crucially through neurochemical feedback. This process reflects the fine-tuning effect of the homeostatic mechanism on the biological clock. When sleep deprivation or insufficient sleep occurs, the sleep pressure of Process S continues to increase, and one of its core physiological indicators is the accumulation of endogenous sleep substances (such as adenosine) in the brain. A study has demonstrated that high concentrations of adenosine not only act on extensive cortical regions and arousal-promoting brain areas to induce sleepiness but also directly bind to adenosine receptors located on SCN neurons.³⁴⁵ High extracellular adenosine, accumulated during prolonged wakefulness, inhibits excitatory retinohypothalamic input to the SCN via presynaptic A1 receptors, thereby reducing Ca²⁺ influx and attenuating light-evoked phase shifts.³⁴⁶ This inhibition of neural excitability further disrupts the ability of light signals to induce core clock genes (such as Per1/2), ultimately resulting in phase shifts of the circadian rhythm (delayed phase during light periods and advanced phase during dark periods) and significantly weakening the amplitude of rhythmic output signals such as cortisol and melatonin.²⁵⁸

The metabolism of different types of cells affects the sleep-wake cycle

By integrating the human sleep stage chart with the EEG spectrogram, it is evident that high-frequency bands above 15 Hz are prominent during wakefulness, diminish during NREM and REM sleep and are nearly absent in the N3 stage of NREM sleep (Fig. 6a). A similar pattern can be observed in the mouse, which was recorded by our laboratory (Fig. 6b, c). Additionally, the hypnogram of mouse sleep reveals evident sleep fragmentation, which may be attributable to species-specific survival traits. Therefore, the mouse might serve as a model for investigating sleep fragmentation. The regulation of extracellular glutamate levels, through interactions within excitatory-inhibitory neuron networks, plays a significant role in the generation and maintenance of gamma band oscillations.³⁴⁷ Hence, during periods of consciousness, the gamma band is present, and extracellular glutamate levels are high, whereas during sleep, the absence of the gamma band coincides with a significant reduction in extracellular glutamate concentrations (Fig. 7).

Fig. 6.

Human and mouse EEG spectrograms and sleep stage charts. a Power spectrogram and hypnogram of human EEG signals and corresponding sleep stages during 6 h of sleep.⁴⁸⁷ b Power spectrogram and hypnogram of mouse EEG signals and corresponding sleep stages during 24 h in a day; W wake, N NREM, R REM. c Power spectral density (PSD) proportions of EEG in the mouse during wake, NREM, and REM states. Sleep stages were annotated using YASA.⁴⁸⁷ Hypnograms were created using customized Visbrain⁴⁸⁸

Fig. 7.

Metabolism of different cell types during wakefulness and sleep. a During wakefulness, the gamma band is present, and extracellular glutamate levels are high. Glutamatergic neurons are activated and emit substantial quantities of glutamate into the extracellular environment. Extracellular glutamate prompts neighboring astrocytes to secrete vitamin C, which is taken up by neurons, blocks glucose uptake, and promotes lactate usage. Extracellular adenosine in glutamatergic neurons mainly comes from intracellular ATP hydrolysis. It is released from neurons via ENTs due to a concentration gradient. Then, extracellular adenosine acts on the A_2B receptors of astrocytes, activating the cAMP-PKA signaling pathway and thereby providing neurons with lactate as an energy substrate. The extracellular adenosine associated with GABAergic neurons in the PZ during wakefulness is primarily derived from ATP released by activated astrocytes, which is subsequently hydrolyzed by CD39 and CD73. The adenosine generated through hydrolysis can bind to A₁ receptors on GABAergic neurons, inhibiting their activity and GABA release, thus maintaining wakefulness. b During sleep, the absence of gamma oscillations results in a significant decline in extracellular glutamate levels. This reduction lowers astrocytic activity, prompting neurons to release vitamin C. The resulting decrease in local vitamin C concentration relieves its inhibitory effect on neuronal glucose uptake, allowing glucose to serve as an energy substrate during sleep. Glucose metabolism in neurons predominantly proceeds through the pentose phosphate pathway (PPP), enhancing intracellular ATP synthesis and adenosine generation. Meanwhile, prolonged wakefulness leads to extracellular adenosine accumulation around glutamatergic neurons. This enhances the activation of A_2B receptors on astrocytes, hence increasing cAMP-PKA pathway activity and lactate production. The metabolism of glucose and lactate synergistically promotes a surge in ATP levels within neurons. The surge in ATP is rapidly hydrolyzed into a substantial amount of adenosine, which is then exported out of neurons via ENT2. The increase in extracellular adenosine can diffuse to A_2A receptor-expressing brain regions, especially the NAc. Subsequent activation of A_2A receptors enhances GABA release, thereby facilitating sleep. Consistently, caffeine exerts an arousal effect by competing with adenosine for binding to the A_2A receptors in the NAc shell. Meanwhile, under conditions of intraneuronal ATP level surge, some ATP can be released via channel proteins and hydrolyzed to ADP by extracellular enzymes. Prefrontal microglia can activate intracellular Ca²⁺ signaling through ADP acting on the G_i protein-coupled P2Y12 receptor, increase extracellular adenosine levels, inhibit norepinephrine propagation, and promote NREM sleep. PZ parafacial zone, NAc nucleus accumbens, Ado adenosine, NE norepinephrine

