Stability of recent and remote contextual fear memory

Following initial encoding, memories undergo a prolonged period of reorganization. While such reorganization may occur in many different memory systems, its purpose is not clear. Previously, we have shown that recall of recent contextual fear memories engages the dorsal hippocampus (dHPC). In contrast, recall of remote contextual fear memories engages a number of different cortical regions, including the anterior cingulate cortex (ACC). To examine whether this reorganization leads to greater memory stability, we examined reconsolidation of 1 d-old (recent) and 36 d-old (remote) contextual fear memory in mice. We infused the protein synthesis inhibitor, anisomycin (ANI), into either the dHPC or ACC immediately following retrieval of either a recent or remote contextual fear memory. In the dHPC, ANI infusions disrupted subsequent expression of recent, but not remote, contextual fear memory. Similar infusions into the ACC had no effect on either recent or remote contextual fear memories, whereas systemically applied ANI blocked subsequent remote memory expression when long re-exposure durations were used. Together, these data suggest that as memories mature they become increasingly stable. Furthermore, the dissociation between the effects of systemically and centrally administered ANI on remote memory suggests that stability is due, in part, to the distributed nature of remote contextual fear memories.     

Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning

Many behavioral and electrophysiological studies in animals and humans have suggested that sleep and circadian rhythms influence memory consolidation. In rodents, hippocampus-dependent memory may be particularly sensitive to sleep deprivation after training, as spatial memory in the Morris water maze is impaired by rapid eye movement sleep deprivation following training. Spatial learning in the Morris water maze, however, requires multiple training trials and performance, as measured by time to reach the hidden platform is influenced by not only spatial learning but also procedural learning. To determine if sleep is important for the consolidation of a single-trial, hippocampus-dependent task, we sleep deprived animals for 0–5 and 5–10 h after training for contextual and cued fear conditioning. We found that sleep deprivation from 0–5 h after training for this task impaired memory consolidation for contextual fear conditioning whereas sleep deprivation from 5–10 h after training had no effect. Sleep deprivation at either time point had no effect on cued fear conditioning, a hippocampus-independent task. Previous studies have determined that memory consolidation for fear conditioning is impaired when protein kinase A and protein synthesis inhibitors are administered at the same time as when sleep deprivation is effective, suggesting that sleep deprivation may act by modifying these molecular mechanisms of memory storage.     

Role of amygdala-prefrontal cortex circuitry in regulating the expression of contextual fear memory

The basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) are inter-connected regions involved in fear memory expression. The reciprocal nature of projections between these areas differs along the rostrocaudal extent of BLA. This study investigated the role of functional interactions between BLA and the prelimbic (PL) subregion of mPFC in mediating contextual fear memory. Freezing served as the measure of conditioned fear. Experiments 1–3 examined the effects of left, right or bilateral infusion of bupivacaine into anterior BLA (aBLA), posterior BLA (pBLA) or PL on fear memory expression. Reversible inactivation of left, right or bilateral aBLA impaired fear memory expression. Bilateral inactivation of pBLA or PL also disrupted the expression of fear memory, although left or right inactivation alone had no significant effects in either region. Experiment 4 examined the effects of functionally disconnecting pBLA and PL on contextual fear memory by infusing bupivacaine unilaterally into pBLA and PL in the ipsilateral or contralateral hemisphere. Fear memory expression was impaired by asymmetric inactivation of pBLA and PL; however, a similar effect was also observed with symmetric inactivation of these regions. Bupivacaine infusion did not affect behavior in the open field, likely ruling out non-specific effects of inactivation on innate fear and locomotor activity. These results demonstrate different roles for rostral and caudal BLA in mediating the expression of contextual fear memory. They also raise the possibility that pBLA–PL circuitry is involved in subserving fear memory expression via complex processing mechanisms, although further research is needed to confirm this preliminary finding.     

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.     

Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity

Somatostatin has been implicated in various cognitive and emotional functions, but its precise role is still poorly understood. Here, we have made use of mice with somatostatin deficiency, based upon genetic invalidation or pharmacologically induced depletion, and Pavlovian fear conditioning in order to address the contribution of the somatostatin system to associative fear memory. The results demonstrate an impairment of foreground and background contextual but not tone fear conditioning in mice with targeted ablation of the somatostatin gene. These deficits were associated with a decrease in long-term potentiation in the CA1 area of the hippocampus. Both the behavioral and the electrophysiological phenotypes were mimicked in wild-type mice through application of the somatostatin-depleting substance cysteamine prior to fear training, whereas no further deficits were observed upon application in the somatostatin null mutants. These results suggest that the somatostatin system plays a critical role in the acquisition of contextual fear memory, but not tone fear learning, and further highlights the role of hippocampal synaptic plasticity for information processing concerning contextual information.     

Failure to condition to a cue is associated with sustained contextual fear

The acquisition of a conditioned fear response is adaptive, as it enables the organism to appropriately respond to predictors of aversive events. Consequently, the absence of predictive cues can be used as a signal for safety. We aimed to study whether deficient fear conditioning might lead to maladaptive fear. Following previous work, we predicted that failure to learn the CS-US association would result in higher contextual fear, and that participants who failed to learn would tend to exhibit higher trait anxiety. Conditioning took place in a virtual environment with two contexts. In one of the two contexts, offset of a CS (light) was associated with a shock. Each participant visited two places (a house and an apartment) in each of 12 blocks. In one of these places shocks were administered at the offset of an 8-s period of lights on (CS). The results showed that half of the participants demonstrated differential shock expectancy between situations in the shock context in which the CS was present versus absent. This indicates that these participants learned the contingencies between the shocks and both the context and the light CS. In contrast, the other half of the participants learned only the association with the context. As predicted, learning the CS-US contingency resulted in reduced self-reported fear in the absence of the CS in the danger context compared to the presence of the CS. On the other hand, participants who failed to learn the association displayed a sustained aversive state throughout the duration of the danger context. Skin conductance measures confirmed this pattern of results. Fear-potentiated startle during the threat context compared to the safe context was significant in both groups, while startle was only potentiated during the CS in the threat context in the group that learned the CS association (trend-level significant). Finally, scores on Spielberger's self-report scale of trait anxiety tended to be higher in the group of participants who did not learn the CS-shock association in the danger context compared to participants who did. In conclusion, these results confirm higher contextual fear in participants who did not acquire a conditioned response to the cue in comparison to participants who did. Also, virtual reality contexts provide a useful tool for the study of context conditioning.     

Methylphenidate enhances extinction of contextual fear

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show that MPH, administered before or immediately following extinction of contextual fear, will enhance extinction retention in C57BL/6 mice. Animals that received MPH (2.5-10 mg/kg) before an extinction session showed decreased freezing response during extinction, and the effect of the 10 mg/kg dose on freezing persisted to the next day. When MPH (2.5-40 mg/kg) was administered immediately following an extinction session, mice that received MPH showed dose-dependent decreases in freezing during subsequent tests. MPH administered immediately after a 3-min extinction session or 4 h following the first extinction session did not cause significant differences in freezing. Together, these findings demonstrate that MPH can enhance extinction of fear and that this effect is sensitive to dose, time of injection, and duration of the extinction session. Because MPH is widely used in clinical treatments, these experiments suggest that the drug could be used in combination with behavioral therapies for patients with fear disorders.     

Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats

Facilitation of memory extinction by manipulation of the endocannabinoid (eCB) system has been recently studied in several paradigms. Our previous results pointed to facilitation of contextual fear memory extinction by a low dose of a cannabinoid agonist, with a suggestion of short-term effects. The aim of the present study was to further investigate the effects of cannabinoid drugs in the short- and long-term extinction of conditioned fear using an extended extinction protocol. Male Wistar rats were placed in a conditioning chamber and after 3 min received a footshock (1.5 mA, 1 s). On the next day, they received i.p. drug treatment (WIN55212-2 0.25 mg/kg, AM404 10 mg/kg, SR141716 A 1 mg/kg) and were re-exposed to the conditioning chamber for 30 min (extinction training). No-Extinction groups received the same drug treatment, but were exposed for 3 min to the conditioning chamber. A drug-free test of contextual memory (3 min) was performed 7 days later. The cannabinoid agonist WI55212-2 and the inhibitor of eCB metabolism/uptake AM404 facilitated short-term extinction. In addition, long-term effects induced by treatments with WIN55212 and AM404 were completely divergent to those of SR141716A treatment. The present results confirm and extend previous findings showing that the eCB system modulates short-term fear memory extinction with long-lasting consequences.     

