Selective neurotoxic lesions of basolateral and central nuclei of the amygdala produce differential effects on fear conditioning.
(1/236)
In the fear conditioning literature, it is generally hypothesized that neurons in the basolateral amygdalar complex (BLA) (lateral and basal nuclei) support the formation of conditioned fear memory and project to neurons in the central nucleus (CeA) for the expression of conditioned fear responses. According to this serial processing-transmission view, damage to either BLA or CeA would comparably disrupt the expression of a variety of conditioned fear responses. In the present study, we further investigated the roles of BLA and CeA in fear conditioning by concurrently assessing freezing and 22 kHz ultrasonic vocalization (USV) as dependent measures of fear in rats. Selective neurotoxins, NMDA for the BLA and ibotenic acid for the CeA, were used to destroy intrinsic neurons [evidenced by thionin dye and NeuN (neuronal nuclei) antibody stainings] without damaging the fibers of passage (confirmed by myelin staining). During the 10 tone-footshock paired training, postshock freezing and USV responses were significantly impaired in BLA-lesioned animals, whereas CeA-lesioned animals exhibited only mild deficits. Similarly, conditioned fear responses assessed 24 hr after training were severely reduced in BLA-lesioned animals but not in CeA-lesioned animals. In contrast to ibotenic lesions of the CeA, small electrolytic lesions of the CeA strongly affected both postshock and conditioned freezing and USV. Together, these results do not support the currently espoused BLA-to-CeA serial processing-transmission view of fear conditioning. Instead, the expression of conditioned fear appears to primarily involve BLA projections that course through the CeA en route to downstream fear response structures. (+info)
An egr-1 (zif268) antisense oligodeoxynucleotide infused into the amygdala disrupts fear conditioning.
(2/236)
Studies of gene expression following fear conditioning have demonstrated that the inducible transcription factor, egr-1, is increased in the lateral nucleus of the amygdala shortly following fear conditioning. These studies suggest that egr-1 and its protein product Egr-1 in the amygdala are important for learning and memory of fear. To directly test this hypothesis, an egr-1 antisense oligodeoxynucleotide (antisense-ODN) was injected bilaterally into the amygdala prior to contextual fear conditioning. The antisense-ODN reduced Egr-1 protein in the amygdala and interfered with fear conditioning. A 250-pmole dose produced an 11% decrease in Egr-1 protein and reduced long-term memory of fear as measured by freezing in a retention test 24 h after conditioning, but left shock-induced freezing intact. A larger 500-pmole dose produced a 25% reduction in Egr-1 protein and significantly decreased both freezing immediately following conditioning and freezing in the retention test. A nonsense-ODN had no effect on postshock or retention test freezing. In addition, 500 pmole of antisense-ODN infused prior to the retention test in previously trained rats did not reduce freezing, indicating that antisense-ODN did not suppress conditioned fear behavior. Finally, rats infused with 500 pmole of antisense-ODN displayed unconditioned fear to a predator odor, demonstrating that unconditioned freezing was unaffected by the antisense-ODN. The data indicate that the egr-1 antisense-ODN interferes with learning and memory processes of fear without affecting freezing behavior and suggests that the inducible transcription factor Egr-1 within the amygdala plays important functions in long-term learning and memory of fear. (+info)
Extinction memory improvement by the metabolic enhancer methylene blue.
(3/236)
We investigated whether postextinction administration of methylene blue (MB) could enhance retention of an extinguished conditioned response. MB is a redox compound that at low doses elevates cytochrome oxidase activity, thereby improving brain energy production. Saline or MB (4 mg/kg intraperitoneally) were administered to rats for 5 d following extinction training of tone-footshock conditioning. Postextinction freezing was lower in rats receiving MB compared with saline, suggesting that MB improved retention of the extinction memory. The MB effect was specific to tone-evoked freezing because there were no differences in pretone freezing. Control subjects similarly injected with MB showed no evidence of nonspecific effects on measures of motor activity and fearfulness. MB-treated rats exhibited both greater retention of extinction and greater overall brain metabolic activity. Rats with higher retention of extinction also showed a relative increase in cytochrome oxidase activity in prefrontal cortical regions, especially anterior infralimbic cortex, dorsal and medial frontal cortex, and lateral orbital cortex. These regional metabolic increases were also correlated to the behavioral freezing index used to assess retention of extinction. It was concluded that MB administered postextinction could enhance retention of extinction memory through an increase in brain cytochrome oxidase activity. (+info)
Olfactory fear conditioning induces field potential potentiation in rat olfactory cortex and amygdala.