Both glucose and lactate can provide energy for glutamatergic neurons. During wakefulness, glutamatergic neurons are excited and release large amounts of glutamate into the extracellular space. Extracellular glutamate stimulates adjacent astrocytes to release vitamin C, which enters neurons, inhibits glucose uptake, and facilitates lactate usage.^348,349 Notably, astrocytes can supply energy to neurons via lactate transport; however, the specific metabolic coupling mechanism between them was unclear before.^350,351 By using experimental in vitro and in vivo animal models, Theparambil et al. found that the metabolic coupling between neurons and astrocytes is dependent on adenosine signaling³⁵² (Fig. 6a). Extracellular adenosine from neuronal metabolism acts on astrocytic A_2B receptors, activating the cAMP-PKA pathway. This quickly boosts astrocytic glucose metabolism and lactate release, supplementing energy substrates for neurons³⁵² (Fig. 6a). During sleep, the activity of glutamatergic neurons decreases significantly, leading to reduced glutamate release. Consequently, the stimulation of astrocytes by glutamate is diminished, resulting in less vitamin C release from these cells. With decreased vitamin C uptake by neurons, the inhibition of glucose uptake is relieved. Hence, glucose can serve as an energy source for neurons during sleep. Due to the low activity of the glycolysis-promoting enzyme PFKFB3 in neurons, glucose metabolism primarily proceeds through the pentose phosphate pathway (PPP),³⁵³ which promotes intracellular ATP synthesis and adenosine generation.³⁵⁴ Meanwhile, after prolonged wakefulness, the progressive accumulation of extracellular adenosine induces augmented activation of astrocytic A_2B receptors. This enhanced supply of metabolic substrates to neuronal populations triggers a transient surge in intracellular ATP concentrations (Fig. 6b). In addition, prefrontal microglia can activate intracellular Ca²⁺ signaling through ADP acting on the G_i protein-coupled P2Y12 receptor. This activation increases extracellular adenosine levels, thereby inhibiting norepinephrine propagation and promoting NREM sleep.³⁵⁵ Under conditions of intraneuronal ATP level surge, some ATP can be released via channel proteins and subsequently hydrolyzed to ADP by extracellular enzymes, hence promoting the ADP-P2Y12 axis (Fig. 6b). Consistently, knockdown of A_2B receptor expression in astrocytes led to reduced delta wave activity and fragmented sleep,³⁵² which is similar to the sleep patterns of adenosine A_2A receptor-knockout mice.³⁵⁶ Hence, the ATP surge in the brain is an important part of how sleep is regulated, particularly in maintaining the energy needed for restorative processes. While it does not directly initiate sleep, it plays a key role during the early stage, especially for entering NREM sleep, which is deep and restorative. Importantly, NREM sleep, particularly slow-wave sleep (N3), can enhance the rate of neurotoxic waste removal for brain health.³⁵⁷ Sleep disorders that inhibit interstitial fluid flow can disrupt brain glymphatic function, potentially contributing to neurodegenerative processes.^358,359 On the other hand, the global cortical dynamics of REM sleep are distinct from NREM sleep³⁶⁰ and are associated with memory consolidation rather than waste clearance. This distinction underscores the unique role and significance of NREM sleep in glymphatic function.

Over a decade ago, Dworak et al.³⁶¹ found that ATP levels were linked to the sleep-wake cycle. By dissecting rats at different times, they discovered that during the early stage of sleep, brain regions active during wakefulness, such as the BF and frontal cortex, exhibited a surge in ATP levels.³⁶¹ In contrast, the VLPO, a brain region active during sleep, did not show this increase.³⁶¹ Moreover, ATP levels were significantly positively correlated with delta wave activity during NREM sleep.³⁶¹ Based on previous findings, the primary source of extracellular adenosine in the hippocampus²⁵⁹ and basal BF²⁶³ is attributed to ENT-mediated cellular transport driven by a concentration gradient rather than the extracellular ATP degradation pathway mediated by CD39 and CD73 (Fig. 6). Consequently, during the early stage of sleep, elevated levels of ATP within wake-promoting brain regions can be hydrolyzed intracellularly to adenosine in large amounts and released into the extracellular space via ENTs. The increase in extracellular adenosine can diffuse to brain regions expressing A_2A receptors, such as the NAc (Fig. 6b). Subsequent activation of A_2A receptors enhances GABA release, thereby facilitating NREM sleep.²⁷² Consistently, caffeine exerts an arousal effect by competing with adenosine for binding to the A_2A receptors in the NAc shell,²⁸² thereby affecting NREM sleep.²⁸³ Recently, Zhou et al.³⁶² discovered that 40 Hz light flickering can enhance the AMPK pathway within neurons in the visual cortex, leading to an increase in intracellular adenosine levels, which are then extruded to the extracellular space via ENT2, increasing extracellular adenosine signaling and thereby promoting sleep. There are two types of ENTs in the nervous system, ENT1³⁶³ and ENT2.³⁶⁴ Although ENT2 has a lower affinity for adenosine than ENT1, its capacity is larger, allowing for the efflux of a significant amount of intracellular adenosine.^365,366 Moreover, ENT2 is expressed at higher levels in neurons and astrocytes than ENT1.^365,366 However, the latest study found that astrocyte activation of the PZ during wakefulness can increase the extracellular adenosine level through extracellular ATP hydrolysis by CD39 and CD73 rather than ENT mediation from neurons.²⁷⁰ Therefore, adenosine produced by extracellular hydrolysis binds to A₁ receptors of PZ^GABA neurons, inhibiting GABAergic neuronal activity to elicit and maintain wakefulness²⁷⁰ (Fig. 6a). Therefore, compared with wild-type mice, CD73-knockout mice have longer spontaneous NREM sleep under normal conditions.³⁶⁷ Given that the PZ is a key brain region regulating NREM sleep^76–78 and that sleep-promoting brain regions do not experience an ATP surge during the early stage of sleep,³⁶¹ this phenomenon may be associated with the distinct metabolic states of wake-promoting and sleep-promoting neurons. Furthermore, these findings indicate a potential role for the BF and frontal cortex in facilitating NREM sleep by releasing adenosine alongside surges in ATP metabolism.