Foreground contextual fear memory consolidation requires two independent phases of hippocampal ERK/CREB activation

Fear conditioning is a popular model for investigating physiological and cellular mechanisms of memory formation. In this paradigm, a footshock is either systematically associated to a tone (paired conditioning) or is pseudorandomly distributed (unpaired conditioning). In the former procedure, the tone/shock association is acquired, whereas in the latter procedure, the context/shock association will prevail. Animals with chronically implanted recording electrodes show enhanced amplitude of the extracellularly recorded field EPSP in CA1 pyramidal cells for up to 24 h after unpaired, but not paired, fear conditioning. This is paralleled by a differential activation of the ERK/CREB pathway in CA1, which is monophasic in paired conditioning (0-15 min post-conditioning), but biphasic (0-1 h and 9-12 h post-conditioning) in unpaired conditioning as revealed by immunocytochemistry and Western blotting. Intrahippocampal injection of the MEK inhibitor U0126 prior to each phase prevents the activation of both ERK1/2 and CREB after unpaired conditioning. Block of any activation phase leads to memory impairment. We finally reveal that the biphasic activation of ERK/CREB activity is independently regulated, yet both phases are critically required for the consolidation of long-term memories following unpaired fear conditioning. These data provide compelling evidence that CA1 serves different forms of memory by expressing differential cellular mechanisms that are dependent on the training regime.     

Resistance to a dynamic world view

The fact that people think is taken for granted. How we go about the thinking process is seldom reflected upon by the individual. In order to be able to grasp complex phenomena, and changing and interdependent relationships students participating in a systems course are required to become aware of their way of performing the thinking process. In discussions with them and based on ‘soft analysis’ it seems that there is resistance to a dynamic, multilevelled thinking process due to habits acquired at school, or perhaps even at an earlier age. The personality structure, and a coherent experience of a complete ‘self’ seems to enhance mental mobility, and the possibility of developing a dynamic world view.     

Post-training administration of corticosterone enhances consolidation of contextual fear memory and hippocampal long-term potentiation in rats

This study was designed to examine the effect of corticosterone on consolidation of contextual fear memory and hippocampal long-term potentiation (LTP) in rats. In Experiment 1, dose–response effects of corticosterone on consolidation of contextual fear memory were determined. Immediately after training in contextual fear conditioning task, rats received different doses of corticosterone. Testing 24 h later, it revealed that corticosterone enhanced memory consolidation in an inverted U shape as evidenced in increased freezing behavior of corticosterone-treated animals. The most effective dose was 3 mg/kg. In Experiment 2, LTP was examined in rats whose memory consolidation has been enhanced with corticosterone. The rats were trained as the above and received corticosterone (3 mg/kg) immediately after training. Immediately or up to one day after retention test, rats were anesthetized with urethane for LTP experiments. For LTP induction, three episodes of high frequency stimuli, 30 s apart, were delivered to the perforant path, each consisting of 10 stimuli at 250 Hz. LTP was assessed by measuring the increase in the initial slope of the population excitatory post-synaptic potentials and the amplitude of the population spikes. Data indicated that animals whose memory has been enhanced by corticosterone, also displayed enhanced hippocampal LTP. The above findings suggest that glucocorticoids may enhance contextual fear memory consolidation via enhancing hippocampal LTP.     

From a linear to a contextual model of the ABCs of RET

The Contextual ABC Model follows from the recognition that the ABCs of RET ... are oversimplified and omit salient information about human disturbance and its treatment (Ellis, 1984). It is an attempt to capture the mutual and reciprocal intricacies of the ABC process, the complexities of human cognition, and the power of the person to create feelings and behaviors, thoughts and ideas, and even environmental events independent of any prior activating stimuli. It is believed that this model adds to the scope and power of RET's theory and practice without subtracting from or omitting what already exists.     

