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.     

情绪唤醒影响记忆巩固过程的神经生理机制

白鼠和人类都对情绪唤醒的经历有更好的记忆。情绪唤醒影响记忆巩固的神经生理机制主要有以下几种方式:(a)情绪唤醒或急性应激,会引发个体内部应激激素的释放,从而增强其记忆巩固过程。(b1)杏仁核的激活对情绪唤醒影响记忆巩固过程十分重要,杏仁核内部去甲肾上腺素(NE)的释放影响记忆巩固过程。(b2)杏仁核投射到负责不同类型记忆加工的脑区,如海马和皮层,从而影响记忆。(c)应激激素影响记忆巩固的过程中,杏仁核内NE的激活在这一过程中扮演着重要角色。综上,情绪唤醒影响记忆巩固的过程,涉及到激素调节、神经调节及二者的共同作用。     

The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition

In this review, we report on studies that have assessed the effects of exogenous and endogenous increases in stress hormones on human cognitive performance. We first describe the history of the studies on the effects of using exogenous stress hormones such as glucocorticoids as anti-inflammatory medications on human cognition and mental health. Here, we summarize the cases that led to the diagnosis of glucocorticoid-induced 'steroid psychosis' in human populations and which demonstrated that these stress hormones could thus cross the blood-brain barrier and access the brain where they could influence cognition and mental health. We then summarize studies that assessed the effects of the exogenous administration of glucocorticoids on cognitive performance supported by the hippocampus, the frontal lobes and amygdala. In the second section of the paper, we summarize the effects of the endogenous release of glucocorticoids induced by exposure to a stressful situation on human cognition and we further dissociate the effects of emotion from those of stress on human learning and memory. Finally, in the last section of the paper, we discuss the potential impact that the environmental context to which we expose participants when assessing their memory could have on their reactivity to stress and subsequent cognitive performance. In order to make our point, we discuss the field of memory and aging and we suggest that some of the 'age-related memory impairments' observed in the literature could be partly due to increased stress reactivity in older adults to the environmental context of testing. We also discuss the inverse negative correlations reported between hippocampal volume and memory for young and older adults and suggest that these inverse correlations could be partly due to the effects of contextual stress in young and older adults, as a function of age-related differences in hippocampal volume.     

Functional asymmetry of human prefrontal cortex: encoding and retrieval of verbally and nonverbally coded information

There are several views about the organization of memory functions in the human prefrontal cortex. One view assumes a process-specific brain lateralization according to different memory subprocesses, that is, encoding and retrieval. An alternative view emphasizes content-specific lateralization of brain systems involved in memory processes. This study addresses this apparent inconsistency between process- and content-specific lateralization of brain activity by investigating the effects of verbal and nonverbal encoding on prefrontal activations during encoding and retrieval of environmental novel sounds using fMRI. An intentional memory task was applied in which subjects were required either to judge the sounds' loudness (nonverbal encoding task) or to indicate whether or not a sound can be verbally described (verbal encoding task). Retrieval processes were examined in a subsequent yes/no recognition test. In the study phase the right posterior dorsolateral prefrontal cortex (PFC) was activated in both tasks. During verbal encoding additional activation of the left dorsolateral PFC was obtained. Retrieval-related fMRI activity varied as a function of encoding task: For the nonverbal task we detected an activation focus in the right posterior dorsolateral PFC whereas an activation in the left dorsolateral PFC was observed for the verbal task. These findings indicate that the right dorsolateral PFC is engaged in encoding of auditory information irrespective of encoding task. The lateralization of PFC activity during retrieval was shown to depend on the availability of verbal codes, with left hemispheric involvement for verbally and right hemispheric activation for nonverbally coded information.     

