Endogenous cortisol level interacts with noradrenergic activation in the human amygdala

Animal studies show that high cortisol levels exert their effect on stressful task performance via modulation of the amygdala. Availability of noradrenaline in this brain region appears to be a critical prerequisite for this effect. This relationship between noradrenaline and cortisol is explained by an animal model where the amygdala constitutes a crucial region for this interaction. In humans this model has not been extensively tested so far. In a previously reported study human subjects (aged 20.93+/-2.38) were scanned using fMRI when watching sets of emotional and neutral pictures after taking the beta-adrenergic antagonist propranolol or placebo. Stimulus sets consisted of 92 pictures, divided in four emotional categories that ranged from neutral scenes of domestic objects (CAT1) to extremely negative scenes of mutilation or accidents (CAT4). Confrontation with arousing emotional pictures, accompanied by increased noradrenaline levels, evoked increased amygdala activation under placebo but not under betablocker condition. This new and additional analysis of this data set was carried out to determine the effect of differential endogenous cortisol levels on amygdala activation. Cortisol levels during scanning were determined using salivary samples and subjects were post hoc divided in a High (n=14) and Low cortisol group (n=14). When subjects were watching emotional stimuli, presumably associated with enhanced noradrenaline (NA) levels, amygdala activation was contrasted between the two cortisol groups. We hypothesized that emotional stimuli would elicit more amygdala activation in the High than in the Low cortisol group. Here we demonstrate indeed a significant interaction effect of the endogenous cortisol level with increasing activation in the amygdala under placebo but not under betablocker condition, thereby extending the rodent based model of a synergistic effect of the two stress hormones to the human.     

The role of the noradrenergic system in emotional memory

This contribution is an overview on the role of noradrenaline as neurotransmitter and stress hormone in emotional memory processing. The role of stress hormones in memory formation of healthy subjects can bear significance for the derailment of memory processes, for example, in post traumatic stress disorder (PTSD). Increased noradrenaline levels lead to better memory performance, whereas blocking the noradrenergic receptors with a betablocker attenuates this enhanced memory for emotional information. Noradrenaline appears to interact with cortisol in emotional memory processes, varying from encoding to consolidation and retrieval. Imaging studies show that confronting human subjects with emotional stimuli results in increased amygdala activation and that this activation is noradrenergic dependent. The role of noradrenaline in other brain areas, such as hippocampus and prefrontal cortex, is shortly summarized. Finally, the pros and cons of a therapeutic application of betablockers in the (secondary) prevention of PTSD will be discussed.     

Interacting noradrenergic and corticosteroid systems shift human brain activation patterns during encoding

Emotionally arousing experiences are usually well retained, an effect that depends on the release of adrenal stress hormones. Animal studies have shown that corticosterone and noradrenaline – representing the two main stress hormone systems – act in concert to enhance memory formation by actions involving the amygdala, hippocampus and prefrontal cortex (PFC). Here we test whether interactions between these two stress hormone systems also affect human memory formation as well as the associated pattern of brain activation. To this end, forty-eight male human subjects received hydrocortisone, yohimbine or both before presentation of emotional and neutral pictures. Activity in the amygdala, hippocampus and PFC was monitored with functional Magnetic Resonance Imaging (fMRI) during encoding of these stimuli, when hormonal levels were elevated. Memory performance was tested 1 week later. We investigated whether an increased level of one of the two hormone systems would lead to differential effects compared to the combined application of the drugs on brain activation and memory performance. We report that the application of cortisol led to an overall enhancing effect on recognition memory, with no significant additional effect of yohimbine. However, during encoding the brain switched from amygdala/hippocampus activation with either hormone alone, to a strong deactivation of prefrontal areas under the influence of the combination of both exogenous hormones. Although we did not find evidence that exogenous stimulation of the noradrenergic and corticosteroid systems led to significant interaction effects on memory performance in this experiment, we conclude that stress hormone levels during encoding did differentially determine the activation pattern of the brain circuits here involved.     

The role of the amygdala in face perception and evaluation

Faces are one of the most significant social stimuli and the processes underlying face perception are at the intersection of cognition, affect, and motivation. Vision scientists have had a tremendous success of mapping the regions for perceptual analysis of faces in posterior cortex. Based on evidence from (a) single unit recording studies in monkeys and humans; (b) human functional localizer studies; and (c) meta-analyses of neuroimaging studies, I argue that faces automatically evoke responses not only in these regions but also in the amygdala. I also argue that (a) a key property of faces represented in the amygdala is their typicality; and (b) one of the functions of the amygdala is to bias attention to atypical faces, which are associated with higher uncertainty. This framework is consistent with a number of other amygdala findings not involving faces, suggesting a general account for the role of the amygdala in perception.     

