Neuronal signalling of fear memory

The learning and remembering of fearful events depends on the integrity of the amygdala, but how are fear memories represented in the activity of amygdala neurons? Here, we review recent electrophysiological studies indicating that neurons in the lateral amygdala encode aversive memories during the acquisition and extinction of Pavlovian fear conditioning. Studies that combine unit recording with brain lesions and pharmacological inactivation provide evidence that the lateral amygdala is a crucial locus of fear memory. Extinction of fear memory reduces associative plasticity in the lateral amygdala and involves the hippocampus and prefrontal cortex. Understanding the signalling of aversive memory by amygdala neurons opens new avenues for research into the neural systems that support fear behaviour.     

Sleep-related hippocampo-cortical interplay during emotional memory recollection

Emotional events are usually better remembered than neutral ones. This effect is mediated in part by a modulation of the hippocampus by the amygdala. Sleep plays a role in the consolidation of declarative memory. We examined the impact of sleep and lack of sleep on the consolidation of emotional (negative and positive) memories at the macroscopic systems level. Using functional MRI (fMRI), we compared the neural correlates of successful recollection by humans of emotional and neutral stimuli, 72 h after encoding, with or without total sleep deprivation during the first post-encoding night. In contrast to recollection of neutral and positive stimuli, which was deteriorated by sleep deprivation, similar recollection levels were achieved for negative stimuli in both groups. Successful recollection of emotional stimuli elicited larger responses in the hippocampus and various cortical areas, including the medial prefrontal cortex, in the sleep group than in the sleep deprived group. This effect was consistent across subjects for negative items but depended linearly on individual memory performance for positive items. In addition, the hippocampus and medial prefrontal cortex were functionally more connected during recollection of either negative or positive than neutral items, and more so in sleeping than in sleep-deprived subjects. In the sleep-deprived group, recollection of negative items elicited larger responses in the amygdala and an occipital area than in the sleep group. In contrast, no such difference in brain responses between groups was associated with recollection of positive stimuli. The results suggest that the emotional significance of memories influences their sleep-dependent systems-level consolidation. The recruitment of hippocampo-neocortical networks during recollection is enhanced after sleep and is hindered by sleep deprivation. After sleep deprivation, recollection of negative, potentially dangerous, memories recruits an alternate amygdalo-cortical network, which would keep track of emotional information despite sleep deprivation.     

Emotional memory and psychopathology.

A leading model for studying how the brain forms memories about unpleasant experiences is fear conditioning. A cumulative body of work has identified major components of the neural system mediating this form of learning. The pathways involve transmission of sensory information from processing areas in the thalamus and cortex to the amygdala. The amygdala''s lateral nucleus receives and integrates the sensory inputs from the thalamic and cortical areas, and the central nucleus provides the interface with motor systems controlling specific fear responses in various modalities (behavioural, autonomic, endocrine). Internal connections within the amygdala allow the lateral and central nuclei to communicate. Recent studies have begun to identify some sites of plasticity in the circuitry and the cellular mechanisms involved in fear conditioning. Through studies of fear conditioning, our understanding of emotional memory is being taken to the level of cells and synapses in the brain. Advances in understanding emotional memory hold out the possibility that emotional disorders may be better defined and treatment improved.     

A Key Role for Nectin-1 in the Ventral Hippocampus in Contextual Fear Memory

Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1—but not nectin-3—protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal hippocampus, respectively, thus opening new venues for the development of treatments to psychopathological alterations linked to impaired contextualization of emotions.     

Task and content modulate amygdala-hippocampal connectivity in emotional retrieval

The ability to remember emotional events is crucial for adapting to biologically and socially significant situations. Little is known, however, about the nature of the neural interactions supporting the integration of mnemonic and emotional information. Using fMRI and dynamic models of effective connectivity, we examined regional neural activity and specific interactions between brain regions during a contextual memory retrieval task. We independently manipulated emotional context and relevance of retrieved emotional information to task demands. We show that retrieval of emotionally valenced contextual information is associated with enhanced connectivity from hippocampus to amygdala, structures crucially involved with encoding of emotional events. When retrieval of emotional information is relevant to current behavior, amygdala-hippocampal connectivity increases bidirectionally, under modulatory influences from orbitofrontal cortex, a region implicated in representation of affective value and behavioral guidance. Our findings demonstrate that both memory content and behavioral context impact upon large scale neuronal dynamics underlying emotional retrieval.     