Energy metabolic disorders predispose individuals to sleep disorders

Sleep disorders constitute a clinical syndrome characterized by abnormal sleep quality, abnormal sleep duration, or disruptions in the sleep-wake rhythm, accompanied by impaired daytime functioning (such as fatigue, daytime sleepiness, and mood disturbances). According to the International Classification of Sleep Disorders (ICSD-3), sleep disorders can be divided into seven major categories, including insomnia disorders, sleep-related breathing disorders (SRBD), central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, sleep-related movement disorders, parasomnias, and other sleep disorders.³⁶⁸ Clinical evidence reveals a strong association between energy metabolism dysregulation and sleep disorders. A markedly elevated prevalence of sleep disorders is observed across populations with energy-metabolic disorders. This is particularly evident in the high burden of obstructive sleep apnea (OSA), which affects up to 50–60% of obese individuals,³⁶⁹ and the approximately 40% increase in insomnia symptoms observed among type 2 diabetes (T2DM) cohorts.³⁷⁰ Similarly, conditions characterized by cellular energy deficit, including mitochondrial diseases, neurodegenerative disorders, and aging, show a 2-4-fold higher rate of insomnia, circadian misalignment, and REM-sleep behavior disorder.³⁷¹

Fatigue and excessive daytime sleepiness

Fatigue and excessive daytime sleepiness are core, clinically significant symptoms of virtually all sleep disorders. They are also the primary reasons for patients to seek medical evaluation due to their profound impact on daily functioning, including impaired cognitive performance, reduced work productivity, and increased risk of accidents. To understand why these symptoms emerge, it is critical to first delineate the multifaceted functions of sleep. The key functions of sleep encompass the restoration of energy,³⁷² repair of physiological processes,³⁷³ and regulation of metabolism and neuroendocrine functions.³ When sleep disorders impair either the quality of sleep or its quantity, the body and brain are unable to complete essential restorative processes and energy replenishment. This failure directly leads to the manifestation of fatigue³⁷⁴ or excessive daytime sleepiness,³⁷⁵ both of which represent fundamental compensatory responses to an unmet sleep need.

Fatigue, more precisely defined, is characterized as a pervasive, subjective sense of exhaustion, weariness, or a profound depletion of energy that is not relieved by rest. It is a highly prevalent symptom associated with nearly all types of sleep disorders.³⁷⁶ In fact, epidemiological and clinical studies suggest that fatigue may be an even more ubiquitous complaint than self-reported sleepiness in many conditions, particularly those involving chronic sleep fragmentation or circadian rhythm disruptions, such as insomnia or shift work disorder.³⁷⁷ The neurobiological underpinnings of fatigue are complex and multifactorial. Sleep disruption is known to dysregulate the hypothalamic‒pituitary‒adrenal (HPA) axis, leading to aberrant cortisol rhythms and altering the release of proinflammatory cytokines.³⁷⁸ This combination of neuroendocrine dysfunction and low-grade systemic inflammation is thought to directly contribute to the sensation of bodily exhaustion and lack of energy.³⁷⁹ Furthermore, disrupted sleep impairs cerebral energy metabolism and synaptic homeostasis in prefrontal cortical regions, which are critical for executive function and motivation. This central deficit can manifest subjectively as mental fatigue, characterized by difficulties with concentration, memory, and goal-directed behavior.³⁸⁰

In contrast, excessive daytime sleepiness is a more specific symptom featured by an overwhelming, irresistible urge to fall asleep during intended wakefulness. It reflects a pathological state of an abnormally enhanced sleep drive within the sleep-wake balance.³⁸¹ It is not merely simple tiredness but rather signifies an impairment in the brain’s ability to maintain wakefulness. The neural basis for sleepiness lies in the dysfunction of ascending arousal systems. Excessive daytime sleepiness is most prominently and specifically observed in sleep disorders that cause one of two primary deficits: either a severe deterioration of nighttime sleep quality that leads to an uncompensated increase in homeostatic sleep pressure or a direct impairment of the wake-promoting neural circuits themselves.³⁸² The first mechanism is typified by disorders such as obstructive sleep apnea (OSA), where recurrent apneas cause continuous sleep fragmentation, preventing the natural progression into deep, restorative slow-wave sleep.³⁸³ Despite adequate time in bed, sleep is nonrestorative, resulting in an immense sleep debt that manifests as severe sleepiness the following day. The second mechanism is evident in disorders of central origin, such as narcolepsy, where the fundamental pathology involves a loss of hypocretin/orexin-producing neurons in the hypothalamus.³⁸⁴ These neurons are pivotal for stabilizing the switch between sleep and wake states. Their deficiency leads to an inherent instability of wakefulness, resulting in intrusive sleep episodes and persistent sleepiness, independent of the prior night’s sleep quality. This distinction is crucial for understanding the phenomenology of different sleep disorders.

