The waking brain: an update

Abstract

Wakefulness and consciousness depend on perturbation of the cortical soliloquy. Ascending activation of the cerebral cortex is characteristic for both waking and paradoxical (REM) sleep. These evolutionary conserved activating systems build a network in the brainstem, midbrain, and diencephalon that contains the neurotransmitters and neuromodulators glutamate, histamine, acetylcholine, the catecholamines, serotonin, and some neuropeptides orchestrating the different behavioral states. Inhibition of these waking systems by GABAergic neurons allows sleep. Over the past decades, a prominent role became evident for the histaminergic and the orexinergic neurons as a hypothalamic waking center.

Fig. 1

Ascending activation of the cortex. The ascending reticular activation system (ARAS) reaches the cortex through a ventral pathway (hypothalamus, basal forebrain), through the aminergic nuclei (containing catecholamines, acetylcholine, and serotonin) and a dorsal pathway, the thalamic relay. Switching between paradoxical sleep (REM-sleep) and slow wave sleep occurs in the reticular formation, whereas the switch between sleep and waking lies in the hypothalamus

Fig. 2

The waking brain. Schematic localization of the brain’s waking systems and their inhibition. NA (noradrenaline, locus coeruleus); ACh (acetylcholine, pedunculo-pontine nucleus, PPN; lateral dorsal tegmentum, LDT; basal forebrain, BF); DA (dopamine, periaquaeductal grey, PAG), 5-HT (serotonin, dorsal raphe, DR); HA (histamine, tuberomamillary nucleus, TMN), OX (orexins, periventricular nucleus, PVN); POA: preoptic area, GABAergic neurons which inhibit all the waking systems, black lines indicate inhibitory pathways

Fig. 3

The histamine H3R as an autoreceptor mediating negative feedback on histamine synthesis and release, and, importantly, as a heteroreceptor suppressing the release of many other transmitters from their varicosities. H3R antagonists and partial agonists are widely developed for several neuropsychiatric indications including sleep disorders

Fig. 4

Effects of an environmental change on the cortical EEG and behavioral states in wild-type (upper) and knockout-mice lacking histamine synthesis (lower). The environmental change (middle) consists of transferring the mice from their habitual home cage (A) to a new cage (B). Upper A wild-type mouse with an intact brain histaminergic system. This mouse placed in the new environment remains highly awake, as indicated by the alert behavior and waking EEG. Lower A knockout mouse without histamine. This mouse falls asleep a few minutes after being placed in the new environment, as shown by the sleeping behavior and EEG signs of slow wave sleep. Histaminergic neurons play a key role in maintaining the brain in an awake state in the presence of behavioral challenges. Modified from Parmentier et al. (2002) Journal of Neuroscience 22:7695–7711

Fig. 5

Different behavioral performance and ability to maintain waking between wild-type and orexin knockout mice when faced with a motor challenge demonstrated using simultaneous electroencephalogram and elecromyogram monitoring (upper). When wild-type mice (middle left) were placed on a wheel, they voluntarily spent their time in turning it and, as a result, remained highly awake. In contrast, orexin knockout mice (middle right) usually tried to adapt a position to stay immobile, thus falling asleep. Note the absence of orexin neurons in the knockout mice (lower). Modified from Anaclet et al. (2009) Journal of Neuroscience 29:14423–14438