Neuro-orchestration of sleep and wakefulness

Abstract

Although considered an inactive state for centuries, sleep entails many active processes occurring at the cellular, circuit and organismal levels. Over the last decade, several key technological advances, including calcium imaging and optogenetic and chemogenetic manipulations, have facilitated a detailed understanding of the functions of different neuronal populations and circuits in sleep-wake regulation. Here, we present recent progress and summarize our current understanding of the circuitry underlying the initiation, maintenance and coordination of wakefulness, rapid eye movement sleep (REMS) and non-REMS (NREMS). We propose a de-arousal model for sleep initiation, in which the neuromodulatory milieu necessary for sleep initiation is achieved by engaging in repetitive pre-sleep behaviors that gradually reduce vigilance to the external environment and wake-promoting neuromodulatory tone. We also discuss how brain processes related to thermoregulation, hunger and fear intersect with sleep-wake circuits to control arousal. Lastly, we discuss controversies and lingering questions in the sleep field.

Figure 1.. The orchestration of wakefulness.

(A) Wakefulness is generated through several concurrent processes. (i) Wake systems stimulate cortical and thalamocortical circuits, suppressing low frequency oscillations (hereafter depicted in yellow). (ii) The release of neuromodulators modulates excitability and information flow in distributed neural networks in support of waking-state processing and behaviors (hereafter depicted in red). (iii) Wake systems inhibit sleep-promoting neurons (hereafter depicted in green). (B) Schematic of wake systems. Neuronal subpopulations distributed throughout the brain generate and maintain wakefulness. PBN, LC, TMN, LH and BF output modulates thalamocortical and cortical circuits and promotes fast cortical oscillations conducive to waking-related processing. Neuromodulatory output from the LC, DR, VTA, PVN, BF, LH and TMN alter the excitability of neural networks spanning from the brainstem to the forebrain. Several wake systems, including those in the SC, LC, TMN, LH and NAc, can inhibit sleep-promoting neurons. Wakefulness may be initiated daily by indirect or direct circadian output from the SCN (pink) onto the PVN, LH, VTA and thalamus. Colors indicate participation in the processes shown in A. (C-F) Inputs, outputs and local-network connectivity of four main wake systems. Complex interactions among multiple subpopulations within the LH, BF, VTA and Thal support wakefulness. Within each region, both excitatory and disinhibitory mechanisms fine-tune arousal regulation. (C) GABAergic (blue), glutamatergic (pink) and peptidergic subpopulations within the LH generate and maintain wakefulness. Most excitatory and inhibitory inputs into the LH promote wakefulness. (D) The BF is critical in opposing the default synchronized cortical state and in producing cortical arousal. Inputs from the PBN and outputs to the cortex are important for this function, whereas outputs to the VTA promote wakefulness. (E) Dopaminergic, glutamatergic and GABAergic VTA neurons are involved in regulating wakefulness. DAergic and glutamatergic VTA neurons are necessary for wake maintenance, even in the presence of highly salient stimuli. (F) Several midline thalamic subpopulations are both necessary and sufficient for the generation of wakefulness and have been implicated in the initiation of wakefulness. Excitatory input from various wake-promoting neurons depolarizes TC neurons during wakefulness, resulting in the induction of fast cortical oscillations. Solid lines represent pathways whose functions have been experimentally interrogated. Dashed lines represent anatomical innervations that have not been functionally tested in the context of sleep/wake regulation. Blue lines represent inputs to wake systems that do not clearly fall into one of the functions described in (A). 5-HT, serotonin; ACh, acetylcholine; BF, basal forebrain; BNST, bed nucleus of the stria terminalis; Calb1+, calbindin1-positive neurons; Cg, Cingulate cortex; CMT, centromedial thalamus; CR+, calretinin-positive neurons; D1, dopamine type-D1 receptor; D2, dopamine type-D2 receptor; DA, dopamine; DMT, dorsomedial thalamus; DR, dorsal raphe; DS, dorsal striatum; GABA, gamma-aminobutyric acid; HA, histamine; Hcrt, hypocretin; LC, locus coeruleus; LH, lateral hypothalamus; MS, medial septum; NA, noradrenaline; NAc, nucleus accumbens; PBN, parabrachial nucleus; PC, peri-coeruleus; POA, preoptic area; PV+, parvalbumin-expressing neurons; PVN, hypothalamic paraventricular nucleus; PVT, paraventricular nucleus of the thalamus; RMTg, rostromedial tegmental nucleus; SC, superior colliculus; SCN, suprachiasmatic nucleus; TC, thalamocortical neurons; Thal, thalamus; TMN, tuberomammillary nucleus; VMT, ventromedial thalamus; VP, ventral pallidum; VTA, ventral tegmental area.