Energy metabolic disorders and sleep disorders

Sleep disorders represent a significant and frequently overlooked comorbidity in individuals with energy metabolic disorders, such as T2DM and obesity. The relationship, however, extends far beyond mere coincidence. It is increasingly recognized as a complex, bidirectional interplay where each pathophysiological process exacerbates the other. Crucially, the brain regions that masterfully regulate sleep-wake cycles, particularly the SCN and hypothalamic circuits, are also central players in the control of energy balance, glucose homeostasis, and endocrine function.³⁸⁵ Consequently, a sleep disruption that impacts duration, timing, or architecture can profoundly dysregulate metabolic pathways. Conversely, the state of cellular energy surplus and insulin resistance characteristic of T2DM and obesity can impair the normal function of these very same brain centers, thereby disrupting sleep.

T2DM and sleep disorders

The relationship between T2DM and sleep disorders is paradigmatic of a vicious, bidirectional cycle. Individuals with T2DM exhibit a markedly high prevalence of sleep problems (50–70%), most notably insomnia and restless legs syndrome during sleep, both of which are significantly associated with poorer glycemic control and reduced quality of life.^386–389 T2DM is characterized by abnormal insulin secretion. Insulin not only regulates peripheral blood glucose but also acts as a neuropeptide that promotes the release of GABA in the central nervous system, thereby reducing neuronal excitability.³⁹⁰ During insulin resistance or insufficient insulin secretion, impaired central insulin signaling leads to attenuated GABAergic neurotransmission. This diminishes the capacity of the central nervous system to promote and maintain sleep drive, consequently resulting in hyperarousal. In addition, hyperglycemia per se can lead to both shorter sleep duration and worse sleep efficiency,³⁹¹ while nocturnal polyuria driven by osmotic diuresis also forces repeated awakenings and reduces sleep efficiency. Concurrent neuropathic pain further prolongs sleep latency and disrupts deep sleep stages, creating a vicious cycle of pain and sleep disturbance.³⁹² Conversely, the resulting sleep deprivation and fragmentation exert profound detrimental effects on glycemic control. Studies robustly show that insufficient sleep acutely induces peripheral insulin resistance.³⁹³ In normal-weight healthy men, a single night of sleep deprivation can increase ghrelin levels and feelings of hunger.³⁹⁴ These changes collectively exacerbate the core metabolic defects of T2DM. Furthermore, circadian misalignment, common in modern society, can directly impair pancreatic beta-cell function and insulin secretion, creating a storm for dysglycemia.³⁹⁵ Therefore, in T2DM, sleep disorders are not merely a symptom but a critical contributor to disease progression, making sleep a novel therapeutic target for improving metabolic outcomes.

Obesity and sleep disorders

Obesity and sleep disorders are inextricably linked, with obstructive sleep apnea (OSA) representing the most prominent and mechanistically direct connection. The pathophysiology is straightforward yet impactful: excessive adipose tissue, particularly in the neck and upper airway, leads to mechanical obstruction during sleep, causing recurrent apneas and hypopneas.³⁹⁶ Nevertheless, 30–40% of OSA patients are not obese, highlighting that nonanatomical factors, such as low arousal threshold, poor upper-airway muscle responsiveness, and ventilatory control instability, also play significant roles.³⁹⁷ These events result in chronic intermittent hypoxia, sleep fragmentation, and exaggerated sympathetic nervous system activation. Leptin, an adipocyte-derived hormone, promotes sleep by signaling energy sufficiency to the brain, thereby reducing metabolic activity and facilitating sleep initiation and maintenance. Conversely, ghrelin, primarily secreted from the stomach, enhances wakefulness and shortens sleep duration by stimulating appetite and increasing energy expenditure, signaling a state of energy need.³⁹⁸ In states of aberrant lipid metabolism, such as obesity, the secretion of leptin and ghrelin becomes severely dysregulated.³⁹⁹ Leptin resistance combined with relative ghrelin excess can directly perturb sleep-wake homeostasis, resulting in a state of hyperarousal.^400,401 Sleep reduction, even in the absence of frank OSA, is a significant risk factor for weight gain and obesity. Short sleep duration decreases leptin and increases ghrelin, leading to greater hunger and a preference for energy-dense foods.⁴⁰² This creates a powerful feedback loop: obesity promotes sleep disorders (such as OSA), which in turn aggravate metabolic dysfunction and promote further weight gain, making weight management exceptionally challenging.