Cognitive neuroscience of emotional memory

Emotional events often attain a privileged status in memory. Cognitive neuroscientists have begun to elucidate the psychological and neural mechanisms underlying emotional retention advantages in the human brain. The amygdala is a brain structure that directly mediates aspects of emotional learning and facilitates memory operations in other regions, including the hippocampus and prefrontal cortex. Emotion-memory interactions occur at various stages of information processing, from the initial encoding and consolidation of memory traces to their long-term retrieval. Recent advances are revealing new insights into the reactivation of latent emotional associations and the recollection of personal episodes from the remote past.     

Stress enhances fear by forming new synapses with greater capacity for long-term potentiation in the amygdala

Prolonged and severe stress leads to cognitive deficits, but facilitates emotional behaviour. Little is known about the synaptic basis for this contrast. Here, we report that in rats subjected to chronic immobilization stress, long-term potentiation (LTP) and NMDA receptor (NMDAR)-mediated synaptic responses are enhanced in principal neurons of the lateral amygdala, a brain area involved in fear memory formation. This is accompanied by electrophysiological and morphological changes consistent with the formation of ‘silent synapses’, containing only NMDARs. In parallel, chronic stress also reduces synaptic inhibition. Together, these synaptic changes would enable amygdalar neurons to undergo further experience-dependent modifications, leading to stronger fear memories. Consistent with this prediction, stressed animals exhibit enhanced conditioned fear. Hence, stress may leave its mark in the amygdala by generating new synapses with greater capacity for plasticity, thereby creating an ideal neuronal substrate for affective disorders. These findings also highlight the unique features of stress-induced plasticity in the amygdala that are strikingly different from the stress-induced impairment of structure and function in the hippocampus.     

Affective modulation of multiple memory systems

The hippocampus and caudate nucleus are anatomical components of relatively independent memory systems and recent research has focused on the nature of the interaction between these two systems. The amygdala exerts a general modulatory influence on memory storage processes related, in part, to an organism's level of affective or emotional arousal. Moreover, affective state can influence the use of different memory systems, and the amygdala may mediate this effect of emotion on memory. Recent evidence indicates that the amygdala modulates the separate types of memory mediated by the hippocampus and caudate nucleus. Recent human brain imaging studies also point to both sex- and hemisphere-related asymmetries in amygdala participation in emotionally influenced memory.     

Neuropeptide S-mediated facilitation of synaptic transmission enforces subthreshold theta oscillations within the lateral amygdala

The neuropeptide S (NPS) receptor system modulates neuronal circuit activity in the amygdala in conjunction with fear, anxiety and the expression and extinction of previously acquired fear memories. Using in vitro brain slice preparations of transgenic GAD67-GFP (Δneo) mice, we investigated the effects of NPS on neural activity in the lateral amygdala as a key region for the formation and extinction of fear memories. We are able to demonstrate that NPS augments excitatory glutamatergic synaptic input onto both projection neurons and interneurons of the lateral amygdala, resulting in enhanced spike activity of both types of cells. These effects were at least in part mediated by presynaptic mechanisms. In turn, inhibition of projection neurons by local interneurons was augmented by NPS, and subthreshold oscillations were strengthened, leading to their shift into the theta frequency range. These data suggest that the multifaceted effects of NPS on amygdaloid circuitry may shape behavior-related network activity patterns in the amygdala and reflect the peptide's potent activity in various forms of affective behavior and emotional memory.     

