Fig. 1

Mechanisms regulating sleep wake modulation. a. Orexinergic neurons originating in the lateral hypothalamus (LH; Green) send excitatory projections to several brainstem nuclei that act to promote arousal. Ascending monoaminergic projections (purple) from the noradrenergic locus coeruleus (LC), glutamaterigic parabrachial (PB) and pedunculopontine (PPT), serotoninergic dorsal raphe (DR), dopaminergic ventral periaqueductal grey (vPAG), tuberomammillary nuceus (TMN) and GABAergic and cholinergic neurons in the basal forebrain (BF) diffusely innervate the cerebral cortex to promote arousal. There are also cholinergic projections (Blue) from the laterodorsal tegmental nuclei (LDT) and PPT nuclei that project to the thalamus to promote arousal. b. GABAergic ventrolateral preoptic (VLPO) neurons (Brown) act to inhibit the majority of the arousal nuclei, including LH orexinergic neurons to promote sleep. c. Homeostatic sleep pressure (Blue line) increases through wakefulness, likely via the accumulation of endogenous somnogens such as adenosine that excites VLPO neurons to promote sleep. This is combined with circadian sleep regulation (Red line) to create a balanced sleep wake cycle that is entrained to external environmental conditions. The circadian component is in part dependent on pituitary adenylate cyclase-activating peptide signalling within the hypothalamic suprachiasmatic nucleus as demonstrated by preclinical research