Context preexposure prevents forgetting of a contextual fear memory: implication for regional changes in brain activation patterns associated with recent and remote memory tests

Contextual fear conditioning was maintained over a 15-day retention interval suggesting no forgetting of the conditioning experience. However, a more subtle generalization test revealed that, as the retention interval increased, rats showed enhanced generalized fear to an altered context. Preexposure to the training context prior to conditioning, however, prevented this enhanced generalized fear from developing. These results support the hypothesis that the memory representation of the context degrades as the memory ages and is responsible for enhanced generalization. The implications of these results for systems consolidation versus forgetting interpretations of regional changes in neural activation patterns that occur as memories age are discussed.     

Biphasic ERK1/2 activation in both the hippocampus and amygdala may reveal a system consolidation of contextual fear memory

There is accumulating evidences to suggest that memory consolidation in some conditions involves two waves of neuronal plastic change. Using two fear conditioning procedures in male C57BL/6J mice, we have recently shown that consolidation of the foreground contextual fear memory required two waves of ERK1/2 activation in hippocampal CA1, while consolidation of cue conditioning was only associated with the early phase of activation. The present experiment further showed that this bi-phasic pattern of ERK1/2 activation was not restricted to hippocampal CA1, but could also be observed in other fear memory-related brain areas. The unpaired conditioning procedure (context in foreground) induced two waves of ERK1/2 activation in hippocampal CA1 and CA3, as well as in the LA and BLA nuclei of the amygdala. In contrast, the paired conditioning procedure (context in background) led to a transient early phase only in hippocampal CA1 and LA. In addition, ERK1/2 phosphorylation in the hippocampus was found to correlate with that in the amygdala nuclei specifically after the unpaired procedure. Taken together, our data suggest that the observed biphasic pattern of neuronal plastic events may reflect the interplay between hippocampal and amygdala activity-dependent plasticity critical for the system consolidation of contextual fear memory.     

Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo

The cannabinoid receptor type 1 (CB1) is abundantly expressed in the central nervous system where it negatively controls the release of several neurotransmitters. CB1 activity plays a crucial role in learning and memory and in synaptic plasticity. In the present study, the role of CB1 was investigated in three different hippocampus-dependent memory tasks and in in vivo hippocampal synaptic plasticity in knockout (CB1-ko) and wildtype mice. There was no difference in short-term and long-term social and object recognition memory between CB1-ko and wildtype mice. In contrast, in background contextual fear conditioning CB1-ko mice showed enhanced freezing levels in the conditioning context and increased generalised contextual fear after a high-intensity conditioning foot shock of 1.5 mA, but not after 0.7 mA. In in vivo field potential recordings in the dentate gyrus, CB1-ko mice displayed a decreased paired-pulse facilitation of the populations spikes, suggesting an altered inhibitory synaptic drive onto hippocampal granule cells. Furthermore, CB1-ko mice displayed significantly higher levels of in vivo long-term potentiation (LTP) in the dentate gyrus. In conclusion, CB1 deficiency leads to enhanced contextual fear memory and altered synaptic plasticity in the hippocampus, supporting the key role of endocannabinoid signalling in learning and memory, in particular following highly aversive encounters.     

Hippocampal and extrahippocampal systems compete for control of contextual fear: Role of ventral subiculum and amygdala