Personnalisation des émotions et cortex médial préfrontal

Functional brain imaging studies in healthy subjects suggest that several regions (prefrontal cortex, amygdala, thalamus, hippocampus, anterior cingulate) have specialized functions for emotional operations. Within these regions, the medial prefrontal cortex (MPFC) is considered to have a general role in emotional processing. Using a memory paradigm with verbal material, we recently demonstrated that the MPFC is specifically involved in self-related processing of emotional stimuli. Study with mood induction also suggest that personality traits may modulate the reactivity of the MPFC to emotional Stressors. Taken together these findings support the hypothesis that the MPFC subserve processes involved in emotion regulation. Dysfunction of the MPFC and related structures (i.e. amygdala) may increase the vulnerability to emotional disorders.     

Human emotion and memory: interactions of the amygdala and hippocampal complex

The amygdala and hippocampal complex, two medial temporal lobe structures, are linked to two independent memory systems, each with unique characteristic functions. In emotional situations, these two systems interact in subtle but important ways. Specifically, the amygdala can modulate both the encoding and the storage of hippocampal-dependent memories. The hippocampal complex, by forming episodic representations of the emotional significance and interpretation of events, can influence the amygdala response when emotional stimuli are encountered. Although these are independent memory systems, they act in concert when emotion meets memory.     

Xenon Impairs Reconsolidation of Fear Memories in a Rat Model of Post-Traumatic Stress Disorder (PTSD)

Xenon (Xe) is a noble gas that has been developed for use in people as an inhalational anesthestic and a diagnostic imaging agent. Xe inhibits glutamatergic N-methyl-D-aspartate (NMDA) receptors involved in learning and memory and can affect synaptic plasticity in the amygdala and hippocampus, two brain areas known to play a role in fear conditioning models of post-traumatic stress disorder (PTSD). Because glutamate receptors also have been shown to play a role in fear memory reconsolidation – a state in which recalled memories become susceptible to modification – we examined whether Xe administered after fear memory reactivation could affect subsequent expression of fear-like behavior (freezing) in rats. Male Sprague-Dawley rats were trained for contextual and cued fear conditioning and the effects of inhaled Xe (25%, 1 hr) on fear memory reconsolidation were tested using conditioned freezing measured days or weeks after reactivation/Xe administration. Xe administration immediately after fear memory reactivation significantly reduced conditioned freezing when tested 48 h, 96 h or 18 d after reactivation/Xe administration. Xe did not affect freezing when treatment was delayed until 2 h after reactivation or when administered in the absence of fear memory reactivation. These data suggest that Xe substantially and persistently inhibits memory reconsolidation in a reactivation and time-dependent manner, that it could be used as a new research tool to characterize reconsolidation and other memory processes, and that it could be developed to treat people with PTSD and other disorders related to emotional memory.     

Adult-onset hypothyroidism enhances fear memory and upregulates mineralocorticoid and glucocorticoid receptors in the amygdala

Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment.     

Contributions of the amygdala to emotion processing: from animal models to human behavior

Research on the neural systems underlying emotion in animal models over the past two decades has implicated the amygdala in fear and other emotional processes. This work stimulated interest in pursuing the brain mechanisms of emotion in humans. Here, we review research on the role of the amygdala in emotional processes in both animal models and humans. The review is not exhaustive, but it highlights five major research topics that illustrate parallel roles for the amygdala in humans and other animals, including implicit emotional learning and memory, emotional modulation of memory, emotional influences on attention and perception, emotion and social behavior, and emotion inhibition and regulation.     

Amnesia and neglect: beyond the Delay-Brion system and the Hebb synapse.

