Glucocorticoids enhance taste aversion memory via actions in the insular cortex and basolateral amygdala

It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function. Corticosterone (1.0 or 3.0 mg/kg) administered subcutaneously to male Sprague–Dawley rats immediately after the pairing of saccharin consumption with the visceral malaise-inducing agent lithium chloride (LiCl) dose-dependently increased aversion to the saccharin taste on a 96-h retention test trial. In a second experiment, rats received corticosterone either immediately after saccharin consumption or after the LiCl injection, when both stimuli were separated by a 3-h time interval, to investigate whether corticosterone enhances memory of the gustatory or visceral stimulus presentation. Consistent with the finding that the LiCl injection, but not saccharin consumption, increases endogenous corticosterone levels, corticosterone selectively enhanced CTA memory when administered after the LiCl injection. Suppression of this training-induced release of corticosterone with the synthesis-inhibitor metyrapone (35 mg/kg) impaired CTA memory, and was dose-dependently reversed by post-training supplementation of corticosterone. Moreover, direct post-training infusions of corticosterone into the insular cortex or basolateral complex of the amygdala, two brain regions that are critically involved in the acquisition and consolidation of CTA, also enhanced CTA retention, whereas post-training infusions into the dorsal hippocampus were ineffective. These findings provide evidence that glucocorticoid effects on memory consolidation are not limited to hippocampus-dependent spatial/contextual information, but that these hormones also modulate memory consolidation of discrete-cue associative learning via actions in other brain regions.     

Mapping of olfactory memory circuits: region-specific c-fos activation after odor-reward associative learning or after its retrieval

Although there is growing knowledge about intracellular mechanisms underlying neuronal plasticity and memory consolidation and reconsolidation after retrieval, information concerning the interaction among brain areas during formation and retrieval of memory is relatively sparse and fragmented. Addressing this question requires simultaneous monitoring of activity in multiple brain regions during learning, the post-acquisition consolidation period, and retrieval and subsequent reconsolidation. Immunoreaction to the immediate early gene c-fos is a powerful tool to mark neuronal activation of specific populations of neurons. Using this method, we are able to report, for the first time, post-training activation of a network of closely related brain regions, particularly in the frontal cortex and the basolateral amygdala (BLA), that is specific to the learning of an odor-reward association. On the other hand, retrieval of a well-established associative memory trace does not seem to differentially activate the same regions. The amygdala, in particular, is not engaged after retrieval, whereas the lateral habenula (LHab) shows strong activation that is restricted to animals having previously learned the association. Although intracellular mechanisms may be similar during consolidation and reconsolidation, this study indicates that different brain circuits are involved in the two processes, at least with respect to a rapidly learned olfactory task.     

Stress, glucocorticoids, and memory: a meta-analytic review

Although a strong psychoneuroendocrine linkage exists between stress, glucocorticoids and memory, the relationship is not always straightforward. Eighty-eight effect sizes and 1642 participants from 28 studies were meta-analyzed for the effects of stress on memory performance and glucocorticoid activation. Analyses showed that stress was associated with glucocorticoid activation and declarative memory decline. In animal studies, predator stress affected memory performance more than physical stress. In human studies, males showed higher cortisol levels than females in response to stress. Further, the correlation between cortisol levels and memory deficits was stronger in studies using laboratory stressors than those examining long term effects of chronic exposure to rising basal levels of glucocorticoids and chronic life stressors. It was concluded that, although the relationship between stress, glucocorticoids, and memory loss was empirically supported, there were other factors, such as stress condition and gender, as well as individual differences within groups, that influenced the association between these variables, and warrant further examination.     