Energy deficiency and sleep disorders

Unlike disorders of energy metabolism, energy-deficient conditions such as mitochondrial diseases, neurodegenerative diseases, and aging share a core pathophysiological feature: impaired ability to produce adenosine triphosphate (ATP), the universal currency of energy. This intrinsic energy crisis directly impacts the highly metabolically active processes underlying both sleep homeostasis and circadian rhythmicity. Studies have found that in conditions of brain energy deficiency, such as primary mitochondrial diseases, neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease), and aging, the incidence of sleep disorders is higher than that in the general population.^403–406

Primary mitochondrial diseases and sleep disorders

Primary mitochondrial diseases are caused by genetic or spontaneous mutations in nuclear DNA or mitochondrial DNA, with defects in oxidative phosphorylation (OXPHOS) being the primary characteristic.⁴⁰⁷ The resultant failure in efficient energy generation creates a critical energy deficit that is particularly detrimental to highly metabolically active tissues. Neurons and muscle cells, with their exceptionally high energy demands for maintaining electrochemical gradients and contractile function, are disproportionately affected. Consequently, mitochondrial diseases typically manifest as progressive and multisystem disorders, with prominent neurological and neuromuscular degeneration being hallmark clinical features.⁴⁰⁸ The high prevalence of sleep disorders in mitochondrial diseases is a direct consequence of cellular energy failure. Sleep-related breathing disorders are the primary type of sleep disturbance associated with mitochondrial diseases. Patients with severe skeletal muscle involvement often experience obstructive sleep apnea (OSA), while those with significant central nervous system involvement predominantly exhibit central sleep apnea (CSA).⁴⁰⁹ Notably, the prevalence of these sleep-disordered breathing events is significantly higher in children with mitochondrial diseases than in the general pediatric population. This observation suggests that sleep-related breathing disturbances may serve as an early and sensitive clinical indicator of disease progression, often appearing before other overt neurological symptoms, thereby demonstrating the importance of routine polysomnographic screening in this vulnerable group.⁴¹⁰

Neurodegenerative diseases and sleep disorders

The brain requires ATP produced from glucose metabolism as a continuous energy supply to maintain normal physiological states, with over 90% of brain ATP generated through OXPHOS.⁴¹¹ In neurodegenerative diseases, brain glucose metabolism deteriorates in a progressive, region specific, and disease-specific manner, ultimately leading to insufficient energy supply to the brain.^323,412,413 Concurrent with this energy failure, clinical studies consistently report a remarkably high incidence of sleep disorders in patients with neurodegenerative conditions.^404,414,415 This co-occurrence is not coincidental but is underpinned by a critical bidirectional relationship. On the one hand, the brain’s energy deficit directly impairs the function of nuclei regulating sleep-wake cycles. On the other hand, sleep disorders amplify the underlying pathology. It is during slow-wave sleep that cerebrospinal fluid flow increases significantly, facilitating the clearance of metabolic waste products, including amyloid-beta and tau proteins.³⁵⁷ Consequently, chronic sleep disorders can compromise this essential cleansing process, leading to the accumulation of neurotoxic aggregates and thereby accelerating neurodegeneration. Nevertheless, the manifestations of sleep disorders linked to various neurodegenerative conditions differ, potentially due to the distinct brain regions impacted by these diseases (Table 3).

Table 3.

The categories of sleep disorders that occur in association with energy metabolism-related diseases and the involvement sites

Energy metabolism-related diseases	Prevalence of Sleep Disorders	Categories of Sleep Disorders	Involvement Site	References
Type 2 diabetes	50–70%390	Insomnia	GABA release, hyperglycemia	391,453
		RLS	Peripheral neuropathy	389
Obesity	50–60%372	OSA	Neck fat accumulation	396
Primary mitochondrial diseases	47.6%452	OSA CSA	Skeletal muscle Neurons	409
Alzheimer’s Disease	up to 45%421,422	Not mentioned	GABA signing	422
		Not mentioned	Tau protein	423
		CRSWD	IDO/SCN	323,424,425
Parkinson’s disease	up to 98%434	Insomnia	Basal ganglia	433
		RBD	Posterior cortex	434–436
		RLS	Posterior cingulate cortex	437
		CRSWD	Melatonin	438
Aging	49.1%454	CRSWD	SCN	442,443
		Insomnia: sleep fragmentation	Hcrt/OX neurons	444–446,448

Alzheimer’s disease (AD) is a common neurodegenerative disorder, with the most notable clinical manifestation being the progressive loss of cognitive function. AD is characterized by a profound cerebral energy deficit stemming from reduced glucose uptake, a dampened tricarboxylic acid cycle, and mitochondrial dysfunction, which collectively compromise the metabolic support provided by astrocytes and oligodendrocytes to neurons.^413,416 Sleep disturbances are common complications in AD patients, and epidemiological studies have reported that up to 45% of AD patients have sleep disorders.^417–420 Sleep disorders are present from the early stages of AD and tend to intensify as the disease progresses.⁴²¹ In AD patients, the expression of GABA signaling in the temporal lobe cortex is reduced, indicating an imbalance in the excitation/inhibition ratio in this region.⁴²² During the progression of AD, the deposition of amyloid-beta (Aβ) and tau proteins occurs. Among these, the tau protein can promote the degeneration of sleep-wake-related neurons, thereby affecting sleep.⁴²³ Aβ and tau can also activate IDO in astrocytes, increasing the kynurenine metabolic pathway of tryptophan and leading to a decrease in the production of melatonin generated from tryptophan via serotonin.³²³ In 1985, Swaab, Fliers, and Partiman found that the volume and number of cells in the SCN of AD patients are significantly reduced.⁴²⁴ Compared to wild-type mice, the A-type potassium current on SCN neurons in the AD mouse model is notably weakened, suggesting the presence of neurophysiological damage in the SCN in AD.⁴²⁵ The impairment of the SCN partly explains the frequent occurrence of circadian rhythm disorders in AD patients. Furthermore, in the 5×FAD mouse model, a reduction in vascular density and decreased blood flow velocity were also observed in the retrosplenial cortex (RSC),⁴²⁶ indicating that this region is in a state of hypometabolism.

