Two Routes to Incidental Memory under Arousal: Dopamine and Norepinephrine

Dopamine rather than norepinephrine supports biased memory selectivity, which may pervade multiple stages of memory processing

A growing body of work suggests that dopamine may enhance memory selectivity for salient information across multiple stages of memory (Shohamy and Adcock, 2010; Murty and Adcock, 2017). However, because the experiment in Hauser et al. (2019) was conducted within a single session, it is unclear which stage was affected by amisulpride to reduce memory selectivity. First, amisulpride may have reduced the preferential encoding or postencoding consolidation of salient stimulus features (i.e., font). Past work shows that this drug abolishes enhanced memory for highly emotional stimuli, which tend to be prioritized due to their salience and relevance to survival (Gibbs et al., 2007). Moreover, this amisulpride effect was observed 1 week after encoding, suggesting that the drug affected early stages of memory processing as opposed to retrieval. Dopamine may also serve to broaden the scope of attention and encoding processes (Clewett and Murty, 2019), such that individuals would encode both task-relevant perceptual features and task-irrelevant semantic information. This broadening of encoding may have left more information available to cue subsequent word retrieval, leading to better memory for different-font words.

Another, nonmutually exclusive possibility is that D2/D3 receptor blockade reduced biased memory selectivity by upregulating hippocampal pattern completion at retrieval (Clos et al., 2019), a process by which partial sensory cues lead to a spread of activation through entire hippocampal memory representations (Duncan and Schlichting, 2018). Here, the semantic information in the word displayed in a different font could be acting as a weaker, partial memory cue for the original word, creating an opportunity for dopamine to modulate pattern completion. While the authors' neural gain hypothesis predicts that the drugs should affect memory for both same-font and different-font words, a pattern completion hypothesis predicts that the drugs should primarily influence memory for different-font words. A qualitative assessment of the data seems to support the latter possibility, with amisulpride predominantly improving memory for different-font words and having little effect on memory for same-font words.

This potential enhancement in pattern completion under amisulpride could be possible due to the interdependence of dopamine receptor families, as antagonizing D2/D3 is not necessarily thought to block all dopamine signaling, but rather to allow excitatory D1 states to predominate. Thus, the current results could also have been driven by enhanced D1-type receptor states of excitation (Kahnt and Tobler, 2016, 2017). The predominant D1 state induced by amisulpride could, then, potentially facilitate a pattern completion process that allows the partial cue to activate the remainder of the representation, thereby leading to successful word recognition.

Interestingly, the authors linked potential gain-related effects on memory selectivity specifically to D2/D3 receptors, despite norepinephrine being predominantly implicated in enhancing neural gain (Aston-Jones and Cohen, 2005; Mather et al., 2016). Considering the task performed, the null effect of β-adrenoreceptor blockade on memory selectivity may have been due to endogenous arousal levels not being high enough to engage the effects of β-adrenoreceptors on memory. This interpretation is rooted in the idea that β-adrenoreceptors may enhance neural gain (i.e., selectivity) by upregulating strong glutamatergic input that transmits high priority, task-relevant representations (Mather et al., 2016). However, because β-adrenoreceptors have a low binding affinity for norepinephrine, they are only likely to be engaged under very high levels of arousal, such as during emotional or motivationally significant events. Supporting this idea, Hauser et al. (2019) specifically linked the arousal-enhancing effects of reward on overall word recognition to β-adrenoreceptors, suggesting that phasic increases in arousal are necessary for norepinephrine to boost memory (Mather et al., 2016).

Norepinephrine rather than dopamine may mediate the beneficial effects of surprise-related arousal on immediate memory

When specifically targeting the effects of arousal on incidental memory, Hauser et al. (2019) found that, whereas the control and amisulpride (blocked dopamine) group showed enhanced memory for words associated with surprising rewards, the propranolol group (blocked norepinephrine) showed no such enhancement. At first blush, it may be surprising that amisulpride did not reduce the effects of arousal on memory, given that the mnemonic benefits of reward delivery are often associated with dopamine signaling (Shohamy and Adcock, 2010). However, this lack of a D2/D3 receptor effect may be due to the delay between study and test: increasing evidence suggests that dopamine's effects on reward-related memory may only emerge after a period of consolidation (Murayama and Kitagami, 2014; Stanek et al., 2019). Thus, because Hauser et al. (2019) only tested memory after a 20 min delay, it is possible that there was not a long enough delay for dopamine elicited by reward to selectively consolidate reward-related information. In future studies, manipulating the delay between encoding and retrieval would be beneficial for two reasons. It would enable researchers both to measure whether reward-related effects of norepinephrine and dopamine on incidental memory differ as a function of consolidation and to disentangle the effects of these two neuromodulators on encoding and retrieval processes (as discussed above).

Another possible reason why amisulpride did not affect the arousal-related memory boost was that the rewards were delivered randomly. This unpredictability may have reduced the utility of generating predictions about potential reward outcomes, which would prevent the dopaminergic system from generating prediction errors (Schultz, 1997). While prior work suggests that prior rewards may be able to enhance memory in an immediate memory test, these effects are driven by the prediction errors elicited by rewards rather than by the reward's absolute value (Jang et al., 2019). Integrating a learning component into the experiment of Hauser et al. (2019) (i.e., manipulating the predictability of reward via a characteristic of the word itself) might therefore uncover effects of D2/D3 receptor blockade on memory, as the dopaminergic system would more likely be engaged when an expectation of reward is violated. In this type of design, reinforcement learning models could also be fitted to the data to explicitly measure the degree of reward prediction error, which may predict the likelihood that the mnemonic benefits of reward are blocked under amisulpride (Rouhani and Niv, 2019).

In conclusion, Hauser et al. (2019) used pharmacological manipulations to disentangle both dopamine's role in memory selectivity and norepinephrine's role in arousal-mediated memory. In future studies, an examination of the interactions between attention, arousal, and reward structure could help to further dissociate the role these neuromodulatory systems play in memory processing. Importantly, combining fMRI with targeted pharmacological manipulations would also enable more direct measurements of how catecholamines influence the dynamic reorganization of the large-scale functional brain networks that coordinate attentional and memory selectivity (M. Warren, 2016; Murty and Adcock, 2017). While the role of dopaminergic and noradrenergic systems in modulating cognitive states has been well established, further characterization of their interdependence would reveal fundamental principles of how the brain captures and stores specific information in memory.