应激激素对恐惧消退作用的神经生理机制

恐惧消退是指反复呈现条件刺激（conditioned stimulus, CS）而不匹配无条件刺激（unconditioned stimulus, US）,从而消除个体已有的恐惧反应。应激激素,如去甲肾上腺素（Norepinephrine,NE）和糖皮质激素（Glucocorticoids,GCs）,可通过影响腹内侧前额叶、杏仁核和海马等与消退学习有关的神经回路的活动,调节恐惧消退学习效果。NE和GCs对恐惧消退学习的调节作用受激素水平与激素用药时间的影响,且其调节效果存在性别差异。未来研究需进一步探索应激激素如何影响恐惧消退学习效果,并思考如何利用其影响效果促进暴露疗法疗效。     

Stress administered prior to encoding impairs neutral but enhances emotional long-term episodic memories

Stressful events frequently comprise both neutral and emotionally arousing information, yet the impact of stress on emotional and neutral events is still not fully understood. The hippocampus and frontal cortex have dense concentrations of receptors for stress hormones, such as cortisol, which at high levels can impair performance on hippocampally dependent memory tasks. Yet, the same stress hormones can facilitate memory for emotional information, which involves interactions between the hippocampus and amygdala. Here, we induced psychosocial stress prior to encoding and examined its long-term effects on memory for emotional and neutral episodes. The stress manipulation disrupted long-term memory for a neutral episode, but facilitated long-term memory for an equivalent emotional episode compared with a control condition. The stress manipulation also increased salivary cortisol, catecholamines as indicated by the presence of alpha-amylase, heart rate, and subjectively reported stress. Stressed subjects reported more false memories than nonstressed control subjects, and these false memories correlated positively with cortisol levels, providing evidence for a relationship between stress and false memory formation. Our results demonstrate that stress, when administered prior to encoding, produces different patterns of long-term remembering for neutral and emotional episodes. These differences likely emerge from differential actions of stress hormones on memory-relevant regions of the brain.     

Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval

It is well established that glucocorticoid hormones, secreted by the adrenal cortex after a stressful event, influence cognitive performance. Some studies have found glucocorticoid-induced memory enhancement. However, many studies have reported impairing effects of glucocorticoids on memory function. This paper reviews recent findings from this laboratory on the acute effects of glucocorticoids in rats on specific memory phases, i.e., memory consolidation and memory retrieval. The evidence suggests that the consequences of glucocorticoid activation on cognition depend largely on the different memory phases investigated. Posttraining activation of glucocorticoid-sensitive pathways involving glucocorticoid receptors enhances memory consolidation in a pattern highly similar to that previously described for adrenal catecholamines. Also, similar to catecholamine effects on memory consolidation, glucocorticoid influences on memory consolidation depend on noradrenergic activation of the basolateral complex of the amygdala and interactions with other brain regions. By contrast, memory retrieval processes are usually impaired with high circulating levels of glucocorticoids or following infusions of glucocorticoid receptor agonists into the hippocampus. The hypothesis is proposed that these apparently dual effects of glucocorticoids on memory consolidation and memory retrieval might be related and that the basolateral complex of the amygdala is a key structure in a memory-modulatory system that regulates, in concert with other brain regions, stress and glucocorticoid effects on both memory consolidation and memory retrieval.     

情绪大脑机制研究的进展

文章综述情绪大脑机制研究的最新进展。情绪的脑机制——大脑回路,包括前额皮层、杏仁核、海马、前部扣带回、腹侧纹状体等。前额皮层中的不对称性与趋近和退缩系统有关,左前额皮层与趋近系统和积极感情有关,右前额皮层与消极感情和退缩有关。杏仁核易被消极的感情刺激所激活,尤其是恐惧。海马在情绪的背景调节中起着重要作用。前额皮层和杏仁核激活不对称性的个体差异是情绪个体差异的生理基础。情绪的中枢回路有可塑性。     

Effect of unpleasant loud noise on hippocampal activities during picture encoding: an fMRI study

The functional link between the amygdala and hippocampus in humans has not been well documented. We examined the effect of unpleasant loud noise on hippocampal and amygdaloid activities during picture encoding by means of fMRI, and on the correct response in humans. The noise reduced activity in the hippocampus during picture encoding, decreased the correct response and increased the activity of the amygdala. A path diagram using structural equation modeling suggested that hippocampus activity might be depressed by high amygdala activity. Therefore, noise should diminish memory by reducing hippocampal activity, which might be depressed by high amygdala activity.     