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder that manifests through a complex cluster of both motor and nonmotor symptoms. Among these, sleep disturbances are the most common nonmotor symptoms of PD, encompassing all forms of sleep disorders.^427–429 The pervasiveness of this issue is starkly highlighted by a comprehensive questionnaire survey, which revealed that up to 98% of PD patients had experienced it. One symptom has led to significant nighttime sleep problems since disease onset.⁴³⁰ The primary pathological signature of PD is the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of the midbrain. Critically, this neuronal degeneration is accompanied by significant mitochondrial fragmentation and dysfunction within this vulnerable region, characterized by impairments in key energy-producing pathways such as reduced glycolysis and a marked decrease in the activity of mitochondrial complex I.^431,432 As previously mentioned, dopaminergic neurons contribute to the regulation of wakefulness and REM sleep and interact intricately with an array of neurotransmitters and neural circuits.¹⁴⁷ The degeneration of these circuits triggers a wide spectrum of specific sleep pathologies. Therefore, PD patients may experience sleep problems such as insomnia,⁴³³ RBD,^434–436 restless leg syndrome (RLS),⁴³⁷ and CRSWD.⁴³⁸

Aging and sleep disorders

Broadly speaking, aging is defined as the time-related functional decline that affects most organisms, characterized by the gradual loss of physiological integrity. As cells and organisms age, the efficiency of the respiratory chain tends to decline, leading to increased electron leakage and reduced ATP production.^439–441 In mammals, advancing age is associated with a progressive deterioration of the SCN,⁴⁴² which can lead to a diminished amplitude of circadian rhythms, reduced rhythmicity, decreased sensitivity to light exposure, and an intensification of the sleep pattern characterized by going to bed and rising earlier than usual.⁴⁴³ Meanwhile, the sleep structure of older adults undergoes a series of noticeable changes, such as prolonged sleep latency, reduced overall sleep time, increased sleep fragmentation, and decreased deep sleep.^444–446 In addition to the overall changes in sleep structure, the sleep characteristic oscillations measured by EEG also change, most notably the reduction of two-component oscillations related to NREM sleep: slow waves and sleep spindles.⁴⁴⁷ Lecea and colleagues found that the expression of KCNQ2/3 channels on hypocretin/orexin neurons in the hypothalamus of aged mice was reduced compared to that in younger mice, making wakefulness-promoting Hcrt/orexin neurons more excitable, thereby leading to a disruption of the sleep-wake cycle.⁴⁴⁸

Medications that optimize energy metabolism can improve sleep

Energy metabolism serves as the fundamental basis of all life activities and is intricately involved in numerous physiological processes. These include maintaining neurotransmitter homeostasis, facilitating protein phosphorylation, and generating endogenous sleep-promoting substances such as adenosine and melatonin. Collectively, these functions underscore that energy metabolism is closely linked to sleep regulation. Therefore, enhancing energy metabolism may be a promising therapeutic strategy for sleep disorders. Several metabolism-modifying agents have now been identified to exert considerable sleep-promoting effects (Table 4). This metabolism-targeted intervention strategy offers a novel therapeutic direction beyond traditional sedative-hypnotic drugs, demonstrating particular potential for treating sleep disorders accompanied by metabolic dysregulation.

Table 4.

Some medications that enhance energy metabolism can improve sleep

Drugs categories	Impact on energy metabolism	Impact on sleep		Reference
Biguanides		Improve glucose metabolism and mitochondrial function	Increase sleep duration and sleep efficiency	455–457
GLP-1 receptor agonists		Improve glucose metabolism and lipid metabolism	Play a crucial role in the management of OSA	461,462
Melatonin and melatonin receptor agonists		Reduce triglycerides and total cholesterol levels, while increase glycemic variability	Regulate the circadian rhythm	463–465
Orexin receptor antagonists and agonists	Orexin receptor antagonists	Reduce appetite and inhibit feeding behavior	Improve sleep onset and sleep maintenance endpoints	472–474
	Orexin receptor agonists	Increase appetite and promote feeding behavior	Enhance wakefulness, reduce daytime sleepiness, and alleviate cataplexy	478
Nicotinamide mononucleotide		Boost insulin sensitivity and muscle function	Ameliorate sleep quality	480–484

Biguanides

Metformin, the first-line pharmacological agent for managing type 2 diabetes mellitus (T2DM), has gained increasing attention not only for its core role in glycemic control but also for its broader beneficial effects. Multiple studies have demonstrated that it can significantly improve metabolic profiles, safeguard mitochondrial function, and potentially decelerate the aging process while extending lifespan.^449,450 It is well established that type 2 diabetes mellitus (T2DM) and sleep disorders exhibit a bidirectional relationship.⁴⁵¹ On the one hand, the presence of sleep disturbances can exert adverse effects on metabolic homeostasis: they disrupt the balance of appetite-regulating hormones and impair insulin sensitivity, thereby increasing the risk of developing T2DM over time.⁴⁵² On the other hand, T2DM can itself impair the initiation and maintenance of sleep through multiple pathways, including compromised central insulin signaling leading to reduced GABA synthesis^390,453 and nocturnal glucose fluctuations resulting in sympathetic nervous system excitation.⁴⁵⁴ Given this bidirectional link, metformin’s efficacy in improving insulin sensitivity and glycemic control may thereby contribute to improved sleep outcomes. A retrospective observational study indicated that individuals with type 2 diabetes treated with metformin exhibit longer sleep duration and better sleep efficiency than those not on metformin.⁴⁵⁵ Moreover, this sleep-benefiting effect of metformin is not limited to T2DM patients. Studies conducted in patients with metabolic syndrome⁴⁵⁶ and polycystic ovary syndrome during adolescence⁴⁵⁷ have also confirmed that metformin treatment increases sleep duration and sleep efficiency, highlighting its potential as a multifaceted agent for addressing metabolic and sleep-related comorbidities.

