Regulation of neocortical circuits by ascending regulatory systems involves all of the classic neurotransmitters. Most of the nuclei located in the brainstem, hypothalamus, and basal forebrain not only are reciprocally connected, but also send direct projections to the neocortex (Jones Reference Jones2011; Saper et al. Reference Saper, Fuller, Pedersen, Lu and Scammel2010; Steriade & McCarley Reference Steriade and McCarley2005). The same applies to release by the hypothalamic nuclei of neuropeptides such as orexin/hypocretin in wakefulness and melanin-concentrating hormone (MCH) in rapid-eye-movement (REM) sleep (Aracri et al. Reference Aracri, Banfi, Pasini, Amadeo and Becchetti2015; Jones & Hassani Reference Jones and Hassani2008; Monti et al. Reference Monti, Torterolo and Lagos2013; and references therein). As a first approximation, these bewildering intricacies can be simplified by focusing on the balance in activity between noradrenergic and cholinergic nuclei, which are crucial regulators of arousal and cognition (e.g., Constantinople & Bruno Reference Constantinople and Bruno2011; Schmidt et al. Reference Schmidt, Chew, Bennett, Hammad and Frölich2013). Both project varicose fibers that widely innervate the neocortex, and their global effects are excitatory. During wakefulness, high levels of norepinephrine (NE) and acetylcholine (ACh) cooperate in regulating arousal and cognitive processes. However, although cholinergic transmission is certainly implicated in synaptic plasticity (e.g., Berg Reference Berg2011), the physiological action of NE is thought to be more persistent and more closely related to memory retention and consolidation (e.g., Constantinople & Bruno Reference Constantinople and Bruno2011; McGaugh Reference McGaugh2013; Schmidt et al. Reference Schmidt, Chew, Bennett, Hammad and Frölich2013). The activity of noradrenergic and cholinergic neurons decreases during non-REM (NREM) sleep, whereas in REM sleep, ACh release increases again, whereas NE activity remains low (Datta Reference Datta2010; Lee et al. Reference Lee, Hassani, Alonso and Jones2005; Saper et al. Reference Saper, Fuller, Pedersen, Lu and Scammel2010; Takahashi et al. Reference Takahashi, Kayama, Lin and Sakai2010) (Fig. 1). The fact that neocortex activation in REM sleep is sustained mainly by ACh is a further indication that the cholinergic tone is more directly related to consciousness and executive functions. In fact, the role of REM sleep in memory consolidation remains controversial (Ackermann & Rasch Reference Ackermann and Rasch2014; Rasch & Born Reference Rasch and Born2013).

Figure 1. Cholinergic and noradrenergic activity through the sleep–wake cycle. The scheme provides a qualitative comparison of the activity of the ascending cholinergic and noradrenergic projections, with no pretension of quantitative precision. AU=arbitrary units.

Does the GANE model help suggest possible explanations of the different functional consequences of activating these regulatory systems during brain states? A first central assumption is that, under strong neuronal activation, spillover glutamate stimulates nearby NE varicosities in an N-methyl-D-aspartate (NMDA) receptor-mediated manner. By activating low-affinity β-adrenoreceptors, high NE release would stimulate neuronal excitability, as well as glutamatergic terminals, thus constituting activity “hotspots” that effectively amplify inputs with high priority under phasic arousal. Are such hotspots possible in the cholinergic system? Not much is known about the glutamatergic regulation of ACh release, but evidence does exist of ionotropic glutamate receptors regulating cholinergic terminals in the neocortex (Ghersi et al. Reference Ghersi, Bonfanti, Manzari, Feligioni, Raiteri and Pittaluga2003; Parikh et al. Reference Parikh, Man, Decker and Sarter2008). Hence, it is conceivable that spillover glutamate also stimulates cholinergic fibers. Because it is well known that ACh increases glutamate release (Marchi & Grilli Reference Marchi and Grilli2010), a positive feedback loop could generate local ACh hotspots, analogous to those hypothesized by Mather and colleagues.

A second tenet of the GANE model is that the low-threshold α2-adrenoreceptors, by responding to low NE concentrations, would inhibit glutamate release in pathways implicated in low priority signaling, under aroused conditions. In this respect, the cholinergic system presents several differences compared with the noradrenergic. In particular: (1) cholinergic fibers form both well-differentiated point-to-point synapses and axon varicosities that sustain diffuse ACh release (Dani & Bertrand Reference Dani and Bertrand2007); and (2) ACh activates both metabotropic (muscarinic, mAChRs) and ionotropic (nicotinic, nAChR) receptors. In prefrontal regions, M1 mAChRs are widespread and produce excitatory effects related to working memory through different cellular mechanisms (e.g., McCormick & Prince Reference McCormick and Prince1986; Gulledge et al. Reference Gulledge, Bucci, Zhang, Matsui and Yeh2009; Proulx et al. Reference Proulx, Suri, Heximer, Vaidya and Lambe2014). Their EC₅₀ for ACh is in the low μM range. On the other hand, nAChRs can be divided into two functional classes (Dani & Bertrand Reference Dani and Bertrand2007). Heteromeric nAChRs have high affinity for ACh (with EC₅₀ in the μM range), relatively low permeability to Ca²⁺ (P_Ca), and slow desensitization in the presence of agonist. Homomeric nAChRs have high P_Ca (in the order of the one displayed by NMDA receptors), but low affinity for ACh (EC₅₀ ≈ 200 µM), and quick desensitization kinetics. A striking difference with NE transmission is immediately apparent. The long-term effects on synaptic consolidation are thought to depend on Ca²⁺ signals. However, within the putative ACh hotspots, the efficacy of high-P_Ca homomeric receptors would be blunted by quick desensitization. High ACh concentrations would also tend to desensitize heteromeric nAChRs. This would prevent sustained Ca²⁺ entry through nAChRs as well as by nAChR-dependent activation of glutamate release, and thus of NMDA receptors. Therefore, it seems unlikely that ACh hotspots can produce long-term cellular effects considerably different from those produced by lower ACh concentrations.

In summary, by following up the GANE model reasoning, one is led to conclude that low and high concentrations of NE and ACh produce distinct functional effects on neocortical networks. Low to moderate ACh release sustains global neocortex arousal in both wakefulness and REM sleep. However, in the absence of NE activity (as in REM sleep), cholinergic activity is unable to yield long-term synaptic changes, such as those implicated in memory retention, which would partly explain the well-known difficulty of recalling oneiric activity. Instead, high levels of ACh seem more able to shape the rapid synaptic responses implicated in executive functions, as the quick kinetics of the low-affinity nicotinic ACh receptors would suggest. We believe that deeper functional studies of the interplay between the ascending regulatory systems, led by heuristic models such as GANE, will greatly lead to progress in understanding the physiological basis of cognition.