Neonatal hippocampal lesion alters the functional maturation of the prefrontal cortex and the early cognitive development in pre-juvenile rats

Mnemonic and executive performance is encoded into activity patterns of complex neuronal networks. Lesion studies revealed that adult recognition memory critically depends on the activation of the prefrontal cortex (PFC) and hippocampus (HP). However, its developmental profile remains poorly elucidated. We previously showed the rat PFC and HP are functionally coupled in theta- and gamma-band oscillations during neonatal [postnatal day (P) 5-8] and pre-juvenile (P10-15) stages of development. Here, we assess the behavioral readout of this early prefrontal-hippocampal activation by investigating the ontogeny and the mechanisms of novelty detection and recognition memory in relationship to the functional integrity of the PFC and HP. Excitotoxic lesion of the HP at birth led to abnormal oscillatory entrainment of the PFC throughout neonatal and pre-juvenile development. Although the onset of novelty detection correlated rather with the maturation of sensory perception and motor skills than with hippocampal integrity, the pre-juvenile performance in item, spatial and temporal order recognition memory significantly decreased after HP lesion at birth. This poorer performance does result neither from abnormal developmental milestones and locomotion nor from increased anxiety. Thus, novelty recognition in rat emerges during the second postnatal week and requires functional integrity of communication within neuronal networks including the PFC and HP.     

Stress during puberty boosts metabolic activation associated with fear-extinction learning in hippocampus, basal amygdala and cingulate cortex

Adolescence is characterized by major developmental changes that may render the individual vulnerable to stress and the development of psychopathologies in a sex-specific manner. Earlier we reported lower anxiety-like behavior and higher risk-taking and novelty seeking in rats previously exposed to peri-pubertal stress. Here we studied whether peri-pubertal stress affected the acquisition and extinction of fear memories and/or the associated functional engagement of various brain regions, as assessed with 2-deoxyglucose. We showed that while peri-pubertal stress reduced freezing during the acquisition of fear memories (training) in both sexes, it had a sex-specific effect on extinction of these memories. Moreover hippocampus, basal amygdala and cingulate and motor cortices showed higher metabolic rates during extinction in rats exposed to peri-pubertal stress. Interestingly, activation of the infralimbic cortex was negatively correlated with freezing during extinction only in control males, while only males stressed during puberty showed a significant correlation between behavior during extinction and metabolic activation of hippocampus, amygdala and paraventricular nucleus. No correlations between brain activation and behavior during extinction were observed in females (control or stress). These results indicate that exposure to peri-pubertal stress affects behavior and brain metabolism when the individual is exposed to an additional stressful challenge. Some of these effects are sex-specific.     

Different types of exercise induce differential effects on neuronal adaptations and memory performance

Different exercise paradigms show differential effects on various forms of memory. We hypothesize that the differential effects of exercises on memory performance are caused by different neuroplasticity changes in relevant brain regions in response to different exercise trainings. We examined the effects of treadmill running (TR) and wheel running (WR) on the Pavlovian fear conditioning task that assesses learning and memory performance associated with the amygdala (cued conditioning) and both the amygdala and hippocampus (contextual conditioning). The skeletal muscle citrate synthase activity, an indicator of aerobic capacity, was elevated in rats received 4 w of TR, but not WR. While both TR and WR elevated the contextual conditional response, only TR facilitated the cued conditional response. Using a single-neuron labeling technique, we found that while both TR and MR enlarged the dendritic field and increased the spine density in hippocampal CA3 neurons, only TR showed these effects in basolateral amygdalar neurons. Moreover, both types of exercise upregulated synaptic proteins (i.e., TrkB and SNAP-25) in the hippocampus; however only TR showed similar effects in the amygdala. Injection of K252a, a TrkB kinase inhibitor, in the dorsal hippocampus or basolateral amygdala abolished the exercise-facilitated contextual or cued fear learning and memory performance, respectively, regardless of the types of exercise. In summary, our results supported that different types of exercise affect the performance of learning and memory via BDNF-TrkB signaling and neuroplasticity in specific brain regions. The brain region-specific neuronal adaptations are possibly induced by various levels of intensity/stress elicited by different types of exercise.     