GLP-1 receptor agonists

GLP-1 receptor agonists have emerged as highly effective therapeutic agents for metabolic disorders, as they improve both glucose metabolism and lipid metabolism disorders, demonstrating excellent effects in lowering blood sugar and promoting weight loss.^458,459 The accumulation of neck fat due to obesity serves as the primary pathological basis for obstructive sleep apnea (OSA).⁴⁶⁰ This extra fat in the neck area presses on the upper airway. When this happens, the airway collapses repeatedly during sleep, disrupting breathing and causing periods of low oxygen. GLP-1 receptor agonists help with this root issue because they lead to significant weight loss. They do this by suppressing appetite and promoting energy expenditure and therefore play a crucial role in the management of OSA.⁴⁶¹ In the phase III SURMOUNT-OSA trial (NCT05412004) of tirzepatide, 52 weeks of treatment reduced the Apnea-Hypopnea Index (AHI) from a baseline of 35.8 events per hour to 8.4 events per hour in patients with obstructive sleep apnea (OSA), representing a 76.5% reduction.⁴⁶² Additionally, 42.2% to 50.2% of patients achieved disease remission, defined as an AHI < 5 events per hour or an Epworth Sleepiness Scale (ESS) score ≤10⁴⁶². Based on these findings, the U.S. Food and Drug Administration (FDA) approved tirzepatide as the first medication for the treatment of moderate-to-severe OSA in patients with obesity.

Melatonin and melatonin receptor agonists

Melatonin is commonly considered a chronobiotic agent and is mainly used for patients with circadian rhythm disorders.⁴⁶³ Beyond its role in regulating circadian rhythms, randomized controlled trials have shed light on other effects of melatonin supplementation. These studies show that it can significantly reduce triglycerides and total cholesterol levels⁴⁶⁴ but increases glycemic variability in patients with type 2 diabetes.⁴⁶⁵ Compared to other hypnotic drugs, melatonin produces fewer side effects but also has a lesser degree of improvement in sleep.⁴⁶³ Melatonin has a short half-life, approximately 20–50 min, which makes it difficult to maintain therapeutic effects throughout the night, limiting its use in patients with difficulty maintaining sleep.⁴⁶⁶ To address this weakness, Circadin, a sustained-release formulation of melatonin, has been developed. This type of medication gradually releases melatonin over several hours, mimicking the secretion pattern during the night.⁴⁶⁷ Currently, two melatonin receptor agonists have been approved for the treatment of sleep disorders: ramelteon and tasimelteon. They both have agonistic effects on MT₁ and MT₂ receptors. In addition, tasimelteon is the only drug approved by the FDA for the treatment of non-24-h sleep-wake disorder, a circadian rhythm disorder affecting blind individuals.^466,468 Notably, similar to melatonin, the impact of melatonin sustained-release formulations and melatonin receptor agonists on overall sleep time appears to be limited.^467,469

Orexin receptor antagonists and agonists

Orexin (also known as hypocretin) is a neuropeptide produced in the hypothalamus that plays two primary physiological roles: regulating the sleep-wake cycle and modulating energy metabolism and appetite. Dual orexin receptor antagonists (DORAs) are a novel class of hypnotic drugs that have emerged in recent years. Suvorexant, Lemborexant, and Daridorexant were approved by the FDA in 2014, 2019, and 2022, respectively.⁴⁷⁰ Compared to traditional hypnotics, DORAs have fewer side effects and can maintain a more natural sleep architecture.^470,471 Clinical trials have shown that DORAs are clinically useful in improving both sleep onset and sleep maintenance endpoints.^472–474 Orexin has already become deficient in narcolepsy,³⁸⁴ so DORAs are contraindicated for these patients. Although cases of sleep paralysis and muscle weakness have been observed in clinical trials, there is no evidence to suggest that treatment with DORAs increases the incidence of cataplexy.^473–475 However, the use of DORAs may affect driving ability, suggesting that DORAs can impair the ability to maintain alertness and attention.^476,477 Type 1 narcolepsy is a hypersomnolence disorder resulting from the degeneration of orexin-producing neurons, leading to deficient orexin signaling in the central nervous system. Treatment with oveporexton, an orexin receptor 2-selective agonist, has been shown to enhance wakefulness, reduce daytime sleepiness, and alleviate cataplexy in affected individuals.⁴⁷⁸