催产素影响恐惧习得和消退的认知神经机制

恐惧是一种基本的情绪, 在人类的生存和适应中发挥着重要作用。先前的研究表明, 杏仁核、背侧前扣带回、脑岛等脑区是条件化恐惧习得的认知神经基础, 杏仁核、海马和腹内侧前额叶等脑区在恐惧消退过程中发挥重要作用。研究发现, 催产素与恐惧习得和恐惧消退过程密切相关。恐惧习得过程中, 催产素影响杏仁核、背侧前扣带回的活动, 影响杏仁核与背侧前扣带回和脑干间的功能连接, 促进或抑制恐惧习得过程; 恐惧消退过程中, 催产素影响了杏仁核和腹内侧前额叶的活动, 并且影响杏仁核与内侧前额叶和海马间的功能连接, 促进或抑制恐惧消退过程。未来研究应从性别差异、神经网络模型、身心发育和病理研究等角度展开, 力图深入理解催产素影响恐惧情绪加工的认知神经机制。     

框架效应的神经机制

框架效应指人们对一个客观上相同问题的不同描述有不同反应的现象。近年来的认知神经研究发现框架效应的产生,可能源自以杏仁核为代表的情绪过程,而以前扣带回与前额叶皮层为代表的认知过程对此可能起到抑制与监控的作用。单侧化研究揭示了大脑两半球所擅长的不同思维方式也可能对框架效应产生影响。未来的研究应整合框架效应的神经机制与理论解释、探索框架效应的领域特异性并探究框架效应的产生根源。     

The amygdala is involved in affective priming effect for fearful faces

The object of this study was to investigate whether the amygdala is involved in affective priming effect after stimuli are encoded unconsciously and consciously. During the encoding phase, each masked face (fearful or neutral) was presented to participants six times for 17ms each, using a backward masking paradigm. During the retrieval phase, participants made a fearful/neutral judgment for each face. Half of the faces had the same valence as that seen during encoding (congruent condition) and the other half did not (incongruent condition). Participants were divided into unaware and aware groups based on their subjective and objective awareness assessments. The fMRI results showed that during encoding, the amygdala elicited stronger activation for fearful faces than neutral faces but differed in the hemisphere according to the awareness level. During retrieval, the amygdala showed a significant repetition priming effect, with the congruent faces producing less activation than the incongruent faces, especially for fearful faces. These data suggest that the amygdala is important in unconscious retrieving of memories for emotional faces whether they are encoded consciously or unconsciously.     

Post-training unilateral amygdala lesions selectively impair contextual fear memories

The basolateral amygdala (BLA) and the dorsal hippocampus (dHPC) are both structures with key roles in contextual fear conditioning. During fear conditioning, it is postulated that contextual representations of the environment are formed in the hippocampus, which are then associated with foot shock in the amygdala. However, it is not known to what extent a functional connection between these two structures is required. This study investigated the effect on contextual and cued fear conditioning of disconnecting the BLA and dHPC, using asymmetrically placed, excitotoxic unilateral lesions. Post-training lesions selectively impaired contextual, but not cued, fear, while pretraining lesions resulted in a similar but nonsignificant pattern of results. This effect was unexpectedly observed in both the contralateral disconnection group and the anticipated ipsilateral control, which prompted further examination of individual unilateral lesions of BLA and dHPC. Post-training unilateral dHPC lesions had no effect on contextual fear memories while bilateral dHPC lesions and unilateral BLA lesions resulted in a near total abolition of contextual fear but not cued conditioned fear. Again, pretraining unilateral BLA lesions resulted in a strong but nonsignificant trend to the impairment of contextual fear. Furthermore, an analysis of context test-induced Fos protein expression in the BLA contralateral to the lesion site revealed no differences between post-training SHAM and unilateral BLA lesioned animals. Therefore, post-training unilateral lesions of the BLA are sufficient to severely impair contextual, but not cued, fear memories.     