Age differences in prefrontal cortical activity in working memory

Working memory (WM) declines with advancing age. Brain imaging studies indicate that ventral prefrontal cortex (PFC) is active when information is retained in WM and that dorsal PFC is further activated for retention of large amounts of information. The authors examined the effect of aging on activation in specific PFC regions during WM performance. Six younger and 6 older adults performed a task in which, on each trial, they (a) encoded a 1- or 6-letter memory set, (b) maintained these letters over 5-s. and (c) determined whether or not a probe letter was part of the memory set. Comparisons of activation between the 1- and 6-letter conditions indicated age-equivalent ventral PFC activation. Younger adults showed greater dorsal PFC activation than older adults. Older adults showed greater rostral PFC activation than younger adults. Aging may affect dorsal PFC brain regions that are important for WM executive components.     

Neural substrates of successful working memory and long-term memory formation in a relational spatial memory task

Working memory (WM) tasks may involve brain activation actually implicated in long-term memory (LTM). In order to disentangle these two memory systems, we employed a combined WM/LTM task, using a spatial relational (object-location) memory paradigm and analyzed which brain areas were associated with successful performance for either task using fMRI. Critically, we corrected for the performance on the respective memory task when analyzing subsequent memory effects. The WM task consisted of a delayed-match-to-sample task assessed in an MRI scanner. Each trial consisted of an indoor or outdoor scene in which the exact configuration of four objects had to be remembered. After a short delay (7–13 s), the scene was presented from a different angle and spatial recognition for two objects was tested. After scanning, participants received an unexpected subsequent recognition memory (LTM) task, where the two previously unprobed objects were tested. Brain activity during encoding, delay phase and probe phase was analyzed based on WM and LTM performance. Results showed that successful WM performance, when corrected for LTM performance, was associated with greater activation in the inferior frontal gyrus and left fusiform gyrus during the early stage of the maintenance phase. A correct decision during the WM probe was accompanied by greater activation in a wide network, including bilateral hippocampus, right superior parietal gyrus and bilateral insula. No voxels exhibited supra-threshold activity during the encoding phase, and we did not find any differential activity for correct versus incorrect trials in the WM task when comparing LTM correct versus LTM incorrect trials.     

17β-Estradiol: Effect on CA1 Hippocampal Synaptic Plasticity

An understanding of synaptic plasticity in the mammalian brain has been one of R. F. Thompson's major pursuits throughout his illustrious career. A current series of experiments of significant interest to R. F. Thompson is an examination of the interactions between sex hormones, synaptic plasticity, aging, and stress. This research is contained within a broader project whose aim is to investigate animal models that evaluate estrogen interactions with Alzheimer's disease. This paper reviews the recent results that have led to a better understanding of how the sex hormone estrogen influences synaptic plasticity in an important structure within the mammalian brain responsible for learning and memory: the hippocampus. In this review, a number of experiments have been highlighted that investigate the molecular mechanisms that underlie estrogen's effect on two specific forms of synaptic plasticity commonly studied in neurophysiology and the behavioral neurosciences: long-term potentiation and long-term depression.     

17beta-estradiol: effect on CA1 hippocampal synaptic plasticity.

An understanding of synaptic plasticity in the mammalian brain has been one of R. F. Thompson's major pursuits throughout his illustrious career. A current series of experiments of significant interest to R. F. Thompson is an examination of the interactions between sex hormones, synaptic plasticity, aging, and stress. This research is contained within a broader project whose aim is to investigate animal models that evaluate estrogen interactions with Alzheimer's disease. This paper reviews the recent results that have led to a better understanding of how the sex hormone estrogen influences synaptic plasticity in an important structure within the mammalian brain responsible for learning and memory: the hippocampus. In this review, a number of experiments have been highlighted that investigate the molecular mechanisms that underlie estrogen's effect on two specific forms of synaptic plasticity commonly studied in neurophysiology and the behavioral neurosciences: long-term potentiation and long-term depression.     

