Attention may be defined as the behavioral and cognitive process that allows us to select the information present in our environment on the basis of their relevance along with the ability to ignore irrelevant stimuli (Sarter et al., 2001). It consists of several components such as sustained, selective and divided attention, which are responsible for the control of the flow of information in the cognitive system (Rieger et al., 2003). Attention involves both top-down processes (knowledge-driven mechanisms) and bottom-up processes (mechanisms driven mainly by the characteristics of the target stimulus and its sensory context; Sarter et al., 2001; Chieffi et al., 2004, 2012). These two processes drive the attentive focus control (Gazzaniga et al., 2002). Attentional processing comprises some generalized states of arousal which refers to the state of physiological reactivity ranging from sleep to excitement or panic (Coull, 1998; Fadel and Burk, 2010).

Changes in arousal typically are deduced from brain activity data (EEG), whereas the study of attention is based on behavioral studies. Moruzzi and Magoun (1949) first demonstrated that cerebral activation is related to changes in EEG waves and has a brainstem origin. The discovery and localization of the brainstem reticular arousal system (RAS) was subsequently made by Moruzzi and Magoun (1949). The more evident arousal effect on EEG activity is the “desynchronization” phenomenon. It refers to the rapid shift from high-amplitude low-frequency EEG activity, typical of sleep, to low-amplitude high-frequency electroencephalographic activity, typical of wakefulness. EEG was the earliest measure used to systematically examine human brain cortical activity. After a long period of decline in clinical interest, EEG is now attracting increasing scientific and clinical interest. This resurgence is due to ongoing advances in signal processing and visualization that increase the spatial resolution of EEG imaging and exploit its ability to image quick transient cortical events and more precise regional changes in cortical activity. For the last few decades, scalp channel EEG data have been analyzed principally either in the time domain via ERP trial averaging, or in the frequency domain using FFT that estimate spectral power within a given frequency. Although phenomena and definitions may vary, EEG spectral power variations are typically dominated by distinct changes in power in few frequency bands. The standard terminology for these bands is: delta (<4 Hz), theta (4–7 Hz), alpha (8–12 Hz), beta (13–25 Hz; often split into beta-1/sensorimotor rhythm (SMR), 13–16 Hz, and beta-2, 17–25 Hz), and gamma (25–50 Hz or even higher frequency broadband activity extending to 200 Hz or greater). Cerebral activation is also detected during rapid eye movement (REM) sleep. Experimental evidence suggest that arousal systems work differently during the wake state and the REM sleep (Krueger et al., 2016). Arousal effects arise from the stimulation of the mesopontine cholinergic nuclei (Montplaisir, 1975; Jones and Webster, 1988) and the locus coeruleus (LC; Steriade and McCarley, 1990), which consist principally of noradrenergic neurons. Conversely, during REM the monoaminergic (noradrenergic and serotoninergic) neurons are silent (Hobson et al., 1975; McGinty and Harper, 1976). It is possible to distinguish brain mechanisms involved in attention from arousal, thanks to changes in task performance following manipulations known to affect attention (De Gangi and Porges, 1990; Schiff and Plum, 2000; Fadel and Burk, 2010). In this case, the interpretation of data resulting from these manipulations is primarily based on behavioral performance data (e.g., detection rates, false alarm rates, etc.) (Sarter and Bruno, 1999; Sarter et al., 2001). The relationship between arousal and attention is not simple. Attentional performance improves with a moderate increase of arousal but drops dramatically during high excitement state (Easterbrook, 1959). On the other hand, sustained attention reduces arousal and induces drowsiness (Babkoff et al., 1991).

