Endogenous noradrenergic activation and memory for emotional material in men and women
Introduction
Abundant evidence from animal studies suggests that noradrenergic activation is related to memory enhancement, particularly for emotionally arousing material. Post-training systemic, or intra-basolateral amygdala (BLA) infusions of adrenergic agonists, leads to retrograde memory enhancement (Ferry et al., 1999, Lalumiere et al., 2003, McGaugh et al., 1984, McGaugh et al., 1996, Soetens et al., 1995, Liang, 1985, Liang et al., 1986, Liang et al., 1990, Hatfield and McGaugh, 1999, Power et al., 2001). In contrast, post-training systemic or intra-BLA infusions of adrenergic antagonists produce retrograde memory impairment (Gallagher et al., 1977, Gallagher and Knapp, 1981, McGaugh et al., 1984, McGaugh et al., 1996, Cahill et al., 2000). A common interpretation of these findings is that stress hormones released during and after emotionally arousing events lead to noradrenergic activation in the BLA, resulting in enhanced memory for emotional events.
In addition to the pharmacological evidence that the adrenergic system is involved in memory modulation, there is evidence to suggest a strong relationship between training-induced endogenous noradrenergic activation, measured directly from the BLA using in vivo microdialysis, and retention of the training experience. Post-training BLA levels of norepinephrine (NE) increase directly with foot shock intensity (Galvez et al., 1996, Quirate et al., 1998) and the amount of increase in NE measured after acquisition of stressful learning tasks strongly correlates with memory performance for those tasks (Galvez et al., 1996, McIntyre et al., 2002). These findings converge with evidence from the pharmacological studies indicating that noradrenergic activation is critically involved in memory modulation for emotional events.
Pharmacological manipulation of the adrenergic system in humans also suggests its participation in modulating human memory for emotional material. In one such experiment, in which subjects viewed a series of images, post-training intra-venous administration of epinephrine enhanced recall 1 week later for those images associated with a greater arousal reaction at initial encoding (Cahill and Alkire, 2003). In another experiment, subjects received either placebo, yohimbine (an alpha-2 adrenergic antagonist), or metoprolol (a selective beta 1A-adrenergic antagonist) prior to viewing an emotional slide show. The results indicated that yohimbine subjects recalled significantly more, and the metoprolol subjects significantly fewer, images than did the placebo subjects (O’Carroll et al., 1999). Several human subject studies have also examined the effects of beta-adrenergic blockade on memory for emotional material via administration of propranolol, an adrenergic receptor blocker (Cahill et al., 1994, O’Carroll et al., 1999, Cahill and vanStegeren, 2003, van Stegeren et al., 1998, van Stegeren et al., 2005). In an experiment in which men and women viewed a range of emotionally arousing images (van Stegeren et al., 2005), beta-blockade significantly decreased amygdala activation in response to emotional, but not neutral pictures. Memory for emotional slides was also significantly reduced in the beta-blocker condition compared to the placebo condition.
Evidence from experiments that indirectly measure autonomic activity also suggests associations between psychophysiological indices of adrenergic activation and memory. Cahill and Alkire (2003) demonstrated enhanced recall for images that elicited higher electrodermal activity at the time of encoding. (Bradley et al., 1992) reported that high levels of arousal, as measured by skin conductance at the time of encoding were associated with faster recognition time. Collectively, these studies are consistent with the findings from animal research in pointing towards the critical role of NE in memory modulation. However, no prior study has related endogenous noradrenergic activation to memory for emotional events in humans, in part because of difficulties associated with measuring endogenous adrenergic activity.
Recently, a kinetic enzyme assay has been developed that measures concentrations of a salivary enzyme, alpha-amylase, a known biomarker for NE (Chatterton et al., 1996). Strong evidence indicates that measurement of this salivary enzyme is a superior assessment of central endogenous noradrenergic activation, as compared with measurement of NE via blood plasma (Ehlert et al., 2006). Alpha-amylase is an isoenzyme that is involved in the transformation of starch into glucose and maltose, and is present in saliva. Evidence from animal experiments, involving infusions of alpha- and beta-adrenergic drugs, indicates that secretion of salivary alpha-amylase (sAA) is primarily mediated by stimulation of beta-adrenergic receptors (Gallacher and Peterson, 1983, Skov et al., 1998). In addition, evidence from several pharmacological experiments in humans and animals supports the notion that sAA is a valid biomarker for noradrenergic activity. Alpha- and beta-adrenergic drugs, such as isoprenaline (beta-adrenergic agonists) and yohimbine (alpha-2 receptor antagonist) significantly increase sAA (Speirs et al., 1974, Ehlert et al., 2006). Conversely, beta-adrenergic antagonists such as atenolol, and propranolol significantly decrease sAA (Speirs et al., 1974, Nederfors and Dahlof, 1992, Nederfors et al., 1994, van Stegeren et al., 2005). There has been some controversy as to whether changes in sAA levels reflect alterations in plasma NE levels (Chatterton et al., 1996, Nater et al., 2006, Rohleder et al., 2004, Ehlert et al., 2006). However, the discrepancy in the correlations between blood plasma NE and sAA appears to reflect the difference in the origin of the sample and suggests that sAA is more reflective of central noradrenergic release (Ehlert et al., 2006). Norepinephrine measured in blood reflects adrenomedullary NE, as well as peripheral spill-over. Salivary alpha-amylase appears to be more accurate a measurement with respect to the timing of alterations in central NE, since animal research indicates that secretions of sAA result primarily from NE released from sympathetic nerves that innervate acinar cells in the parotid gland (Ehlert et al., 2006, Castle and Castle, 1998, Whelton, 1996). Norepinephrine binding to g-protein coupled receptors on the acinar cells of the parotid gland activates cAMP, resulting in the synthesis and secretion of alpha-amylase within approximately twenty seconds of NE binding to the receptors (Yoshimura et al., 2002). Thus the discrepancy between NE levels in the blood, and alpha-amylase levels in saliva is likely attributable to the difference in origin between central and peripheral NE (Ehlert et al., 2006). Furthermore, since alterations in sAA levels are detected almost immediately after NE binds to the receptor in these acinar cells, it is a much more accurate measurement of central NE activity than NE in blood plasma. The pharmacological evidence, along with the almost immediate sAA synthesis in response to norepinephrine binding, strongly indicates that sAA is an appropriate biomarker for endogenous noradrenergic activation in humans.
