Noradrenaline mediates amygdala activation in men and women during encoding of emotional material
Introduction
A critical function of the human amygdala is the processing of emotional information. This process varies from the perception of stimuli that have emotional significance (Anderson and Phelps, 2001) to the continuing stages in the memory process. Exposure to aversive stimuli in multiple sensory modalities induces activation of the amygdala. Several imaging studies using a variety of visual, auditory, olfactory, or gustatory stimuli evoked amygdala activation in humans. Even unpleasant interoceptive or painful sensations appear to induce amygdala activation (Zald, 2003). Although the activation pattern of the amygdala was consistently found in reaction to aversive stimuli (Fischer et al., 2003, Garrett and Maddock, 2001, O'Doherty et al., 2001, Phan et al., 2004, Phelps et al., 2001, Stark et al., 2003, Zald and Pardo, 2002), activation was also found in reaction to positively valenced stimuli from multiple sensory modalities (Garavan et al., 2001, Hamann et al., 1999, Lane et al., 1997, Lane et al., 1999). Recent findings also provide evidence for a role of the amygdala in reaction to visual sexual stimuli as contrasted with nonsexual stimuli (Canli and Gabrieli, 2004, Hamann et al., 2004) as well as for an important role in regulating human sexual behavior (Baird et al., 2004). It appears that all these responses are modulated by the arousal level, hedonic strength, or motivational value of the stimuli.
With respect to the role of the amygdala in memory processes, this structure was shown to be active during the encoding of emotional stimuli (Adolphs et al., 2000, Cahill et al., 1996, Canli et al., 2000, Hamann et al., 1999) or emotional context (Erk et al., 2003). Other studies stressed the important role of the amygdala in enhancing the strength of long-term memory for emotional stimuli, hence its role in consolidation processes (Cahill et al., 1996, McGaugh et al., 1996). The role of the amygdala as part of a neural network in relation to emotional memory was put forward in several studies. Two of these recent reports stressed the importance of the interaction between the amygdala and hippocampus that appears to be essential for a successful encoding and consolidation of emotional stimuli and situations (Phelps, 2004, Richardson et al., 2004). A recent path analysis using structural equation modeling also addressed aspects of the ‘memory modulation hypothesis’. They showed increased functional connectivity between the amygdala and the ipsilateral parahippocampal gyrus and ventrolateral prefrontal cortex during emotional relative to a neutral film viewing condition (Kilpatrick and Cahill, 2003). Using event-related fMRI during encoding of emotional and neutral pictures, Dolcos et al. (2004) found support for the modulation hypothesis, stating that better memory for emotionally arousing events (compared with nonarousing neutral events) is due to an effect of the amygdala on the medial temporal lobe (MTL) memory system.
More anecdotal evidence shows that memories of emotionally arousing events tend to be more vivid and to persist longer than do memories of neutral events. Apparently, the relevance and salience of a stimulus is important in survival of the species. It seems likely that processing of emotional information is mediated by neurotransmitters that have a relation to arousal, such as noradrenaline.
In animal studies, noradrenaline was shown to be one of the essential neurotransmitters in the (basolateral) amygdala, related to emotional processing (McGaugh, 2000). Pharmacological findings indicate that activation of postsynaptic alpha1-adrenoreceptors potentiates beta-adrenoceptor-mediated activation of cAMP (cyclic Amino-Mono-Phosphate) formation (Ferry et al., 1999a, Ferry et al., 1999b). However, this has only been shown in animal studies, where noradrenergic agonists, such as clenbuterol, injected directly into the amygdala, improved memory performance in rats (Ferry and McGaugh, 1999). In contrast, noradrenaline antagonistic agents such as propranolol, atenolol, or zinterol, not only injected directly into the amygdala but also in several nuclei around the amygdaloidal complex and projecting on the amygdala, had the opposite (i.e., deteriorating) effect on later memory performance (Quirarte et al., 1997). These data support the hypothesis that the memory-modulating effect of the amygdala adrenergic system is mediated, at least in part, by the activation of beta-adrenoceptors in the amygdala.
In humans, central noradrenergic mechanisms appeared to be essential in memory performance for emotional material. Beta-adrenergic blockade with a central and peripheral acting agent (propranolol) did affect memory for emotional stimuli (Cahill et al., 1994, van Stegeren et al., 1998), whereas a peripherally acting betablocker (nadolol) did not have the same memory disturbing properties (van Stegeren et al., 1998). Moreover, stimulation of the central noradrenergic system with yohimbine resulted in the enhancement, whereas blockade with the betablocker metoprolol resulted in a reduction of recall and recognition of emotional material in man (O'Carroll et al., 1999). Until now, it has remained unclear where in the human brain these centrally acting noradrenergic receptors exert their effect.
In this study, we monitored amygdala activation with fMRI during encoding of sets of pictures after having taken a betablocker (a noradrenergic antagonist) on 1 day or a placebo on the second day. We wanted to test the specific hypothesis—known from the animal literature—that the amygdala is mediated by noradrenergic activation in the human brain as well. We hypothesized that if noradrenergic activation in the amygdala is essential in processing emotional information, amygdala activation under betablocker condition should be lower than under placebo condition, when subjects are confronted with emotional stimuli.
Section snippets
Subjects
Thirty right-handed subjects (15 male, 15 females; mean age 20.93 ± 2.38, ranging from 18 to 28 years) without medical or psychiatric history were selected after an introduction interview, where they were screened with the Symptom Check List (SCL-90) (mean score = 104.03 ± 9.48) and a biographic questionnaire. Screening with the SCL-90 was carried out and scored using normative ratings for a healthy population. All subjects fell in the “normal range” with scores ‘below average’ and ‘low’. This
Physiological measures
Heart rate was used as a marker to check for successful betablockade by propranolol. Heart rate was registered at baseline (BL), just before subjects entered the scanner (Pre-scan) and immediately after the scanning procedure (Post-scan) and was analyzed with a General Linear Model (GLM) (3 time × 2 drug). Baseline heart rate levels for all subjects were higher on day 1 compared to day 2 (P < 0.05), perhaps expressing a higher level of anticipation anxiety before the first scanning session
Discussion
The results of this study support our hypothesis about the role of noradrenaline in amygdala activation during the processing of emotional information. Neutral and very light emotional pictures do not activate the amygdala significantly compared with baseline levels, but negative emotional pictures lead to a significant increase in amygdala activation under placebo condition. When the (central and peripheral) noradrenergic receptors were ‘blocked’ with this dosage of 80 mg propranolol, amygdala
Acknowledgments
This study was supported by a grant from the Foundation for Behavioral and Educational Sciences of the Netherlands Organization of Scientific Research (NWO) and the CSC Amsterdam. The authors thank Martine Hoogman and Martine Baaij for their assistance.
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