Furthermore, physiological studies and data collected on patients suffering from injuries or neurological diseases provide a wealth of information on the neural mechanisms of attention processes. Thus, it is important to determine the brain networks mediating attention both to understand the neural mechanisms underlying these cognitive functions to expand knowledge on neurodevelopmental disorders characterized by impairments in attentional functions (Sarter et al., 2001; Esposito and Carotenuto, 2010, 2014; Carotenuto et al., 2016). Among these networks, the basal forebrain (BF) cholinergic system is considered as a major component of top-down processes in the mediation of attention, it is known to play a role in several aspects of attentional function (Fadel and Burk, 2010; Viggiano et al., 2014) and to be necessary for normal attentional performance (Sarter et al., 2001; Boschen et al., 2009). This system can be activated by different afferent inputs and can influence how attentional resources are allocated (Chieffi et al., 2009; Fadel and Burk, 2010). Among the various afferent inputs to the BF cholinergic projection system, the hypothalamus represents an important source of projections. The available data demonstrate that orexin neurons, whose cell bodies are present in the lateral hypothalamus, contribute substantially to these projections (Cullinan and Záborszky, 1991). Orexin neurons have widespread projections to a number of brain regions, including cholinergic BF structures. In the last decade, several studies have focused on specific neuronal pathways through which the orexin-producing neurons may promote not only arousal, but also attention. Their results suggest that the basal forebrain may be a key site through which these neurons act. In this article, we review the effects of orexin-producing neurons and their projection to the BF to support the hypothesis that orexin system may contribute to attentional processing through increased cortical-acetylcholine (Ach) release.

In the BF, cholinergic neurons are codistributed with several other cell populations, including GABAergic and various neurons containing calcium binding protein for example calbindin, calretinin or parvalbumin (Fadel and Burk, 2010). These neurons project to all areas and layers of the cortex (Sarter and Bruno, 1997). The cholinergic projections modulate the response of pyramidal cells to other cortical-glutamatergic inputs (McCormick, 1993), facilitating the bottom-up sensory information processing within the cortex (Figure 1; Muir et al., 1994; Sarter et al., 2001). Furthermore, the long radiating dendrites of the cholinergic BF neurons receive inputs from all the brainstem and hypothalamic arousal systems, for example cholinergic ponto-mesencephalic neurons, noradrenergic LC neurons, dopaminergic ventral-mesencephalic neurons, histaminergic tubero-mammillary neurons and orexinergic perifornical neurons (Jones and Cuello, 1989; Panula et al., 1989; Zaborszky and Cullinan, 1996; Peyron et al., 1998; Semba et al., 1998).

The cholinergic basal forebrain neurons have been implicated in mechanisms of synaptic plasticity, learning, memory, arousal and attention (McCormick, 1993; Leanza et al., 1996); all these functions are related to cortical activation (Jones, 2003). For instance, pharmacological manipulations of cholinergic receptors in extra-striate occipital and superior-medial parietal cortices affect attentional performance (Bentley et al., 2004), and lesions of the BF in monkeys also interfere with attention (Voytko et al., 1994).

The cholinergic basal forebrain neurons are hyperpolarized by ACh released by brainstem or forebrain neurons; both muscarinic and nicotinic receptors are involved in this effect, and could modulate the cortical and forebrain activity during particular states across the sleep–waking cycle (McCormick, 1993; Khateb et al., 1997). In the cerebral cortex and in the hippocampus, Ach release is maximal during wakefulness and REM sleep (Jasper and Tessier, 1971; Marrosu et al., 1995), while it decreases during non-REM sleep (Arrigoni et al., 2010). Inglis et al. (1994) suggested that the BF neurons may be involved, together with dopaminergic neurons, in the regulation of attention and in rewarding activities including food intake because high amount of Ach is released during eating. Many other neurotransmitters can excite the BF neurons, for example glutamate (Khateb et al., 1995a), noradrenaline (NA; Fort et al., 1995), histamine (Khateb et al., 1995a,b), orexin (Eggermann et al., 2001), or can inhibit them for example serotonin (Khateb et al., 1993).