Evidence from several studies suggests that the adrenergic system is critically involved in memory enhancement for emotional, but not neutral material (O’Carroll et al., 1999, Cahill and vanStegeren, 2003, Strange and Dolan, 2004, Dolcos et al., 2004, van Stegeren et al., 2005). For example, experiments in animals as well as humans have demonstrated that administration of stress hormones such as epinephrine or cortisol enhanced memory for emotional, but not neutral material (Cahill and Alkire, 2003, Buchanan and Lovallo, 2001, Okuda et al., 2003, Rimelle et al., 2003, Kuhlman and Wolf, 2006, Roozendaal et al., 2006). There is evidence to suggest that stress hormones administered post-training interact with the degree of arousal at encoding, enhancing memory only for the material encoded with some degree of arousal (Okuda et al., 2003, Roozendaal et al., 2006).
If it is the case that noradrenergic activation is crucial to enhanced long-term memory for emotionally arousing material that induces NE release, then it should be possible to demonstrate a significant, positive relationship between the degree of endogenous NE activation in response to viewing emotional stimuli, and the strength of subsequent long-term memory for those stimuli. The primary goal of this experiment was to determine whether such a relationship could be detected in subjects for whom emotional material activated endogenous NE release, as indicated by sAA. In addition, and given the considerations described above, we hypothesized that increases in sAA after viewing images ranging in emotional intensity, would relate significantly to subsequent memory for emotional, but not neutral, material.
Section snippets
Subjects
Eighty-four healthy subjects (56 women; 28 men) between the ages of 18–35 were selected after an initial screening interview. Subjects were students at the University of California, Irvine and received either course credit or payment for participation in this experiment. Subjects were informed that they were participating in a study of physiological responses to emotion, and that the experiment would take place on two separate sessions, each measuring responses to different stimuli. All
Salivary alpha-amylase response
Of the 67 subjects who participated in this experiment, 24 displayed an increase in sAA as measured from the time point taken immediately after subjects viewed the IAPS images compared to sAA levels at baseline. These subjects will be referred to as “Responders”. The remainder of the 43 subjects did not display an increase in sAA in response to viewing the images. These subjects will be referred to as “Non-Responders”. For a summary of average sAA responses for Responders and Non-Responders
Discussion
The main finding from the current study was a significant positive correlation between the degree of endogenous noradrenergic activation, assessed via sAA, in response to viewing a series of emotionally arousing slides and subsequent long-term memory for the slides. More specifically, noradrenergic activation correlated significantly, and selectively, with memory for emotionally arousing slides. The results are the first to demonstrate in humans, that the degree of endogenous noradrenergic
Role of the funding source
Funding for this study was provided by NIMH Grant R01 MH57808. The NIMH had no further role in study design, data collection, analysis, and interpretation of data, writing of the report or the decision to submit the paper for publication.
Conflict of interest
This is to certify that there are no potential conflicts of interest for any contributors with respect to the data presented here.
Acknowledgement
We would like to thank the NIMH for funding for this study (NIMH Grant R01 MH57808).
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2021, Clinical Psychology ReviewCitation Excerpt :Specifically, it has been repeatedly demonstrated that emotional memories are prone to be more strongly consolidated than other memories, and this seems to be a result of noradrenergic activation at the time of encoding (McGaugh, 2000). This conclusion is indicated by findings that memory for emotional, but not neutral, stimuli is associated with endogenous noradrenergic activation at the point of encoding (Segal & Cahill, 2009). Further, administration of adrenergic receptor blockers decreases memory for emotional events (Cahill, Prins, Weber, & McGaugh, 1994), whereas beta-blockades reduce activation in the amygdala, as well as memory for emotional (but not neutral) material (van Stegeren et al., 2005).
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