Nicotinamide mononucleotide

NMN is a key precursor molecule for nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in the human body. NAD⁺ participates in a wide range of vital physiological processes. It is deeply involved in cellular metabolism,⁴⁴⁶ DNA repair, and mitochondrial maintenance.⁴⁷⁹ As people age, their body’s NAD+ levels usually start to drop. This decline is linked to a variety of health issues, from reduced cellular function to increased risk of age-related conditions. However, research has shown that supplementation with NMN can help reverse this trend by boosting NAD+ levels in the body. For middle-aged and senior adults, NMN supplementation has been found to improve insulin sensitivity, which helps regulate blood sugar more effectively.⁴⁸⁰ It also enhances muscle function in healthy older men, supporting mobility and strength.⁴⁸¹ Additionally, there is evidence suggesting that it may slow the aging process and even extend life expectancy. Importantly, double-blind, randomized, placebo-controlled clinical trials have provided further proof of NMN’s benefits. These trials show that taking NMN supplements can improve sleep quality, with positive effects seen in both people with chronic insomnia and elderly individuals.^482–484

Conclusion and future perspectives

Sleep is a fundamental, universally observed phenomenon across the natural world, present in nearly all complex organisms from humans to many animals. Beyond its role as a period of rest, ensuring sufficient high-quality sleep is a critical factor in sustaining overall health and enhancing quality of life. It supports immune function, cognitive performance, emotional regulation, and metabolic balance, all of which are essential for long-term well-being. Sleep is not an isolated process and is closely linked to a wide range of factors. Environmental elements such as noise, light exposure, and temperature can disrupt sleep cycles. Mental and psychological states, such as stress, anxiety, or depression, often interfere with falling or staying asleep. Demographic factors such as gender and age also significantly affect sleep, with women and older adults being more susceptible to insomnia and declining sleep quality, respectively. Additionally, lifestyle behaviors such as irregular sleep schedules, excessive caffeine intake, or lack of physical activity, as well as genetic predispositions to certain sleep disorders, all contribute to shaping an individual’s sleep health.

Given the complexity of factors influencing sleep, it is clear that a one-size-fits-all approach is insufficient for treating sleep disorders. Instead, we should develop comprehensive and personalized therapeutic strategies tailored to each patient’s unique circumstances. This is especially important when managing sleep disorders in patients who also have disturbances in glucose or lipid metabolism. For example, patients with insulin resistance or T2DM often struggle with sleep, and poor sleep can further worsen their glycemic control. Similarly, those with hyperlipidemia or obesity face higher risks of obstructive sleep apnea, a condition that in turn exacerbates metabolic issues. In these cases, treatment must address both the sleep disorder and the underlying metabolic problems simultaneously. When selecting medications for sleep disorders, careful consideration of potential side effects is crucial, especially in patients with comorbid metabolic conditions. While drugs such as olanzapine and quetiapine are sometimes used off-label to treat insomnia, particularly in patients who also have anxiety, depression, or other psychiatric disorders, their metabolic adverse effects are well documented. These effects include weight gain, increased insulin resistance, and elevated lipid levels, all of which can worsen existing glucose or lipid metabolism disorders.^485,486 For this reason, these agents should be avoided as much as possible in patients with coexisting metabolic issues.

Another important connection to consider is the link between sleep disorders, mitochondrial function, and age-related or degenerative diseases. As previously noted, conditions such as mitochondrial diseases, neurodegenerative disorders (such as AD or PD), and even the natural aging process are often accompanied by mitochondrial dysfunction and energy deficiency. Mitochondria function as the “powerhouses” of the cell, generating ATP to supply the primary energy required for cellular activities. When mitochondrial function declines, energy production drops, and this can disrupt the capability of the brain to regulate sleep-wake cycles. Sleep disorders frequently appear in the early stages of these conditions. As the disease progresses, these sleep problems often become more severe, creating a vicious cycle where poor sleep further impairs mitochondrial function and accelerates disease progression. This connection suggests that sleep disorders can serve as an early warning sign for these diseases. Early pharmacological intervention to enhance energy metabolism and improve sleep may help delay or prevent disease onset. Furthermore, in cases where sleep disorders already coexist with mitochondrial diseases, neurodegenerative diseases or age-related energy deficiency, clinicians should consider incorporating pharmacological agents that enhance mitochondrial function and energy metabolism into the sleep management plan. By targeting the underlying energy deficit, these agents can address the root cause of sleep disorders, leading to more effective and sustainable improvements in sleep quality and overall health.

In summary, this review discusses the role of energy metabolism in sleep from multiple perspectives, including its involvement in supporting neural activity during sleep-wake cycles, maintaining circadian rhythm stability, and modulating the function of sleep regulating brain regions. It emphasizes that normal energy metabolism is not only essential for sustaining normal sleep but also a key prerequisite for preventing sleep disorders triggered by metabolic imbalances. Additionally, the review provides a novel therapeutic angle for treating sleep disorders by targeting and improving energy metabolism pathways, offering potential alternatives to conventional symptomatic treatments. However, there remains a notable gap in research regarding the specific molecular mechanisms underlying the interaction between energy metabolism and sleep, such as how mitochondrial function or metabolite signaling directly regulates the sleep-wake cycle. Thus, more in depth, mechanism-focused studies are urgently needed in the future to bridge this knowledge gap and guide the development of targeted interventions.

Author contributions

J.S.K. and J.K.L. designed and wrote the manuscript. R.Y.W. and X.Y.M. performed the literature search. J.S.K. and J.K.L. prepared the Tables and Figures. All authors listed have made a substantial contribution to the work. All authors have read and approved the article.

Competing interests

The authors declare no competing interests. J.-S.K. is the editorial board member of Signal Transduction and Targeted Therapy, but he has not been involved in the process of manuscript handling.