Two neural systems, a hippocampal system and an extrahippocampal system compete for control over contextual fear, and the hippocampal system normally dominates. Our experiments reveal that output provided by the ventral subiculum is critical for the hippocampal system to win this competition. Bilateral electrolytic lesions of the ventral subiculum after conditioning, but not before conditioning, impaired contextual fear conditioning. Reversibly inactivating this region by bilateral injections of muscimol produced the same results—no impairment when the injection occurred prior to conditioning but a significant impairment when this region was inactivated after conditioning. Thus, the extrahippocampal system can support contextual fear conditioning if the ventral subiculum is disabled before conditioning but not if it is disabled after conditioning. Our experiments also reveal that the basolateral region of the amygdala (BLA) is where the two systems compete for associative control of the fear system. To test this hypothesis we reasoned that the extrahippocampal system would also acquire associative control over the fear system, even if the hippocampal system were functional, if the basal level of plasticity potential in the BLA could be increased. We did this by injecting the D1 dopamine agonist, {"type":"entrez-protein","attrs":{"text":"SKF82958","term_id":"1156217255","term_text":"SKF82958"}}SKF82958, into the BLA just prior to conditioning. This treatment resulted in a significant increase in freezing when the ventral subiculum was disabled prior to the test. These results are discussed in relationship to the idea that D1 agonists increase plasticity potential by increasing the pool of available extrasynaptic GluR1 receptors in the population of neurons supporting acquired fear.It is generally believed that contextual fear conditioning depends on the hippocampus. However, it is now clear that an extrahippocampal system exists that can also support contextual fear conditioning. The last statement is based on the fact that damage to the hippocampus prior to conditioning has a minor impact on contextual fear (Maren et al. 1997; Frankland et al. 1998; Cho et al. 1999; Wiltgen et al. 2006). In fact, the conclusion that the hippocampus is normally involved in contextual fear conditioning is now based primarily on the finding that damage to the hippocampus after conditioning greatly impairs fear to the context in which conditioning occurs (Maren et al. 1997; Frankland et al. 1998; Anagnostaras et al. 1999; Bannerman et al. 1999; Richmond et al. 1999; Fanselow 2000; Rudy et al. 2004; Wiltgen et al. 2006). Maren et al. (1997) were the first to appreciate the implications of this set of findings. Specifically, they proposed that (1) in the normal animal there is competition between the hippocampal system and an extrahippocampal system for support of contextual fear conditioning, and (2) the hippocampal system normally dominates the extrahippocampal system—preventing it from acquiring the information needed to support fear to the context. This competition hypothesis provides a reasonable account of the lesion data. If the hippocampus is damaged prior to conditioning, then the extrahippocampal system will be able to acquire control over the fear system and generate a fear response at the time of testing. However, if the hippocampal system is functional during conditioning, it will (1) acquire control of the fear system, and (2) prevent the acquisition of control by the extrahippocampal system. Thus, if the hippocampal system is damaged after conditioning, the expression of contextual fear will be impaired, because the information that was acquired by the hippocampal system will not be available and the extrahippocampal system never acquired the relevant information.Maren et al.''s competition hypothesis is accepted by a number of other researchers (Wiltgen and Fanselow 2003; Rudy et al. 2004; Driscoll et al. 2005; Wiltgen et al. 2006). Nevertheless, very little is known about the mediators of this competition. The experiments in this study were aimed at filling some of the gaps in our knowledge of the neural basis of this competition. They are organized around two hypotheses:

• The ability of the hippocampal system to dominate the extrahippocampal system depends on information it provides through the ventral subiculum, a major output region of the hippocampus.
• The locus of the competition is the basolateral region of the amygdala (BLA), which is thought to be critical to the acquisition of conditioned fear and is where information from the hippocampal and extrahippocampal system can converge.

     

Using contextual analysis to investigate the nature of spatial memory

The present study investigated the properties of episodic spatial memory by conducting contextual analysis on spatial memory tasks in a large sample of individuals (N = 778) between the ages of 18 and 92. The results suggest that episodic spatial memory as measured by a dot location task is not uniquely influenced by memory but is strongly influenced by fluid ability (Gf). The spatial memory–Gf relationship is evident and robust even when spatial memory is operationalized with a very simple single-dot location task, suggesting that allocation of attention across space may play a role in the relationship. Results also indicate that the spatial memory–Gf relations are not dependent on complexity of processing, because Gf has a similar magnitude of relations with a more complex version of the dot location task. Collectively, the results suggest that spatial memory likely represents some aspect of fluid intelligence and is not uniquely related to measures of verbal memory.