Hippocampal damage in people causes impairments of episodic memory, but in rats it causes impairments of spatial learning. Experiments in macaque monkeys show that these two kinds of impairment are functionally similar to each other. After any lesion that interrupts the Delay-Brion system (hippocampus, fornix, mamillary bodies and anterior thalamus) monkeys are impaired in scene-specific memory, where an event takes place against a background that is specific to that event. Scene-specific memory in the monkey corresponds to human episodic memory, which is the memory of a unique event set in a particular scene, as opposed to scene-independent human knowledge, which is abstracted from many different scenes. However, interruption of the Delay-Brion system is not sufficient to explain all of the memory impairments that are seen in amnesic patients. To explain amnesia the specialized function of the hippocampus in scene memory needs to be considered alongside the other, qualitatively different functional specializations of other memory systems of the temporal lobe, including the perirhinal cortex and the amygdala. In all these specialized areas, however, including the hippocampus, there is no fundamental distinction between memory systems and perceptual systems. In explaining memory disorders in amnesia it is also important to consider them alongside the memory disorders of neglect patients. Neglect patients fail to represent in memory the side of the world that is contralateral to the current fixation point, in both short- and long-term memory retrieval. Neglect was produced experimentally by unilateral visual disconnection in the monkey, confirming the idea that visual memory retrieval is retinotopically organized; patients with unilateral medial temporal-lobe removals showed lateralized memory impairments for half-scenes in the visual hemifield contralateral to the removal. Thus, in scene-memory retrieval the Delay-Brion system contributes to the retrieval of visual memories into the retinotopically organized visual cortex. This scene memory interpretation of hippocampal function needs to be contrasted with the cognitive-map hypothesis. The cognitive-map model of hippocampal function shares some common assumptions with the Hebb-synapse model of association formation, and the Hebb-synapse model can be rejected on the basis of recent evidence that monkeys can form direct associations in memory between temporally discontiguous events. Our general conclusion is that the primate brain encompasses widespread and powerful memory mechanisms which will continue to be poorly understood if theory and experimentation continue to concentrate too much, as they have in the past, on the hippocampus and the Hebb synapse.     

Hippocampal memory consolidation during sleep: a comparison of mammals and birds

The transition from wakefulness to sleep is marked by pronounced changes in brain activity. The brain rhythms that characterize the two main types of mammalian sleep, slow‐wave sleep (SWS) and rapid eye movement (REM) sleep, are thought to be involved in the functions of sleep. In particular, recent theories suggest that the synchronous slow‐oscillation of neocortical neuronal membrane potentials, the defining feature of SWS, is involved in processing information acquired during wakefulness. According to the Standard Model of memory consolidation, during wakefulness the hippocampus receives input from neocortical regions involved in the initial encoding of an experience and binds this information into a coherent memory trace that is then transferred to the neocortex during SWS where it is stored and integrated within preexisting memory traces. Evidence suggests that this process selectively involves direct connections from the hippocampus to the prefrontal cortex (PFC), a multimodal, high‐order association region implicated in coordinating the storage and recall of remote memories in the neocortex. The slow‐oscillation is thought to orchestrate the transfer of information from the hippocampus by temporally coupling hippocampal sharp‐wave/ripples (SWRs) and thalamocortical spindles. SWRs are synchronous bursts of hippocampal activity, during which waking neuronal firing patterns are reactivated in the hippocampus and neocortex in a coordinated manner. Thalamocortical spindles are brief 7–14 Hz oscillations that may facilitate the encoding of information reactivated during SWRs. By temporally coupling the readout of information from the hippocampus with conditions conducive to encoding in the neocortex, the slow‐oscillation is thought to mediate the transfer of information from the hippocampus to the neocortex. Although several lines of evidence are consistent with this function for mammalian SWS, it is unclear whether SWS serves a similar function in birds, the only taxonomic group other than mammals to exhibit SWS and REM sleep. Based on our review of research on avian sleep, neuroanatomy, and memory, although involved in some forms of memory consolidation, avian sleep does not appear to be involved in transferring hippocampal memories to other brain regions. Despite exhibiting the slow‐oscillation, SWRs and spindles have not been found in birds. Moreover, although birds independently evolved a brain region—the caudolateral nidopallium (NCL)—involved in performing high‐order cognitive functions similar to those performed by the PFC, direct connections between the NCL and hippocampus have not been found in birds, and evidence for the transfer of information from the hippocampus to the NCL or other extra‐hippocampal regions is lacking. Although based on the absence of evidence for various traits, collectively, these findings suggest that unlike mammalian SWS, avian SWS may not be involved in transferring memories from the hippocampus. Furthermore, it suggests that the slow‐oscillation, the defining feature of mammalian and avian SWS, may serve a more general function independent of that related to coordinating the transfer of information from the hippocampus to the PFC in mammals. Given that SWS is homeostatically regulated (a process intimately related to the slow‐oscillation) in mammals and birds, functional hypotheses linked to this process may apply to both taxonomic groups.     