Muscarinic cholinergic influences in memory consolidation

The central cholinergic system and muscarinic cholinergic receptor (mR) activation have long been associated with cognitive function. Although mR activation is no doubt involved in many aspects of cognitive functioning, the extensive evidence that memory is influenced by cholinergic treatments given after training either systemically or intra-cranially clearly indicates that cholinergic activation via mRs is a critical component in modulation of memory consolidation. Furthermore, the evidence indicates that activation of mRs in the basolateral amygdala (BLA) plays an essential role in enabling other neuromodulatory influences on memory consolidation. Memory can also be affected by posttraining activation of mRs in the hippocampus, striatum and cortex. Evidence of increases in hippocampal and cortical acetylcholine (ACh) levels following learning experiences support the view that endogenous ACh release is involved in long-term memory consolidation. Furthermore, the findings indicating that mR drug treatments influence plasticity in the hippocampus and in sensory cortices strongly suggest that mR activation is involved in the storage of information in these brain regions.     

Systemic and intrahippocampal administrations of the glucocorticoid receptor antagonist RU38486 impairs fear memory reconsolidation in rats

Reconsolidation is the process by which previously consolidated memories are stabilized after retrieval. Several lines of evidence indicate that glucocorticoids modulate distinct phases of learning and memory. These effects are considered to be mediated by mineralocorticoid receptors and glucocorticoid receptors (GRs), which display a high concentration and distinct distribution in the hippocampus. The role of glucocorticoid system in fear memory reconsolidation is the subject of some controversy. Moreover, we found no studies that assessed the role of hippocampal GRs in fear memory reconsolidation. Here, we investigated the effect of GR blockade on fear memory reconsolidation in rats. Rats were trained and tested in an inhibitory avoidance task. Intrahippocampal or systemic administration of the GR antagonist RU38486 immediately following memory reactivation produced a deficit in post-retrieval long-term memory that persisted over test sessions, and memory did not re-emerge following a footshock reminder. These results indicate that hippocampal GRs are required for reconsolidation of fear-based memory.     

Effects of stress hormones on traumatic memory formation and the development of posttraumatic stress disorder in critically ill patients

A majority of patients after intensive care treatment report traumatic memories from their stay in the intensive care unit (ICU). Traumatic memories can be associated with the development of posttraumatic stress disorder (PTSD) in a subpopulation of these patients. In contrast to other patient populations at risk for PTSD, patients in the ICU often receive exogenously administered stress hormones like epinephrine, norepinephrine, or cortisol for medical reasons and are extensively monitored. ICU patients therefore represent a suitable population for studying the relationship between stress hormones, traumatic memories, and the development of PTSD. Studies in long-term survivors of ICU treatment demonstrated a clear and vivid recall of different categories of traumatic memory such as nightmares, anxiety, respiratory distress, or pain with little or no recall of factual events. The number of categories of traumatic memory recalled increased with the total administered dosages of stress hormones (both catecholamines and cortisol), and the evaluation of these categories at different time points after discharge from the ICU showed better memory consolidation with higher dosages of stress hormones administered. However, the administration of stress doses of cortisol to critically ill patients resulted in more complex findings as it caused a significant reduction in PTSD symptoms measured after recovery. This effect can possibly be explained by a differential influence of cortisol on memory. Increased serum cortisol levels not only result in consolidation of emotional memory but are also known to cause a temporary impairment in memory retrieval which appears to be independent of glucocorticoid effects on memory formation. Disrupting retrieval mechanisms with glucocorticoids during critical illness may therefore act protectively against the development of PTSD by preventing recall of traumatic memories. Our findings indicate that stress hormones influence the development of PTSD through complex and simultaneous interactions on memory formation and retrieval. Our studies also demonstrate that animal models of aversive learning are useful in analyzing and predicting clinical findings in critically ill humans.     

