Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or glutamatergic neurons in behaving mice produced significant effects on state consolidation and/or the electroencephalogram but had no effect on total wake. Similar activation of BF GABAergic neurons produced sustained wakefulness and high-frequency cortical rhythms, whereas chemogenetic inhibition increased sleep. Our findings reveal a major contribution of BF GABAergic neurons to wakefulness and the fast cortical rhythms associated with cognition. These findings may be clinically applicable to manipulations aimed at increasing forebrain activation in dementia and the minimally conscious state.

Work in animals and humans suggest the existence of a slow–wave sleep (SWS) promoting/EEG synchronizing center in the mammalian lower brainstem. While sleep–active GABAergic neurons in the medullary parafacial zone (PZ) are needed for normal SWS, it remains unclear if these neurons can initiate and maintain SWS or EEG slow wave activity (SWA) in behaving mice. We used genetically targeted activation and optogenetic–based mapping to uncover the downstream circuitry engaged by SWS–promoting PZ neurons, and we show that this circuit uniquely and potently initiates SWS and EEG SWA, regardless of the time of day. PZ neurons monosynaptically innervate and release synaptic GABA onto parabrachial neurons that in turn project to and release synaptic glutamate onto cortically–projecting neurons of the magnocellular basal forebrain; hence a circuit substrate is in place through which GABAergic PZ neurons can potently trigger SWS and modulate the cortical EEG.

Abbreviations AbstractNarcolepsy is characterized by excessive daytime sleepiness(EDS), cataplexy, direct onsets of rapid eye movement(REM) sleep from wakefulness(DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H3-receptor agonist. In narcoleptic orexin-/-mice, tiprolisant enhanced HA and noradrenaline neuronal activity, promoted wakefulness and decreased abnormal DREMs, all effects being amplified by co-administration of modafinil, a currently prescribed wake-promoting drug. In a pilot single-blind trial on 22 patients receiving a placebo followed by tiprolisant, both for one week, the Epworth Sleepiness Scale(ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo(p>0.05) and 5.9 with tiprolisant(p<0.001). Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant-dosing. H3-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.

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Histamine H 3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H 3 receptor. On the stimulation of guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a K i value of 0.16 nM and as an inverse agonist with an EC 50 value of 1.5 nM and an intrinsic activity ϳ50% higher than that of ciproxifan. Its in vitro potency was ϳ6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED 50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.The cerebral histaminergic neurons seem to play a critical role in the maintenance of wakefulness and higher cerebral functions, e.g., attention or learning (for review, see Schwartz et al., 1991;Haas and Panula, 2003). Hence, druginduced activation of histaminergic neurotransmission in the central nervous system represents a promising therapeutic target in a large variety of neuropsychiatric disorders in which these functions are compromised and for which available therapeutic opportunities are limited in this respect .Stimulation of postsynaptic H 1 and/or H 2 receptors by agonists is, however, not acceptable due to unavoidable and detrimental actions of these drugs at peripheral, i.e., mainly cardiovascular and gastric targets. In contrast, presynaptic H 3 receptors are almost exclusively expressed in the central nervous system, and their blockade by drugs such as thioperamide markedly enhances the activity of histaminergic neurons, as shown namely by the increases in histamine (HA) release and turnover in rodent brain (Arrang et al., Article, publication date, and citation information can be found at

Summary The largest synaptic input to the sleep-promoting ventrolateral preoptic area (VLPO) [1] arises from the lateral hypothalamus [2], a brain area associated with arousal [3–5]. However, the neurochemical identity of the majority of these VLPO-projecting neurons within the LH, as well as their function in the arousal network, remains unknown. Herein we describe a population of VLPO-projecting neurons in the LH that express the vesicular GABA transporter (VGAT; a marker for GABA-releasing neurons). In addition to the VLPO, these neurons also project to several other established sleep and arousal nodes, including the tuberomammillary nucleus, ventral periaqueductal gray and locus coeruleus. Selective and acute chemogenetic activation of LH VGAT+ neurons was profoundly wake-promoting whereas acute inhibition increased sleep. Because of its direct and massive inputs to the VLPO, this population may play a particularly important role in wake-sleep switching.

BackgroundPrevious work has suggested, but not demonstrated directly, a critical role for both glutamatergic and GABAergic neurons of the pontine tegmentum in the regulation of rapid eye movement (REM) sleep.Methodology/Principal FindingsTo determine the in vivo roles of these fast-acting neurotransmitters in putative REM pontine circuits, we injected an adeno-associated viral vector expressing Cre recombinase (AAV-Cre) into mice harboring lox-P modified alleles of either the vesicular glutamate transporter 2 (VGLUT2) or vesicular GABA-glycine transporter (VGAT) genes. Our results show that glutamatergic neurons of the sublaterodorsal nucleus (SLD) and glycinergic/GABAergic interneurons of the spinal ventral horn contribute to REM atonia, whereas a separate population of glutamatergic neurons in the caudal laterodorsal tegmental nucleus (cLDT) and SLD are important for REM sleep generation. Our results further suggest that presynaptic GABA release in the cLDT-SLD, ventrolateral periaqueductal gray matter (vlPAG) and lateral pontine tegmentum (LPT) are not critically involved in REM sleep control.Conclusions/SignificanceThese findings reveal the critical and divergent in vivo role of pontine glutamate and spinal cord GABA/glycine in the regulation of REM sleep and atonia and suggest a possible etiological basis for REM sleep behavior disorder (RBD).

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