应激诱发复吸的动物模型及其神经生物学基础

复吸是药物成瘾的重要特征,应激是诱发复吸的因素之一。该文介绍了用于研究应激诱发复吸的动物恢复模型,阐述了涉及应激诱发复吸的神经生物学基础。大量研究结果表明,下丘脑外侧的终纹床核与杏仁核内的促肾上腺皮质激素释放因子和去甲肾上腺素是参与应激诱发复吸的重要神经递质。内侧前额叶皮层可能是介导应激、药物点燃及药物相关线索等各类因素诱发复吸的共同通路     

Is the contribution of the amygdala to the sex- and enhancement-related effects of emotional memory time-dependent?

A new focus in the field of emotional memory is the study of sex-related differences. Whether the sex-related lateralization of amygdala function (i.e., the female-left/male-right effect) in the emotional enhancement of memory (EEM) is time-dependent remains unclear. To evaluate this phenomenon, we conducted a two time-point study (20 min vs. 24 h) using fMRI and behavioral paradigms. We found that the right amygdala predicted 20-min EEM, while the left amygdala predicted 24-h EEM. The sex-related lateralization of amygdala function was not detected in either the 20-min or the 24-h EEM. Our results further confirm and extend the idea that the amygdala exhibits a lateralized and time-dependent dissociation, occurring even in the 24-h EEM relative to the 20-min EEM. The present and previous studies indicate that sex-related lateralization of amygdala function occurs in the 2- to 3-week EEM, but it does not occur in the 1-week, 24-h, or less than 30-min EEM, suggesting that this effect on emotional memory may also be time-dependent.     

The amygdala, reward and emotion

Recent research provides new insights into amygdala contributions to positive emotion and reward. Studies of neuronal activity in the monkey amygdala and of autonomic responses mediated by the monkey amygdala show that, contrary to a widely held view, the amygdala is just as important for processing positive reward and reinforcement as it is for negative. In addition, neuropsychological studies reveal that the amygdala is essential for only a fraction of what might be considered 'stimulus-reward processing', and that the neural substrates for emotion and reward are partially nonoverlapping. Finally, evidence suggests that two systems within the amygdala, operating in parallel, enable reward-predicting cues to influence behavior; one mediates a general, arousing effect of reward and the other links the sensory properties of reward to emotion.     

Emotion-specific modulation of early visual perception

Exposure to fearful facial expressions enhances vision at low spatial-frequencies and impairs vision at high spatial-frequencies. This perceptual trade-off is thought to be a consequence of a fear-related activation of the magnocellular visual pathway to the amygdala. In this study we examined the generality of the effect of emotion on low-level visual perception by assessing participants' orientation sensitivity to low and high spatial-frequency targets following exposure to disgust, fear, and neutral facial expressions. The results revealed that exposure to fear and disgust expressions have opposing effects on early vision: fearful expressions enhanced low spatial-frequency vision and impaired high spatial-frequency vision, while disgust expressions, like neutral expressions, impaired low spatial-frequency vision and enhanced high spatial-frequency vision. Thus we show the effect of exposure to fear on visual perception is not a general emotional effect, but rather one that may that depend on amygdala activation, or one that may be specific to fear.     

Conditioning Method Dramatically Alters the Role of Amygdala in Taste Aversion Learning

Although an important role for the amygdala in taste aversion learning has been suggested by work in a number of laboratories, results have been inconsistent and interpretations varied. The present series of studies reevaluated the role of the amygdala in taste aversion learning by examining the extent to which conditioning methods, testing methods and lesioning methods, influence whether amygdala lesions dramatically affect conditioned taste aversion (CTA) learning. Results indicated that when animals are conditioned with an intraoral (I/O) taste presentation, lesions of amygdala eliminate evidence of conditioning whether animals are tested intraorally or with a two-bottle solution presentation. Dramatic effects of amygdala lesions on CTA learning were seen whether lesions were made electrolytically or using an excitotoxin. In contrast, when animals were conditioned using bottle presentation of the taste, electrolytic lesions attenuated CTAs but did not eliminate them, and excitotoxic lesions had no effect. These results are consistent with the hypothesis that neural structures critical for CTA learning may differ depending on the extent to which the method of conditioned stimulus delivery incorporates a response component.     

