The Ventral Hippocampus Supports a Memory Representation of Context and Contextual Fear Conditioning: Implications for a Unitary Function of the Hippocampus.

The authors report that either inactivating the ventral hippocampus (VH) with muscimol prior to context preexposure or injecting anisomycin into the VH after preexposure significantly impaired rats' memory for context. Injecting anisomycin into the VH prior to contextual fear conditioning also greatly reduced long-term memory (48-hr retention test) but had no effect on short-term memory (1-hr retention test) for contextual fear. Together with other results, these data suggest that the memory for a novel context is distributed throughout the longitudinal extent of the hippocampus and that this representation helps to support contextual fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Predator odor-induced conditioned fear involves the basolateral and medial amygdala.

The basolateral (BLA) and medial nucleus (MeA) of the amygdala participate in the modulation of unconditioned fear induced by predator odor. However, the specific role of these amygdalar nuclei in predator odor-induced fear memory is not known. Therefore, fiber-sparing lesions or temporary inactivation of the BLA or MeA were made either prior to or after exposure to cat odor, and conditioned contextual fear behavior was examined the next day. BLA and MeA lesions produced significant reductions in cat odor-induced unconditioned and conditioned fear-related behavior. In addition, temporary pharmacological neural inactivation methods occurring after exposure to cat odor revealed subtle behavioral alterations indicative of a role of the BLA in fear memory consolidation but not memory retrieval. In contrast, the MeA appears to play a specific role in retrieval but not consolidation. Results show that the BLA participates in the conditioned and unconditioned cat odor stimulus association that underlies fear memory, underscore a novel role of the MeA in predator odor contextual conditioning, and demonstrate different roles of the BLA and MeA in modulating consolidation and retrieval of predator odor fear memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory Reconsolidation Hypothesis Revived but Restrained: Theoretical Comment on Biedenkapp and Rudy (2004).

J. C. Biedenkapp and J. W. Rudy (2004; see record 2004-19432-009) reported that the protein synthesis inhibitor anisomycin administered into the hippocampus after context preexposure or contextual fear conditioning impaired subsequent retention performance. In contrast, anisomycin administered after context memory retrieval did not impair subsequent contextual fear conditioning. Their findings challenge the hypothesis that memory retrieval induces memory reconsolidation and suggest that the hypothesis needs to be constrained to account for negative findings. However, their evidence does not suggest compelling clues to how the hypothesis might be constrained to accommodate the findings. Thus, it is not yet clear whether their findings can be explained by a revised reconsolidation hypothesis, or whether some other hypothesis is required to account for postretrieval memory impairment, when it is observed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Isolation reduces contextual but not auditory-cue fear conditioning: A role for endogenous opioids.

Isolation for several hours after fear conditioning reduces contextual but not auditory-cue fear conditioning (J. W. Rudy, 1996). This isolation effect is reversed by both centrally and peripherally acting opioid receptor antagonists. As in isolation, systemically administered morphine given immediately after conditioning also reduces contextual fear conditioning. Morphine's effect is also reversed by both centrally and peripherally acting opioid receptor antagonists. Exposure to the conditioning context has been shown to eliminate the effect of isolation on contextual fear conditioning (J. W. Rudy, 1996). Context preexposure also eliminated the effect of morphine on contextual fear conditioning. These results imply that opioids released in the periphery play an important role in producing the isolation effect and that they do so by disrupting the postconditioning memory consolidation processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination

We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a severe deficit in contextual fear if made 1 d, but not 28 d, after fear conditioning (). As such, the hippocampus seems to play a time-limited role in the consolidation of contextual fear conditioning. Here, we examine retrograde amnesia of contextual fear produced by DH lesions in a within-subjects design. Unlike our previous reports, rats had both a remote and recent memory at the time of the lesion. Rats were given 10 tone-shock pairings in one context (remote memory) and 10 tone-shock pairings in a distinct context (with a different tone) 50 d later (recent memory), followed by DH or sham lesions 1 d later. Relative to controls, DH-lesioned rats exhibited no deficit in remote contextual fear, but recent contextual fear memory was severely impaired. They also did not exhibit deficits in tone freezing. This highly specific deficit in recent contextual memory demonstrated in a within-subjects design favors mnemonic over performance accounts of hippocampal involvement in fear. These findings also provide further support for a time-limited role of the hippocampus in memory storage.     

Ontogeny of contextual fear conditioning in rats: Implications for consolidation, infantile amnesia, and hippocampal system function.

