The noradrenergic system is intimately related to the autonomic system and is thought to play a key role at the interface between arousal and cognition. The GANE (glutamate amplifies noradrenergic effects) theory proposes a complete account of that role, with an emphasis on the quantitative effect of noradrenaline on stimulus processing. This is in marked contrast to network reset theory, which emphasizes the qualitative effect of noradrenaline of updating the representation of the environment.

The GANE (glutamate amplifies noradrenergic effects) model described by Mather et al. offers a neurophysiological basis for the arousal mechanism which is essential for empirical aesthetics and Gestalt processing. More generally, the core principle of perception can be interpreted as a continuous processing of competing arousal states, yielding selective amplification and inhibition of percepts to deduce the meaning of a scene.

Bodily arousal modulates stimulus processing and memory, contributing to expression of emotional salience. The “glutamate amplifies noradrenergic effects” (GANE) model proposed by Mather and colleagues can be extended to account for the differential impact of interoceptive (notably cardiac afferent) signals on sensory processing. However, some emotion-specific effects, for example, for fear, may further depend on functional anatomical organisation of affect-related brain structures.

Previous work has suggested that an interaction between local selective (e.g., glutamatergic) excitation and global gain modulation (via norepinephrine) amplifies selectivity in information processing. Mather et al. extend this existing theory by suggesting that localized gain modulation may further mediate this effect – an interesting prospect that invites new theoretical and experimental work.

Within a predictive coding approach, the arousal/norepinephrine effects described by the GANE (glutamate amplifies noradrenergic effects) model seem to modulate the precision attributed to prediction errors, favoring the selective updating of predictive models with larger prediction errors. However, to explain how arousal effects are triggered, it is likely that different kinds of prediction errors (including interoceptive/affective) need to be considered.

Mather and colleagues' arguments require rethinking at the mechanistic level. The arguments on the physiological effects of norepinephrine at the cortical level are inconsistent with large parts of the literature. There is no evidence that norepinephrine induces local “hotspots”: Norepinephrine mainly decreases evoked responses; facilitating effects are rare and not localized. More generally, the idea that perception benefits from “local hotspots” is hardly compatible with the fact that neural representations involve largely distributed activation of cortical and subcortical networks.

Early experiences play a crucial role in programming brain function, affecting selective attention, learning, and memory. Infancy literature suggests an extension of the GANE (glutamate amplifies noradrenergic effects) model to conditions with minimal priority-map inputs, yet suggests qualifications by noting that its efficacy is increased when tonic levels of arousal are maintained in an optimal range, in manners that are age and exposure dependent.

It is suggested that the dentate gyrus and hilar region in the hippocampus perform memory selection and that the selectivity of the gating of memory by this circuit is modulated by the norepinephrine–glutamate loop described by Mather et al.

The function of emotion and its underlying neural mechanisms are often left underspecified. I extend the GANE (glutamate amplifies noradrenergic effects) model by examining its success in accounting for findings in emotion regulation. I also identify points of alignment with construction models of emotion and with the hypothesis that emotion states function to push neural activity toward rapid and efficient action.

We applaud Mather and colleagues' model, which emphasizes the neurobiological pathways by which affective arousal tunes attention and memory. This commentary offers a friendly discussion of several potential limitations of the theory. We suggest the model is strong when predicting task-driven demands but is limited when predicting the impact of individual biases, interpretations, and experiential feelings.

The glutamate amplifies noradrenergic effects (GANE) model emphasizes the role of focal glutamate–noradrenaline interactions in creating functional hotspots for prioritized processing of salient stimuli. Here, we briefly outline current evidence that synergistic action of noradrenaline and cortisol enables emotional stimuli to gain privileged access to amygdala–hippocampus circuits, eventually resulting in the formation of indelible memories and posttraumatic stress disorder (PTSD).

I argue that the GANE (glutamate amplifies noradrenergic effects) model basically explains an arousal-based amplification of emotional stimuli, whereas effects on neutral stimuli indicate a contextualization process aiming to reduce stimulus ambiguity. To extend the model's validity, I suggest distinguishing between internal and external emotional sources, as well considering the stimulus valence and addressing age-related differences in attention and memory preferences.

We summarize evidence that input to the apical tufts of neocortical pyramidal cells modulates their response to basal input. Because this apical amplification and disamplification provide intracortical mechanisms for prioritization, Mather and colleagues' arguments suggest that their effects are enhanced by noradrenergic arousal. Though that is likely, it has not yet been adequately studied. Their article shows that it should be.

Arousal is typically conceived as a key component of emotional response. We describe here the psychological processes thought to elicit arousal – in particular, the processes involved in the appraisal of affective relevance. The key role of relevance in attentional and memory processing, and its links with arousal, is discussed with respect to the GANE (glutamate amplifies noradrenergic effects) model described by Mather et al.

The study of sexual arousal is at the interface of affective and social neurosciences. Recent results regarding the motor correlates of sexual arousal demonstrating an early freezing response are in perfect accordance with the GANE (glutamate amplifies noradrenergic effects) model's sustaining the double role of the arousal dimension on emotional processing.

Mather and colleagues provide an impressive cross-level account of how arousal levels modulate behavior, and they support it with data ranging from receptor pharmacology to measures of cognitive function. Here we consider two related questions: (1) Why should the brain engage in different arousal levels? and (2) What are the predicted consequences of age-related changes in norepinephrine signaling for cognitive function?

The GANE (glutamate amplifies noradrenergic effects) theory posits a mechanism for amplifying noradrenergic modulatory actions and enhancing the processing of high-priority sensory signals for immediate or future experience-guided action. This theoretical construct is thought provoking with respect to the central processing of high-priority versus low-priority stimuli, but it requires some refinement to account for physiological fluctuations in NE efflux as a function of naturally occurring transitions in behavioral state and the experimentally observed phenomena associated with noradrenergic regulation of sensory signal transfer.

The emotion–cognition integration in Mather et al. can be extended by specifying the relationship between competition and arousal in the reverse direction. According to affective monitoring, competition raises arousal, which, when sustained, results in negative affect, evoking theta oscillations, and when resolved, in positive affect, evoking gamma oscillations. Competition should be considered a core process in both cognition and emotion.

In an adaptive memory system, events should be prioritized in memory based on their own significance, as well as the significance of preceding or following events. Here we argue that tag-and-capture models complement the GANE (glutamate amplifies noradrenergic effects) model by describing a mechanism that supports the transfer of memory benefits from one event to the next.

Mather and colleagues postulate that norepinephrine promotes selective processing of emotionally salient information through local “hotspots” where norepinephrine release interacts with glutamatergic activity. However, findings in rodents and humans indicate that norepinephrine is ineffective in modulating mnemonic processes in the absence of a functional amygdala. We therefore argue that emphasis should shift toward modulatory effects of amygdala-driven changes at the network level.