Dopaminergic modulation of the persistence of one-trial hippocampus-dependent memory

The persistence of new memory traces in the hippocampus, encoded following appropriate activation of glutamatergic receptors and the induction of synaptic plasticity, can be influenced by heterosynaptic activation of neuromodulatory brain systems. We therefore investigated the effects of a hippocampus-specific blockade of dopamine D1/D5 receptors on the persistence of spatial memory encoded in one trial using a delayed matching-to-place (DMP) task in a watermaze in which rats learn a new escape location each day. A within-subjects design was used such that both short (20 min) and long (6 h) retention intervals, and both drug (SCH23390, a D1/D5 receptor antagonist) and vehicle (aCSF) infusions were tested on different days in the same animals. Bilateral intrahippocampal infusion of SCH23390 (5 microg in 1 microL per side) prior to trial 1 (encoding) caused a differential impairment as a function of memory delay-with no effect during trial 2 (memory retrieval) after a 20-min interval, but a block of memory at 6 h. Further experiments revealed that infusion of SCH23390 immediately after trial 1 had no effect on retention 6 h later, and the poor memory seen at long retention intervals when the drug was present at encoding was not due to a state-dependent failure of retrieval. These results suggest that activation of D1/D5 receptors during memory encoding is necessary for the formation of a persistent memory trace in the hippocampus. The complementary effects of D1/D5 receptor blockade on the persistence of LTP and the duration of memory are consistent with the idea that changes in synaptic strength underlie memory.     

Enhanced human memory consolidation with post-learning stress: interaction with the degree of arousal at encoding

Abundant evidence indicates that endogenous stress hormones such as epinephrine and corticosterone modulate memory consolidation in animals. We recently provided the first demonstration that an endogenous stress hormone (epinephrine) can enhance human memory consolidation. However, these findings also suggested that post-learning stress hormone activation does not uniformly enhance memory for all recently acquired information; rather, that it interacts with the degree of arousal at initial encoding of material in modulating memory for the material. Here we tested this hypothesis by administering cold pressor stress (CPS) or a control procedure to subjects after they viewed slides of varying emotional content, and assessing memory for the slides 1 wk later. CPS, which significantly elevated salivary cortisol levels, enhanced memory for emotionally arousing slides compared with the controls, but did not affect memory for relatively neutral slides. These findings further support the view that post-learning stress hormone-related activity interacts with arousal at initial encoding to modulate memory consolidation.     

Enhancement of spatial learning by predator odor in mice: Involvement of amygdala and hippocampus

Olfaction has particular links with learning and memory compared with other sensory cues, due to the interrelations between their neural circuitry. The present study deals with the effects of a putative stressor (i.e. a predator odor) on visuo-spatial learning in mice. Firstly, the results show that a predator odor spread during the Morris water maze task led to learning enhancement. In addition, a stereotaxic approach was used to investigate the involvement of the amygdala in this hippocampus-dependent type of learning. Thus, the performance of mice in visuo-spatial learning under predator odor conditions was dramatically reduced by an ibotenate bilateral amygdala lesion. The involvement of the amygdala was confirmed by a reduced expression of c-fos in the CA1 hippocampus of amygdala-lesioned mice at the end of the learning procedure.Mild exposure to a predator odor during hippocampus-dependent learning therefore leads to an enhancement of performance through the co-activation of the amygdala, probably by a stress mediated mechanism.     

睡眠对恐惧学习的影响及其认知神经机制

睡眠问题可能会诱发恐惧相关情绪障碍(焦虑、创伤性应激障碍、恐怖症等),研究睡眠影响恐惧学习的认知神经机制,有助于增强对恐惧相关情绪障碍的预测、诊断和治疗。以往研究表明睡眠剥夺影响恐惧习得和消退主要是通过抑制vmPFC活动,阻碍其与杏仁核的功能连接,从而导致恐惧习得增强或是消退学习受损。进一步研究发现睡眠不同阶段对恐惧学习相关脑区有独特的影响:剥夺(缺乏)快速眼动睡眠会抑制vmPFC活动、增强杏仁核、海马激活,导致恐惧习得增强,消退学习受损,此外边缘皮层的功能连接减少破坏了记忆巩固(恐惧记忆和消退记忆);而慢波睡眠主要与海马变化有关,慢波睡眠期间进行目标记忆重激活可促进恐惧消退学习。未来研究需要增加睡眠影响恐惧泛化的神经机制研究、及昼夜节律中断对恐惧消退的影响,以及关注动物睡眠研究向人类睡眠研究转化中存在的问题。