Presents developmental evidence that contextual fear conditioning is supported by a short-term memory system that supports conditioning immediately after a shock and by a long-term memory system that supports contextual conditioning 24 hrs after training. This is based on the finding that after 1 conditioning trial, rats 18–32 days old show the same amount of conditioned freezing when tested immediately after conditioning but 18-day-old rats show much less conditioned freezing than the older rats when the retention interval is 24 hrs. The data also suggest that the long-term memory representation of context that mediates conditioned fear is not available until several hours after the conditioning trial. Implications of these findings for memory consolidation processes, infantile amnesia, and hippocampal formation development are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Correlational relationship between shock intensity and corticosterone secretion on the establishment and subsequent expression of contextual fear conditioning.

A role for corticosterone in the consolidation of contextual fear conditioning has previously been proposed. In this study, physiological evidence was found to support this view. The extent of conditioned fear and the levels of plasma corticosterone in rats, after context exposure at training and at different posttraining times (24 hr and 7 days), depended on the intensity of the unconditional stimulus (footshock). In each experimental session, a positive correlation was found between the magnitude of corticosterone levels and the fear-related behavioral inhibition exhibited in the context. Results support the involvement of corticosterone on the processes that occur during consolidation in determining the strength at which the contextual fear conditioning is stored as a long-term memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretraining NMDA receptor blockade in the basolateral complex, but not the central nucleus, of the amygdala prevents savings of the conditional fear.

The acquisition of conditional freezing is abolished by N-methyl-D-aspartate (NMDA) receptor antagonism in the basolateral complex of the amygdala (BLA) during fear conditioning, suggesting that memory formation is prevented. The present study examined whether there is residual memory, or "savings," for fear conditioning in rats trained under amygdaloid NMDA receptor blockade. Rats infused with D,L-2-amino-5-phosphonovalerate (APV) into the BLA or central nucleus of the amygdala (CEA) during fear conditioning did not acquire either auditory or contextual fear conditioning. However, savings of conditional fear was exhibited by rats infused with APV into the CEA but not the BLA. These results suggest that both the BLA and CEA play a critical role in the acquisition of conditional fear but that the BLA is able to process and retain some aspects of aversive memories in the absence of the CEA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of dorsal hippocampus and basolateral amygdala NMDA receptors in the acquisition and retrieval of context and contextual fear memories.

The authors used 3-phase context preexposure facilitation methodology to study the contribution of N-methyl-D-aspartate (NMDA) receptors in dorsal hippocampus (DH) and the basal lateral region of the amygdala (BLA) to (a) acquisition of the context memory, (b) retrieval of the context memory, (c) acquisition of context-shock association, and (d) retrieval of the context-shock association. The NMDA receptor antagonist D-2-amino-5 phosphonopentanoic acid (D-AP5) was injected into either the DH or BLA prior to (a) the context preexposure phase, (b) the immediate shock phase, or (c) the test for contextual fear. Antagonizing NMDA receptors in the DH impaired the acquisition of the context memory but did not affect its retrieval or retrieval of the fear memory. Antagonizing NMDA receptors with D-AP5 in the BLA impaired acquisition of the context-shock association but had no effect on the expression of fear. However, both DL-AP5 and L-AP5 reduced the expression of fear when they were injected into the amygdala prior to testing for contextual fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sleep selectively enhances hippocampus-dependent memory in mice.

Sleep has been implicated as playing a critical role in memory consolidation. Emerging evidence suggests that reactivation of memories during sleep may facilitate the transfer of declarative memories from the hippocampus to the neocortex. Previous rodent studies have utilized sleep-deprivation to examine the role of sleep in memory consolidation. The present study uses a novel, naturalistic paradigm to study the effect of a sleep phase on rodent Pavlovian fear conditioning, a task with both hippocampus-dependent and -independent components (contextual vs. cued memories). Mice were trained 1 hour before their sleep/rest phase or awake/active phase and then tested for contextual and cued fear 12 or 24 hr later. The authors found that hippocampus-dependent contextual memory was enhanced if tested after a sleep phase within 24 hr of training. This enhancement was specific to context, not cued, memory. These findings provide direct evidence of a role for sleep in enhancing hippocampus-dependent memory consolidation in rodents and detail a novel paradigm for examining sleep-induced memory effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Postconditioning isolation disrupts contextual conditioning: an experimental analysis

Contextual-fear conditioning requires a lengthy retention period to fully emerge. This phenomenon might reflect the consolidation of a representation of the context that can be used to evoke fear. To investigate this hypothesis, 25 day-old rats that were returned to their home cages after conditioning were compared with rats that were isolated in a novel room. Isolation disrupted contextual but not auditory-cue fear conditioning when the conditioning-isolation interval was 2 hr or less, but not when it was 24 hr. Preexposure to the context prevented the isolation effect, and isolation disrupted this effect of context preexposure. These results support the consolidation hypothesis and the view that contextual- and auditory-cue fear conditioning depend on different processes.     