The orexin/hypocretins are neuropeptides synthesized by a cluster of neurons within the postero-lateral hypothalamus that produce excitatory effects on target neurons. Two independent research groups discovered simultaneously these neuropeptides in the late 1990s. One group named these peptides orexins, from the Greek word “orexis”, meaning “appetite”, because they seemed to be involved in the control of feeding and metabolism (Sakurai et al., 1998; Sakurai, 2007). The other group named these peptides hypocretins, because these peptides share significant sequence homology with the members of the glucagon/vasoactive intestinal polypeptide/secretin (incretin) family (de Lecea et al., 1998). Therefore, as hypocretin, de Lecea et al. (1998), intended to indicate a hypothalamic member of the incretin family. However, the terms are interchangeable in the literature. Orexin-A (orexin-A/hypocretin-1, Orx-A) and orexin-B (orexin-B/hypocretin-2, Orx -B) are cleaved from a single gene product, prepro-orexin (Sakurai et al., 1998). Orexins act on two different G-protein coupled receptors: orexin 1 receptor (Orx1R), which binds selectively Orx A, and orexin 2 receptor (Orx2R), which binds both Orx-A and Orx-B with equal affinity (Sakurai et al., 1998; Sakurai, 2007). Orexin neurons also release other neurotransmitters, such as glutamate on histamine tubero-mammillary neurons (critical for the maintenance of arousal), the inhibitory neuropeptide dynorphin (which also modulate appetite) and pentraxin (regulator of AMPA receptors clustering; Chou et al., 2001; Reti et al., 2002; Schone et al., 2012). The orexin neurons may integrate a variety of interoceptive and homeostatic signals related to environmental, physiological and emotional stimuli to promote wakefulness and behavioral arousal in response to emotions, stress, hunger and circadian rhythms (Yoshida et al., 2006; Viggiano et al., 2009). Furthermore several brain regions involved in the central regulation of autonomic and endocrine processes or attention are targets of extensive orexin projections (Horvath et al., 1999; Chieffi et al., 2014a,b). Neurons containing the neuropeptide orexin send axons to numerous regions, throughout the central nervous system; their projections are widely distributed in the brain (Chemelli et al., 1999). These neurons innervate all brain regions known to promote wakefulness and arousal (Saper et al., 2005) including the cerebral cortex, BF, tubero-mammillary nucleus (TMN), LC, and dorsal raphe (DR; Peyron et al., 1998; Yoshida et al., 2006). Furthermore, they innervate brain nuclei that regulate motivation and emotions (Sakurai and Mieda, 2011; Thompson and Borgland, 2011; Di Bernardo et al., 2014), and brain regions that regulate motor and autonomic functions (Nattie and Li, 2012). Thus, the orexin system is anatomically well positioned to coordinate many aspects of arousal and attention (Alexandre et al., 2013). Indeed, the orexin neurons are important in regulation of sleep/wakefulness states and lack of the peptide or the receptor caused narcolepsy in humans, dogs and mice (Chemelli et al., 1999; Lin et al., 1999; Thannickal et al., 2000).

In attention regulation, orexins play a significant role likely via interactions with multiple ascending neuromodulatory systems, including dopamine neurons in the ventral midbrain (Vittoz and Berridge, 2006), noradrenergic neurons in the LC (Horvath et al., 1999; Espana et al., 2005) and the basal forebrain cholinergic system (Fadel and Burk, 2010). In the BF, orexin peptides increase cell activity and Ach release, thus they modulate attentional mechanisms (Fadel and Burk, 2010). Attentional deficits present in neurodegenerative conditions such as Alzheimer’s disease, schizophrenia, drug addiction, and age-related cognitive decline may be related with alterations in the interactions between orexin neurons and cortical ACh neurons (Fadel and Burk, 2010). An imbalance in orexin regulation may also be involved in the pediatric Attention Deficit Hyperactivity Disorder syndrome (ADHD), comprising cognitive alterations, and in narcoleptic and/or obese and/or migrainous subjects as summarized in the Prader-Willi syndrome (Cortese et al., 2008; Carotenuto et al., 2009; Verrotti et al., 2013, 2015a,b; Morandi et al., 2015; Miano et al., 2016). Orexin neurons activity varies with the degree of arousal and is linked to heightened attentional states. Their activity promotes arousal, with maximal discharge during active wakefulness (Lee et al., 2005; Mileykovskiy et al., 2005; Viggiano et al., 2010), while their discharge decreases during quiet waking, in the absence of movement, and are silent in slow wave sleep and tonic periods of REM sleep, with occasional burst of activity during REM sleep (Lee et al., 2005; Mileykovskiy et al., 2005). In addition to arousal, orexins promote eating and are likely to have a role in physiological functions such as regulation of blood pressure, the neuroendocrine system, body temperature, and energy homeostasis (Peyron et al., 1998; Hara et al., 2001; Jones, 2003; Messina et al., 2014). Blouin et al. (2013) demonstrated that, in the human brain, Orx-A levels are maximal during positive emotion, social interaction, anger and increase at wake onset, suggesting that these levels are linked to specific emotions and state transitions.