Figure 2.. The orchestration of NREMS

(A) Proposed ‘de-arousal model of sleep initiation’. The transition from wakefulness to sleep is preceded by a transitional phase during which physiological and behavioral tranquilization enable a brain-wide shift in excitability, functional connectivity and information flow. (i) Circadian and homeostatic drives promote a behavioral preparation for sleep. (ii) The manifestation of repetitive, pre-sleep behaviors, such as grooming and nest-building, reduces vigilance toward the external environment and decreases the tone of wake-promoting neuromodulators. The decreased wake neuromodulatory tone further promotes the manifestation of pre-sleep behaviors. (iii) Low neuromodulatory tone also results in the release of TC neurons from their stimulation, the propagation of cortical slow oscillations and the disinhibition of sleep-promoting neurons, imposing sleep upon the organism. (B) NREMS regulatory circuitry. POA_GABA neurons have a central role in generating and maintaining NREMS. Additional NREMS-promoting populations have been identified in the medulla, midbrain, ZI, amygdala, striatum and cortex. NREMS is maintained by the continuous inhibition of wake systems. Thalamic, cortical and PZ_GABA neurons are implicated in driving characteristic NREMS oscillations. Blue, NREMS-promoting neurons. Gray, wake systems inhibited by NREMS-promoting neurons. Solid lines represent pathways whose functions have been experimentally interrogated. Dashed lines represent anatomical innervations that have not been functionally tested in the context of sleep/wake regulation. CeA, central nucleus of the amygdala; DMH, dorsomedial hypothalamus; eGP, external globus pallidus; OT, olfactory tubercle; pIII, perioculomotor midbrain; PH, posterior hypothalamus; PZ, parafacial zone; SNr, substantia nigra pars reticulata; vlPAG, ventrolateral periaqueductal gray; vmM, ventromedial medulla; VP, ventral pallidum; ZI, zona incerta.

Figure 3.. The orchestration of REMS.

(A) Gatekeeping neurons in the vlPAG, dorsal DpMe, DR and LC prevent REMS initiation during wakefulness and NREMS by inhibiting REMS-generating populations. REMS is likely initiated by the simultaneous inhibition of gatekeepers and activation of pontine and hypothalamic structures, including the SLD, PPT/LDT, PC and LH. (B) The main neuronal populations generating and maintaining REMS are located in the brainstem (pons and medulla), and additional REMS regulatory populations have been identified in the LH, ZI, POA and VTA. (C) Tonic features of REMS are generated by different neuronal circuits. Muscle atonia during REMS is attained by SLD_glut neuronal input to vmM_Gly/GABA neurons, which inhibit spinal cord motoneurons. The suspension of thermoregulation may be induced by inhibitory DMH_Gal projections to the raphe pallidus. Finally, several brain regions have been implicated in the generation of cortical and hippocampal theta oscillations during REMS, including the MS and BF/LPO. The SuM and CL are implicated in the activation of several limbic and cortical regions during REMS. (D) Phasic features of REMS are thought to be orchestrated by PPT/LDT neurons through projections to the brainstem, thalamic and forebrain areas, as well as propagating theta oscillations. Dorsal medulla NP_Calb/glut neurons have been implicated in generating REMS rapid eye movements through projections to the oculomotor nucleus. Myoclonic twitching during REMS involves the activation of cholinergic PPT/LDT/SLD neurons, as well as of red nucleus neurons, generating brief episodes of atonia cessation in tandem with glutamate-mediated activation of spinal cord motoneurons. PGO waves are associated with neuronal activation in several neuronal populations in the pons. Phasic increases in heart rate during REMS may be promoted by the phasic inhibition of cardiac vagal neurons in the nucleus ambiguous by REMS-active LPGi_Gly/GABA neurons. ACC, anterior cingulate cortex; Amb, nucleus ambiguous; Amy, amygdala; BAT, brown adipose tissue; BLA, basolateral amygdala; CL, claustrum; CVNs, cardiac vagal neurons; DG, dentate gyrus; dmM, dorsomedial medulla; DpMe, deep mesencephalic nucleus; Gi, gigantocellular nuclei; gly, glycinergic neurons; Hyp, hypothalamus; IN, spinal cord interneurons; LDT, laterodorsal tegmental nuclei; LPGi, lateral paragigantocellular nuclei; MC, motor cortex; mEC, medial entorhinal cortex; MNs, spinal cord motoneurons; NI, nucleus incertus; NP, nucleus papilio; OM, oculomotor nucleus; PPT, pedunculopontine tegmental nucleus; RN, red nucleus; RSC, retrosplenial cortex; SLD, sublaterodorsal tegmental nucleus; SuM, supramammillary nucleus; vM, ventral medulla; VTn, ventral tegmental nucleus of Gudden.