Wake-sleep circuitry: an overview

Abstract

Although earlier models of brain circuitry controlling wake-sleep focused on monaminergic and cholinergic arousal systems, recent evidence indicates that these play mainly a modulatory role, and that the backbone of the wake-sleep regulatory system depends upon fast neurotransmitters, such as glutmate and GABA. We review here recent advances in understanding the role these systems play in controlling sleep and wakefulness.

Figure 1

A diagram summarizing the fast neurotransmitter systems that appear to play the largest role in promoting wakefulness, based on results of lesions and opto- and chemogenetic excitation and inhibition. Note that the monoaminergic, cholinergic, and peptidergic neurons in the brainstem and hypothalamus, which were prominent in earlier models, are here shown in brown as they appear to play a modulatory role, but lesions in these locations have little effect on wake-sleep amounts. The backbone of the arousal system in this model, shown in red, is the glutamatergic input from the parabrachial nucleus (PB) and pedunculopontine tegmental nucleus (PPT) to the basal forebrain, and the GABAergic and cholinergic neurons in the basal forebrain (BF) that diffusely innervate the cerebral cortex. Lesions at these sites cause complete loss of consciousness, whereas lesions of supramammillary (SUM) glutamatergic neurons or dopaminergic (DA) neurons in the ventral periaqueductal gray matter (vPAG) near the dorsal raphe nucleus cause about a 20% loss of wake time. In addition, two populations of GABAergic neurons in the lateral hypothalamus (LH), shown in purple, have recently been proposed to promote wakefulnes by inhibiting sleep promoting neurons in the thalamus and preoptic area. Abbreviations: 5HT, serotonin; Ach, acetylcholine; Hist, histamine; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus NA, noradrenlaine; ORX, orexin; TMN, tuberomammillary nucleus Modified with permission from [2].

Figure 2

A diagram summarizing the fast neurotransmitter systems that contribute to sleep promotion (shown in purple). Ventrolateral preoptic (VLPO) and median preoptic (MnPO) GABAergic neurons send axons to most components of the arousal system (shown in red, yellow, and green), and are thought to inhibit them in a coordinated fashion. Parafacial zone (PFZ) GABAergic neurons in the medulla induce sleep mainly by inhibiting the parabrachial glutamatergic arousal neurons. Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus contain both GABA and glutamate, and may be able to release them at different terminal sites. They innervate neurons in the brainstem that control REM sleep (see text for details). Other abbreviations as in Fig. 1. Modified with permission from [2].