Amygdala modulation of memory consolidation: interaction with other brain systems

There is a strong consensus that the amygdala is involved in mediating influences of emotional arousal and stress on learning and memory. There is extensive evidence that the basolateral amygdala (BLA) is a critical locus of integration of neuromodulatory influences regulating the consolidation of several forms of memory. Many drug and stress hormone influences converge in activating the release of norepinephrine (NE) within the BLA. Evidence from studies using in vivo microdialysis and high-performance liquid chromatography indicates that increases in amygdala NE levels assessed following inhibitory avoidance training correlate highly with subsequent retention. Other evidence indicates that NE influences on memory consolidation require muscarinic cholinergic activation within the BLA provided by projections from the nucleus basalis magnocellularis (NB). Evidence from several experiments indicates that activation of the BLA plays an essential role in modulating memory consolidation processes involving other brain regions. These findings provide strong support for the hypothesis that the BLA plays a critical role in regulating the consolidation of lasting memories of significant experiences.     

Hormonal and monoamine signaling during reinforcement of hippocampal long-term potentiation and memory retrieval

Recently it was shown that holeboard training can reinforce, i.e., transform early-LTP into late-LTP in the dentate gyrus during the initial formation of a long-term spatial reference memory in rats. The consolidation of LTP as well as of the reference memory was dependent on protein synthesis. We have now investigated the transmitter systems involved in this reinforcement and found that LTP-consolidation and memory retrieval were dependent on β-adrenergic, dopaminergic, and mineralocorticoid receptor (MR) activation, whereas glucocorticoid receptors (GRs) were not involved. Blockade of the β-adrenergic signaling pathway significantly increased the number of reference memory errors compared with MR and dopamine receptor inhibition. In addition, β-adrenergic blockade impaired the working memory. Therefore, we suggest that β-adrenergic receptor activation is the main signaling system required for the retrieval of spatial memory. In addition, other modulatory interactions such as dopaminergic as well as MR systems are involved. This result points to specific roles of different modulatory systems during the retrieval of specific components of spatial memory. The data provide evidence for similar integrative interactions between different signaling systems during cellular memory processes.     

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。     

Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory

Evidence suggests that plasticity of the amygdalar and hippocampal GABAergic system is critical for fear memory formation. In this study we investigated in wild-type and genetically manipulated mice the role of the activity-dependent 65-kDa isozyme of glutamic acid decarboxylase (GAD65) in the consolidation and generalization of conditioned fear. First, we demonstrate a transient reduction of GAD65 gene expression in the dorsal hippocampus (6 h post training) and in the basolateral complex of the amygdala (24 h post training) during distinct phases of fear memory consolidation. Second, we show that targeted ablation of the GAD65 gene in Gad65(-/-) mice results in a pronounced context-independent, intramodal generalization of auditory fear memory during long-term (24 h or 14 d) but not short-term (30 min) memory retrieval. The temporal specificity of both gene regulation and memory deficits in Gad65 mutant mice suggests that GAD65-mediated GABA synthesis is critical for the consolidation of stimulus-specific fear memory. This function appears to involve a modulation of neural activity patterns in the amygdalo-hippocampal pathway as indicated by a reduction in theta frequency synchronization between the amygdala and hippocampus of Gad65(-/-) mice during the expression of generalized fear memory.     

How chunks, long-term working memory and templates offer a cognitive explanation for neuroimaging data on expertise acquisition: a two-stage framework

Our review of research on PET and fMRI neuroimaging of experts and expertise acquisition reveals two apparently discordant patterns in working-memory-related tasks. When experts are involved, studies show activations in brain regions typically activated during long-term memory tasks that are not observed with novices, a result that is compatible with functional brain reorganization. By contrast, when involving novices and training programs, studies show a decrease in brain regions typically activated during working memory tasks, with no functional reorganization. We suggest that the latter result is a consequence of practice periods that do not allow important structures to be completely acquired: knowledge structures (i.e., Ericsson and Kintsch's retrieval structures; Gobet and Simon's templates) and in a lesser way, chunks. These structures allow individuals to improve performance on working-memory tasks, by enabling them to use part of long-term memory as working memory, causing a cerebral functional reorganization. Our hypothesis is that the two brain activation patterns observed in the literature are not discordant, but involve the same process of expertise acquisition in two stages: from decreased activation to brain functional reorganization. The dynamic of these two physiological stages depend on the two above-mentioned psychological constructs: chunks and knowledge structures.     