The interplay of attention and emotion: top-down attention modulates amygdala activation in psychopathy

Psychopathic behavior has long been attributed to a fundamental deficit in fear that arises from impaired amygdala function. Growing evidence has demonstrated that fear-potentiated startle (FPS) and other psychopathy-related deficits are moderated by focus of attention, but to date, no work on adult psychopathy has examined attentional modulation of the amygdala or concomitant recruitment of relevant attention-related circuitry. Consistent with previous FPS findings, here we report that psychopathy-related differences in amygdala activation appear and disappear as a function of goal-directed attention. Specifically, decreased amygdala activity was observed in psychopathic offenders only when attention was engaged in an alternative goal-relevant task prior to presenting threat-relevant information. Under this condition, psychopaths also exhibited greater activation in selective-attention regions of the lateral prefrontal cortex (LPFC) than did nonpsychopaths, and this increased LPFC activation mediated psychopathy’s association with decreased amygdala activation. In contrast, when explicitly attending to threat, amygdala activation did not differ in psychopaths and nonpsychopaths. This pattern of amygdala activation highlights the potential role of LPFC in mediating the failure of psychopathic individuals to process fear and other important information when it is peripheral to the primary focus of goal-directed attention.     

Chronic nicotine exposure induces a long-lasting and pathway-specific facilitation of LTP in the amygdala

Nicotine, in the form of tobacco, is the most commonly used drug of abuse. In addition to its rewarding properties, nicotine also affects many cognitive and emotional processes that involve several brain regions, including hippocampus and amygdala. Long-term changes in synaptic strength in these brain regions after drug exposure may be importantly correlated with behavioral changes induced by nicotine. Here, we study the effect of chronic oral administration of nicotine on the long-term synaptic potentiation in the amygdala, a key structure for emotional memory. We find that oral administration of nicotine for 7 d produces a significant enhancement of LTP in the amygdala. This facilitation is pathway specific: Nicotine selectively facilitates LTP in the cortical-lateral amygdala pathway, but not the thalamic-lateral and the lateral-basolateral synaptic pathway. The synaptic facilitation induced by a 7-d exposure to nicotine is long-lasting, it persists for 72 h after cessation of nicotine but decays 8 d after its cessation. In contrast, a shorter exposure of nicotine (24 h) induces only a short-lasting facilitation of synaptic plasticity that dissipates 24 and 72 h after cessation of nicotine. The facilitation of LTP in the amygdala after exposure to nicotine is mediated by removal of GABAergic inhibition, is dependent on the activation NMDA receptors, and can be prevented by blocking either α7 or β2 nACh receptors. Our results indicate that chronic exposure to nicotine can promote the induction of long-lasting modifications of synapses in a specific pathway in the amygdala.These changes in synaptic plasticity may contribute to the complex neural adaptations and behaviors caused by nicotine.     

Flavor-illness aversions: potentiation of odor by taste is disrupted by application of novocaine into amygdala

Taste and odor have different properties in toxiphobic conditioning. When each is used alone, taste becomes aversive when followed by immediate or delayed poison, while odor becomes aversive only if followed by immediate poison. However, if odor and taste are presented as a compound and followed by delayed poison, then odor does become aversive when tested alone. It is as if taste has potentiated the odor signal. Several experiments assessed the role of the amygdala in this potentiation effect by anesthetizing the amygdala with 10% novocaine. Novocaine applied 30 min before presentation (Pre-CS) of an odor-taste compound disrupted the potentiated odor aversion but not the taste aversion. In contrast, novocaine applied 1 min after the compound odor-taste or 1 min prior to LiCl poison did not dissociate odor and taste aversions; both odor and taste aversions were facilitated. Novocaine applied 30 min before an odor alone also disrupted an odor aversion induced by immediate LiCl. But identical treatment did not disrupt odor avoidance conditioned by immediate foot-shock, suggesting that amygdala anesthesia does not simply produce anosmia. Pre-CS novocaine treatment also disrupted flavor neophobia prior to conditioning. The results suggest that novocaine applied to the amygdala disrupts the integration of odor with taste and illness during toxiphobic conditioning.     

Automaticity and the Amygdala: Nonconscious Responses to Emotional Faces

The human face is an evolved adaptation for social communication. This implies that humans are genetically prepared to produce facial gestures that are automatically decoded by observers. Psychophysiological data demonstrate that humans respond automatically with their facial muscles, with autonomic responses, and with specific regional brain activation of the amygdala when exposed to emotionally expressive faces. Attention is preferentially and automatically oriented toward facial threat. Neuropsychological data, as well as a rapidly expanding brain-imaging literature, implicate the amygdala as a central structure for responding to negative emotional faces, and particularly to fearful ones. However, the amygdala may not be specialized for processing emotional faces, but may instead respond to faces because they provide important information for the defense appraisal that is its primary responsibility.     