Both pre- and posttraining excitotoxic lesions of the basolateral amygdala abolish the expression of olfactory and contextual fear conditioning

The present study examined whether the basolateral amygdaloid complex (BLA) participates in the expression of fear conditioned to both an olfactory conditioned stimulus (CS) and the training context. In Experiment 1, pretraining excitotoxic lesions of the BLA abolished immediate postshock freezing, conditioned freezing to an olfactory CS, and conditioned freezing to the training context. Control experiments indicated that lesioned and sham-lesioned subjects did not differ in locomotor activity or in acquisition of a successive-cue odor discrimination task, suggesting that deficits in freezing behavior exhibited by BLA subjects were not due to an impairment in primary aspects of olfaction or to a general enhancement of locomotor activity. In Experiment 2, excitotoxic lesions of the BLA produced either 1 day or 15 days after olfactory fear conditioning abolished both odor-elicited and contextual freezing. Collectively, these data support the notion that the BLA participates in an enduring manner in the expression of conditioned freezing behavior elicited by both olfactory and contextual stimuli.     

N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats.

Three experiments examined the effects of intra-amygdaloid infusions of an N-methyl-D-aspartate (NMDA) receptor antagonist, D,L-2-amino-5-phosphonovalerate (APV), on contextual fear conditioning in rats. In Experiment 1, APV infusion into the basolateral amygdala (BLA), before training, disrupted the acquisition of contextual fear. In Experiment 2, APV produced a disruption of both the acquisition and expression of contextual fear. This blockade of contextual fear was not state dependent, not due to a shift in footshock sensitivity, and not the result of increased motor activity in APV-treated rats. In Experiment 3, fear conditioning was not affected by a posttraining APV infusion into the BLA. These results indicate that NMDA receptors in the BLA are necessary for both the acquisition and expression of Pavlovian fear conditioning to contextual cues in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats

NMDA receptors in the amygdala seem to be critical for fear conditioning in naive rats. Recent spatial-learning studies suggest that previous learning protected animals from the amnesic effect of NMDA antagonists on new learning (of a similar behavioral task). Therefore, the present study examined whether blocking of NMDA receptors in the basolateral nucleus of the amygdala (BLA) prevents new fear learning in previously fear-conditioned rats, as measured by freezing behavior. Intra-BLA infusions of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) completely blocked fear conditioning to a tone stimulus in animals that had previously been fear-conditioned to a light stimulus. Similar results were obtained with intra-BLA infusions of APV before contextual fear conditioning in rats that had been fear-conditioned to a different context. Additional experiments showed that intra-BLA APV infusions substantially interfere with the expression and extinction of conditioned fear to tone, light, and context stimuli. Together, these results indicate that NMDA receptors in the BLA are crucial for the encoding of new fear memories (i.e., the formation of specific conditioned stimulus-unconditioned stimulus association), the expression of conditioned fear responses, and the extinction of acquired fear.     

DHEA-S selectively impairs contextual-fear conditioning: Support for the antiglucocorticoid hypothesis.

The authors had reported that glucocorticoids play a selective role in fear conditioning. The adrenal steroid dehydroepiandrosterone (DHEA) has been reported to act as a functional antiglucocorticoid. If DHEA has antiglucocorticoid properties, then its effects on fear conditioning might resemble those produced by adrenalectomy. The authors now report that chronic exposure to high levels of dehydroepiandrosterone sulfate (DHEA-S; converted in vivo to DHEA) produced the same pattern of results as adrenalectomy. Specifically, treatment with DHEA-S impaired contextual fear conditioning 24 hr after conditioning but not immediately after conditioning, and like adrenalectomy, DHEA-S had no effect on auditory-cue fear conditioning. Preexposure to the context before drug treatment eliminated the amnestic effects of DHEA-S, suggesting that, like adrenalectomy, DHEA-S exerted its effect by interfering with the construction of a contextual memory representation. Thus, DHEA appears to act as a functional antiglucocorticoid in the processes that mediate learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Associative structure of fear memory after basolateral amygdala lesions in rats.