Effects of oral cortisol treatment in healthy young women on memory retrieval of negative and neutral words

Studies in rodents have demonstrated that glucocorticoids enhance memory consolidation but impair delayed memory retrieval. Similar findings have been reported in humans. Emotional items are better remembered than neutral items. However, it is unknown if emotional valence influences the effects of cortisol on retrieval. In this double-blind crossover study, 16 healthy women learned a wordlist containing 15 neutral and 15 negative words. Delayed recall was tested 5h later. Cortisol administered before recall testing significantly reduced retrieval (p<.01). Exploratory follow-up analysis revealed that cortisol significantly impaired retrieval of negative words (p<.01), while having no significant effect on neutral words (p=.47). The current findings could suggest that emotional material is especially sensitive to the memory modulating effects of stress hormones.     

Glucocorticoid administration into the dorsal striatum [corrected] facilitates memory consolidation of inhibitory avoidance training but not of the context or footshock components

It is well established that glucocorticoid administration into a variety of brain regions facilitates memory consolidation of fear-conditioning tasks, including inhibitory avoidance. The present findings indicate that the natural glucocorticoid corticosterone administered into the dorsal striatum (i.e., caudate nucleus) of male Wistar rats produced dose- and time-dependent enhancement of inhibitory avoidance memory consolidation. However, as assessed with a modified inhibitory avoidance procedure that took place on two sequential days to separate context training from footshock training, corticosterone administration into the dorsal striatum did not enhance memory of either the contextual or aversively motivational aspects of the task.     

Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: dependence upon training intensity

Reactivation of stabilized memories returns them to a labile state and causes them to undergo extinction or reconsolidation processes. Although it is well established that administration of glucocorticoids after training enhance consolidation of contextual fear memories, but their effects on post-retrieval processes are not known. In this study, we first asked whether administration of corticosterone after memory reactivation would modulate subsequent expression of memory in rats. Additionally, we examined whether this modulatory action would depend upon the strength of the memory. We also tested the effect of propranolol after memory reactivation. Adult male Wistar rats were trained in a fear conditioning system using moderate (0.4 mA) or high shock (1.5 mA) intensities. For reactivation, rats were returned to the chamber for 90 s 24h later. Immediately after reactivation, rats were injected with corticosterone (1, 3 or 10mg/kg) or vehicle. One, 7 and 14 days after memory reactivation, rats were returned to the context for 5 min, and freezing behavior was scored. The findings indicated that corticosterone when injected after memory reactivation had no significant effect on recall of a moderate memory, but it impaired recall of a strong memory at a dose of 3mg/kg. Propranolol (5mg/kg) given after the reactivation treatment produced a modest impairment that persisted over three test sessions. Further, the results showed that corticosterone, but not propranolol deficit was reversed by a reminder shock. These findings provide evidence that administration of glucocorticoids following memory reactivation reduces subsequent retrieval of strong, but not moderate, contextual conditioned fear memory likely via acceleration of memory extinction. On the other hand, propranolol-induced amnesia may result from blockade of reconsolidation process. Further studies are needed to determine the underlying mechanisms.     

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.     

Acute memory deficits in chemotherapy-treated adults

Data from research on amnesia and epilepsy are equivocal with regards to the dissociation, shown in animal models, between rapid and slow long-term memory consolidation. Cancer treatments have lasting disruptive effects on memory and on brain structures associated with memory, but their acute effects on synaptic consolidation are unknown. We investigated the hypothesis that cancer treatment selectively impairs slow synaptic consolidation. Cancer patients and their matched controls were administered a novel list-learning task modelled on the Rey Auditory Verbal Learning Test. Learning, forgetting, and retrieval were tested before, and one day after patients’ first chemotherapy treatment. Due to difficulties recruiting cancer patients at that sensitive time, we were only able to study 10 patients and their matched controls. Patients exhibited treatment-dependent accelerated forgetting over 24 hours compared to their own pre-treatment performance and to the performance of control participants, in agreement with our hypothesis. The number of intrusions increased after treatment, suggesting retrieval deficits. Future research with larger samples should adapt our methods to distinguish between consolidation and retrieval causes for treatment-dependent accelerated forgetting. The presence of significant accelerated forgetting in our small sample is indicative of a potentially large acute effect of chemotherapy treatment on forgetting, with potentially clinically relevant implications.     