Orexin neurons are controlled by positive and negative feedback mechanisms mediated by the lateral hypothalamus/perifornical area (LH/PFA; Figure 2). The Orx2R, Orx-A or Orx-B form a positive-feedback loop which opens nonselective cation channels and depolarizes orexin neurons and modulates presynaptic glutamate release (Yamanaka et al., 2010). Indirectly, glutamatergic transmissions stimulate orexin neurons through glutamate activation of astrocytes that release lactate and protons into the extracellular space through monocarboxylate transporters (MCTs; Pellerin et al., 1998; Burt et al., 2011). Furthermore, to sustain physical activity, orexin neurons metabolize astrocyte-derived lactate as an energy source; moreover, the release of protons due to MCT activity causes a local decrease in extracellular pH that can result in depolarization of orexin neurons (Williams et al., 2007). Even adenosine triphosphate (ATP), released by astrocytes and neurons, has an excitatory effect on orexin neurons through the ionotropic P2X receptors (Wollmann et al., 2005). ATP can be hydrolyzed by ectonucleotidases releasing adenosine in the extracellular space (Wall and Dale, 2008) which inhibits voltage-gated Ca²⁺ currents in orexin neurons leading to their inhibition (Liu and Gao, 2007). Negative feedback pathways have also been identified, for example Dynorphin and Nociceptin/Orphanin FQ (N/OFQ), either co-expressed by orexin neurons (Chou et al., 2001; Maolood and Meister, 2010). Dynorphin attenuates glutamate release acting on presynaptic excitatory terminals, while N/OFQ inhibits both excitatory and inhibitory transmission (Li and van den Pol, 2006). The balance between the excitatory and inhibitory effects determines the activity levels of the postsynaptic cell (Burt et al., 2011). In addition, the glutamate released synaptically creates a negative feedback loop acting on presynaptic autoreceptors to inhibit glutamate and GABA released through group III metabotropic glutamate receptors (mGluRs; Acuna-Goycolea et al., 2004). Even other distinct neuronal populations in the LH/PFA create synaptic contacts with orexin neurons for example neurons expressing melanin concentrating hormone (MCH) and leptin receptor-expressing (LepRb+) neurons. The MCH neurons form reciprocal connections with orexin neurons and are directly depolarized by Orexin A and B which stimulate presynaptic glutamate release, whereas dynorphin and N/OFQ directly induce hyperpolarization of MCH neurons (Li and van den Pol, 2006). MCH can reduce the presynaptic glutamate release induced by orexin receptors to antagonize the excitatory effects on orexin neurons (Rao et al., 2008). Leptin receptor-expressing (LepRb+) neurons are excited by leptin and use GABA as a neurotransmitter (Leinninger et al., 2009). Leptin inhibits orexin neurons through hyperpolarization of these neurons (Yamanaka et al., 2003), because the activation of the LepRb+ neurons produces an inhibition of orexin neurons (Burt et al., 2011). Orexin neurons are also innervated by afferents of non-cholinergic terminals from the BF cholinergic cell area. BF glutamatergic neurons can excite orexin neurons involved in arousal, whereas GABAergic neurons can inhibit orexin neurons promoting behavioral quiescence and sleep (Henny and Jones, 2006). In summary, different peptides released by orexin neurons or distinct populations of LH/PFA neurons modulate orexin neurons and exert different excitatory and inhibitory influences during wake or sleep states. Others studies showed that LC neurons have an important role in waking and REM sleep (REMS; Mallick et al., 2012; Choudhary et al., 2014). Kumar et al. (2012) have constructed a mathematical model of waking, NREMS and REMS, showning the importance of orexinergic neurons in stabilizing the wake-sleep cycle and demonstrating that even small changes in inputs to or from those neurons can have a large impact on the ensuing dynamics. The results from this model help to understand the neural mechanisms of regulation and the patho-physiology of REMS.

Collectively, the available data strongly support the hypothesis that orexin stimulation of the BF is able to promote cortical activation and attention by acting on cholinergic and non-cholinergic neurons in response to salient stimuli. In fact, orexins excite cholinergic neurons, thus the increase in acetylcholine release within the cerebral cortex contributes to the cortical activation associated with attention. We have reviewed evidence suggesting that the BF may be a key target through which orexin neurons promote attention, even if many questions remain to be answered. Defining if orexin signaling in the BF is sufficient to maintain attention and the interaction between orexin and dynorphin within the BF should provide novel data to explain the role of orexin in several aspects of attention.

IV, AM, MC and AVa carried out the study; AVi, FM, TE, VM, ME and FP participated in the design of the study; SC, GC, MM and GM participated in the design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.