Exposure to neonatal separation stress alters exploratory behavior and corticotropin releasing factor expression in neurons in the amygdala and hippocampus

Evidence is accumulating that early emotional experience interferes with the development of the limbic system, which is involved in perception and regulation of emotional behaviors as well as in learning and memory formation. Limbic brain regions, as well as hypothalamic regions and other, nonlimbic areas contain specific neuron subpopulations, which express and release corticotropin releasing factor (CRF). Since these neurons serve to connect limbic function to endocrine, stress-related responses, we proposed that stressful experience during early postnatal brain development should interfere with the development of CRF-containing neurons, particularly in brain regions essential for emotional regulation. Applying neonatal separation stress (daily 1 h separation from the parents and litter mates) as stressor, the number of immunocytochemically identified CRF-expressing neurons/fibers was quantified in the amygdala, hippocampus, paraventricular nucleus of the hypothalamus, piriform cortex, and the somatosensory cortex of 3-week-old stressed and nonstressed Octodon degus, a semi-precocial rodent. Compared to controls neonatally stressed animals showed significantly lower levels of CRF-positive fibers (-60%) in the central amygdala, significantly less CRF-positive neurons in the dentate gyrus (-28%) and the CA1 region (-29%) and significantly lower CRF cell densities in the somatosensory cortex (-26%). On the other hand, we found significantly higher numbers of CRF-immunoreactive neurons in the basolateral amygdaloid complex (+192%) of stressed animals compared to nonstressed controls. No differences in CRF-immunoreactive cell densities were detected in the other regions. Additional behavioral analysis revealed significantly elevated exploratory behavior (+34%) in stressed animals compared to controls, which might indicate reduced anxiety in the stressed animals.     

A distinct role for norepinephrine in memory retrieval

A role for norepinephrine in learning and memory has been elusive and controversial. A longstanding hypothesis states that the adrenergic nervous system mediates enhanced memory consolidation of emotional events. We tested this hypothesis in several learning tasks using mutant mice conditionally lacking norepinephrine and epinephrine, as well as control mice and rats treated with adrenergic receptor agonists and antagonists. We find that adrenergic signaling is critical for the retrieval of intermediate-term contextual and spatial memories, but is not necessary for the retrieval or consolidation of emotional memories in general. The role of norepinephrine in retrieval requires signaling through the beta(1)-adrenergic receptor in the hippocampus. The results demonstrate that mechanisms of memory retrieval can vary over time and can be different from those required for acquisition or consolidation. These findings may be relevant to symptoms in several neuropsychiatric disorders as well as the treatment of cardiac failure with beta blockers.     

Stress ulcer modulation by limbic system structures.

A number of studies suggest that the telencephalic limbic system modulates stress ulcer development. The amygdala is assumed to connect sensory experiences, including stressful stimuli, with the emotional reactions and gastrointestinal effects normally produce. The hippocampal formation (entorhinal cortex, dentate gyrus, hippocampus) is part of a gating system, modulating the organism's coping ability. Changes in transmission in this temporal brain region are linked to individual differences in stress ulcer severity. Interactions among "classical" transmitters and several neuropeptides mediate these differences.     

Synaptic plasticity, memory and the hippocampus: a neural network approach to causality

Two facts about the hippocampus have been common currency among neuroscientists for several decades. First, lesions of the hippocampus in humans prevent the acquisition of new episodic memories; second, activity-dependent synaptic plasticity is a prominent feature of hippocampal synapses. Given this background, the hypothesis that hippocampus-dependent memory is mediated, at least in part, by hippocampal synaptic plasticity has seemed as cogent in theory as it has been difficult to prove in practice. Here we argue that the recent development of transgenic molecular devices will encourage a shift from mechanistic investigations of synaptic plasticity in single neurons towards an analysis of how networks of neurons encode and represent memory, and we suggest ways in which this might be achieved. In the process, the hypothesis that synaptic plasticity is necessary and sufficient for information storage in the brain may finally be validated.