The authors have recently demonstrated that rats with basolateral amygdala (BLA) lesions acquire Pavlovian fear conditioning after overtraining. However, it is not known whether the associative basis of Pavlovian fear memory acquired by rats with BLA lesions is similar to that of intact rats. Associations are typically formed between the conditional (CS) and unconditional (US) stimuli (stimulus-stimulus; S-S), although it is possible for stimuli to enter into association with the responses they produce (stimulus-response; S-R). Indeed, the central nucleus of the amygdala, which is essential for fear conditioning in rats with BLA lesions, may mediate S-R associations in some Pavlovian tasks. The authors therefore used a postconditioning US inflation procedure (i.e., exposure to intense footshock USs) to assess the contribution of S-S associations to fear conditioning after overtraining in rats with BLA lesions. In Experiment 1, intact rats that were overtrained and later inflated displayed elevated freezing levels when tested, indicating that S-S associations contribute to overtrained fear memories. Interestingly, neither neurotoxic BLA lesions nor temporary inactivation of the BLA during overtraining prevented the inflation effect (Experiment 2 and 3, respectively). These results reveal that S-S associations support Pavlovian fear memories after overtraining in both intact rats and rats with BLA lesions, and imply that the central nucleus of the amygdala encodes CS-US associations during fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nicotine Enhances Contextual Fear Conditioning and Ameliorates Ethanol-Induced Deficits in Contextual Fear Conditioning.

Nicotine and ethanol are 2 commonly used and abused drugs that have divergent effects on learning. The present study examined the effects of acute nicotine (0.25 mg/kg), ethanol (1.0 g/kg), and ethanol-nicotine coadministration on fear conditioning in C57BL/6 mice. Mice were assessed for contextual and cued fear conditioning at 1 day and 1 week posttraining. Ethanol disrupted acquisition but not consolidation of contextual fear conditioning; nicotine enhanced contextual fear conditioning and ameliorated ethanol-associated deficits in contextual fear conditioning. Mecamylamine antagonized this effect. Fear conditioning was reassessed 1 week after initial testing with no drug administered. At the 1-week retest, mice previously treated with nicotine continued to show enhanced contextual fear, and mice previously treated with ethanol continued to show contextual fear deficits. Thus, nicotine both produces a long-lasting enhancement of contextual fear conditioning and protects against ethanol-associated deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disruption of contextual freezing, but not contextual blocking of fear-potentiated startle, after lesions of the dorsal hippocampus.

[Correction Notice: An erratum for this article was reported in Vol 114(2) of Behavioral Neuroscience (see record 2007-17251-001). The captions for Figure 4 (p. 70) and Figure 5 (p. 72) were printed incorrectly. The caption used for Figure 4 should appear under Figure 5, and the caption used for Figure 5 should appear under Figure 4.] The role of the dorsal hippocampus in contextual fear conditioning was investigated with a contextual blocking paradigm. In Experiment 1, rats were given pairings of a light conditioned stimulus (CS) and footshock after preexposure either to footshock or to the context alone. The group preexposed to footshock showed poorer fear conditioning to the light CS, as measured by the fear-potentiated startle reflex. In Experiment 2, a group preexposed to footshock in the same context showed poorer fear conditioning to the light CS than did a group preexposed to footshock in a different context, indicating contextual blocking of fear-potentiated startle. In Experiment 3, lesions of the dorsal hippocampus had no effect on contextual blocking, even though contextual freezing was disrupted. The sparing of contextual blocking indicated that contextual memory was intact following hippocampal lesions, despite the disruption of contextual freezing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: Absence of a temporal gradient.

The role of the basolateral amygdala (BLA) in the acquisition and expression of Pavlovian fear conditioning was examined in 80 rats. Excitotoxic lesions were made in the BLA using N-methyl-{d}-aspartate 7 days before or 1, 14, or 28 days after Pavlovian fear conditioning. Conditioning consisted of three pairings of a tone with an aversive footshock in a novel chamber, and freezing behavior served as an index of conditional fear. BLA lesions abolished conditional freezing to both the contextual and acoustic conditional stimuli at all training-to-lesion intervals, and the magnitude of the impairment did not vary as a function of the training-to-lesion interval. Reacquisition training elevated levels of freezing in rats with BLA lesions but did not reduce the magnitude of their deficit in relation to that of controls. These results reveal that neurons in the BLA have an enduring role in the expression of conditional fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampal formation supports conditioning to memory of a context.

It has been proposed that contextual fear conditioning depends on 2 processes: (a) construction of a conjunctive representation of the features that make up the context and (b) association of the representation with shock. Support for this view comes from studies indicating that prior exposure to the conditioning context facilitates contextual fear conditioning supported by immediate shock. Thus, conditioning produced by immediate shock is to the memory representation of the preexposed context, which is activated by retrieval cues associated with this context. The authors' experiments support this interpretation and indicate that this process depends on an intact hippocampal formation. These results support the hypothesis that the hippocampal formation supports contextual fear conditioning by storing a conjunctive representation of context. (PsycINFO Database Record (c) 2010 APA, all rights reserved)