Basolateral amygdala inactivation impairs learned (but not innate) fear response in rats

Numerous studies have suggested that the amygdala is involved in the formation of aversive memories, but the possibility that this structure is merely related to any kind of fear sensation or response could not be ruled out in previous studies. The present study investigated the effects of bilateral inactivation of the amygdaloid complex in rats tested in the plus-maze discriminative avoidance task. This task concomitantly evaluates aversive memory (by discrimination of the two enclosed arms) and innate fear (by open-arm exploration). Wistar rats (3-5 months-old) were implanted with bilateral guide cannulae into basolateral amygdala. After surgery, all subjects were given 1 week to recover before behavioral experiments. Afterwards, in experiment 1, 15 min prior to training, 0.5 μl of saline or muscimol (1 mg/ml) was infused in each side via microinjection needles. In experiment 2 the animals received injections immediately after the training session and in experiment 3 rats were injected prior to testing session (24 h after training). The main results showed that (1) pre-training muscimol prevented memory retention (evaluated by aversive arm exploration in the test session), but did not alter innate fear (evaluated by percent time in open arms); (2) post-training muscimol impaired consolidation, inducing increased percent in aversive arm exploration in the test session and (3) pre-testing muscimol did not affect retrieval (evaluated by aversive enclosed arm exploration in the test session). The results suggest that amygdala inactivation specifically modulated the learning of the aversive task, excluding a possible secondary effect of amygdala inactivation on general fear responses. Additionally, our data corroborate the hypothesis that basolateral amygdala is not the specific site of storage of aversive memories, since retention of the previously learned task was not affected by pre-testing inactivation.     

Activation of amygdaloid PKC pathway is necessary for conditioned cues-provoked cocaine memory performance

Drug-associated cues are critical in reinstating the drug taking behavior even during prolonged abstinence and thus are thought to be a key factor to induce drug craving and to cause relapse. Amygdaloid complex has been known for its physiological function in mediating emotional experience storage and emotional cues-regulated memory retrieval. This study was undertaken to examine the role of basolateral nuclei of amygdala and the intracellular signaling molecule in drug cues-elicited cocaine memory retrieval. Systemic anisomycin treatment prior to the retrieval test abolished the cues-provoked cocaine conditioned place preference (CPP) memory. Likewise, a similar blockade of cues-provoked cocaine CPP performance was achieved by infusion of anisomycin and cycloheximide into the basolateral nuclei of amygdala before the test. Intra-amygdaloid infusion of H89, a protein kinase A inhibitor, or U0126, a MEK inhibitor, did not affect retrieval of the cues-elicited cocaine CPP memory. In contrast, intra-amygdaloid infusion of NPC 15437, a PKC inhibitor, abolished the cues-elicited cocaine CPP expression, while left the memory per se intact. Intra-amygdaloid infusion of NPC 15437 did not seem to affect locomotor activity or exert observable aversive effect. Taken together, our results suggest that activation of PKC signaling pathway and probably downstream de novo protein synthesis in the basolateral nuclei of amygdala is required for the cues-elicited cocaine memory performance. However, temporary inhibition of this signaling pathway does not seem to affect cocaine CPP memory per se.     

Older adults’ neural activation in the reward circuit is sensitive to face trustworthiness

We examined older adult (OA) and younger adult (YA) neural sensitivity to face trustworthiness in reward circuit regions, previously found to respond to trustworthiness in YA. Interactions of face trustworthiness with age revealed effects exclusive to OA in the amygdala and caudate, and an effect that was not moderated by age in the dorsal anterior cingulate cortex (dACC). OA, but not YA, showed a nonlinear amygdala response to face trustworthiness, with significantly stronger activation response to high than to medium trustworthy faces, and no difference between low and medium or high. This may explain why an earlier study investigating OA amygdala activation to trustworthiness failed to find a significant effect, since only the linear low versus high trustworthiness difference was assessed. OA, but not YA, also showed significantly stronger activation to high than to low trustworthy faces in the right caudate, indicating a positive linear effect, consistent with previous YA research, as well as significantly stronger activation to high than to medium but not low trustworthy faces in the left caudate, indicating a nonlinear effect. Activation in dACC across both age groups showed a positive linear effect consistent with previous YA research. Finally, OA rated the faces as more trustworthy than did YA across all levels of trustworthiness. Future research should examine whether the null effects for YA were due to our inclusion of older faces. Research also should investigate possible implications of our findings for more ecologically valid OA responses to people who vary in facial trustworthiness.