应激对记忆影响的脑科学研究及其教育启示

大量脑科学的研究揭示,应激对与海马相关的陈述性记忆的调节主要通过应激激素,尤其是糖皮质激素的分泌而发生作用,而影响的方向取决于一些调节变量,包括糖皮质激素升高的水平以及记忆的不同阶段等。研究发现基底外侧杏仁核是糖皮质激素对记忆不同阶段产生差异性影响的关键部位。因此,在教育过程中,既要科学地认识应激对记忆的消极影响,又要有效利用应激对记忆产生的调节作用,来提高学生的学习效率。     

Immediate recall influences the effects of pre-encoding stress on emotional episodic long-term memory consolidation in healthy young men

The stress-associated activation of the hypothalamus-pituitary-adrenal axis influences memory. Several studies have supported the notion that post-learning stress enhances memory consolidation, while pre-retrieval stress impairs retrieval. Findings regarding the effects of pre-encoding stress, in contrast, have been rather inconsistent. In the current two studies, the impact of an immediate retrieval task on these effects was explored. In the first study, 24 healthy young male participants were exposed to a psychosocial laboratory stressor (Trier Social Stress Test) or a control condition before viewing positive, negative, and neutral photographs, which were accompanied by a brief narrative. Immediate as well as delayed (24?h later) free recall was assessed. Stress was expected to enhance emotional long-term memory without affecting immediate recall performance. Stress caused a significant increase in salivary cortisol concentrations but had no significant effects on immediate or delayed retrieval performance, even though a trend toward poorer memory of the stress group was apparent. Based on these findings, the second experiment tested the hypothesis that the beneficial effects of stress on emotional long-term memory performance might be abolished by an immediate recall test. In the second study (n?=?32), the same design was used, except for the omission of the immediate retrieval test. This time stressed participants recalled significantly more negative photographs compared to the control group. The present study indicates that an immediate retrieval attempt of material studied after stress exposure can prevent or even reverse the beneficial effects of pre-encoding stress on emotional long-term memory consolidation.     

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.     

Modulation of memory consolidation by the basolateral amygdala or nucleus accumbens shell requires concurrent dopamine receptor activation in both brain regions

Previous findings indicate that the basolateral amygdala (BLA) and the nucleus accumbens (NAc) interact in influencing memory consolidation. The current study investigated whether this interaction requires concurrent dopamine (DA) receptor activation in both brain regions. Unilateral, right-side cannulae were implanted into the BLA and the ipsilateral NAc shell or core in male Sprague-Dawley rats ( approximately 300 g). One week later, the rats were trained on an inhibitory avoidance (IA) task and, 48 h later, they were tested for retention. Drugs were infused into the BLA and NAc shell or core immediately after training. Post-training intra-BLA infusions of DA enhanced retention, as assessed by latencies to enter the shock compartment on the retention test. Infusions of the general DA receptor antagonist cis-Flupenthixol (Flu) into the NAc shell (but not the core) blocked the memory enhancement induced by the BLA infusions of DA. In the reverse experiment, post-training intra-NAc shell infusions of DA enhanced retention and Flu infusions into the BLA blocked the enhancement. These findings indicate that BLA modulation of memory consolidation requires concurrent DA receptor activation in the NAc shell but not the core. Similarly, NAc shell modulation of memory consolidation requires concurrent DA receptor activation in the BLA. Together with previous findings, these results suggest that the dopaminergic innervation of the BLA and NAc shell is critically involved in the modulation of memory consolidation.