(4/236)
The widely used Pavlovian fear-conditioning paradigms used for studying the neurobiology of learning and memory have mainly used auditory cues as conditioned stimuli (CS). The present work assessed the neural network involved in olfactory fear conditioning, using olfactory bulb stimulation-induced field potential signal (EFP) as a marker of plasticity in the olfactory pathway. Training consisted of a single training session including six pairings of an odor CS with a mild foot-shock unconditioned stimulus (US). Twenty-four hours later, the animals were tested for retention of the CS as assessed by the amount of freezing exhibited in the presence of the learned odor. Behavioral data showed that trained animals exhibited a significantly higher level of freezing in response to the CS than control animals. In the same animals, EFPs were recorded in parallel in the anterior piriform cortex (aPC), posterior piriform cortex (pPC), cortical nucleus of the amygdala (CoA), and basolateral nucleus of the amygdala (BLA) following electrical stimulation of the olfactory bulb. Specifically, EFPs recorded before (baseline) and after (during the retention test) training revealed that trained animals exhibited a lasting increase (present before and during presentation of the CS) in EFP amplitude in CoA, which is the first amygdaloid target of olfactory information. In addition, a transient increase was observed in pPC and BLA during presentation of the CS. These data indicate that the olfactory and auditory fear-conditioning neural networks have both similarities and differences, and suggest that the fear-related behaviors in each sensory system may have at least some distinct characteristics. (+info)
Nonassociative learning processes determine expression and extinction of conditioned fear in mice.
(5/236)
Freezing to a tone following auditory fear conditioning is commonly considered as a measure of the strength of the tone-shock association. The decrease in freezing on repeated nonreinforced tone presentation following conditioning, in turn, is attributed to the formation of an inhibitory association between tone and shock that leads to a suppression of the expression of fear. This study challenges these concepts for auditory fear conditioning in mice. We show that acquisition of conditioned fear by a few tone-shock pairings is accompanied by a nonassociative sensitization process. As a consequence, the freezing response of conditioned mice seems to be determined by both associative and nonassociative memory components. Our data suggest that the intensity of freezing as a function of footshock intensity is primarily determined by the nonassociative component, whereas the associative component is more or less categorical. We next demonstrate that the decrease in freezing on repeated nonreinforced tone presentation following conditioning shows fundamental properties of habituation. Thus, it might be regarded as a habituation-like process, which abolishes the influence of sensitization on the freezing response to the tone without affecting the expression of the associative memory component. Taken together, this study merges the dual-process theory of habituation with the concept of classical fear conditioning and demonstrates that sensitization and habituation as two nonassociative learning processes may critically determine the expression of conditioned fear in mice. (+info)
Plasticity in the entorhinal cortex suppresses memory for contextual fear.
(6/236)
Several studies have delineated a role for the hippocampus in fear conditioning. However, in this task, the role of the entorhinal cortex (EC), the main input-output structure for the hippocampus, is uncertain. The extracellular signal-regulated kinase (ERK) cascade has been shown to be a molecular correlate for long-term memory, and its activity is required for various types of memory storage, including fear memory. In this study, we show that ERK activity in the EC increased 90 min after fear conditioning. Post-training intra-EC infusion of ERK cascade inhibitors (PD098059, UO126) at 40 min, but not at 10 min, resulted in increased freezing to the context, but not to the tone, during a 48 hr retention test. Interestingly, both PD098059- and UO126-infused animals also demonstrated anticipatory freezing in the context, freezing maximally at the time the shock was given during training. This anticipatory behavior was also seen in naive animals receiving additional training. Together, these results suggest that ERK-mediated plasticity in the EC normally suppresses context-specific fear memory, especially the temporal nature of the freezing response, and that blocking this plasticity mimics the effects of additional training. (+info)
The neuronal response to a Ca2+ stimulus is a complex process involving direct Ca2+/calmodulin (CaM) actions as well as secondary activation of multiple signaling pathways such as cAMP and ERK (extracellular signal-regulated kinase). These signals can act in both the cytoplasm and the nucleus to control gene expression. To dissect the role of nuclear from cytoplasmic Ca2+/CaM signaling in memory formation, we generated transgenic mice that express a dominant inhibitor of Ca2+/CaM selectively in the nuclei of forebrain neurons and only after the animals reach adulthood. These mice showed diminished neuronal activity-induced phosphorylation of cAMP response element-binding protein, reduced expression of activity-induced genes, altered maximum levels of hippocampal long-term potentiation, and severely impaired formation of long-term, but not short-term, memory. Our results demonstrate that nuclear Ca2+/CaM signaling plays a critical role in memory consolidation in the mouse. (+info)
Perirhinal and postrhinal contributions to remote memory for context.
(8/236)
The perirhinal (PER) and postrhinal (POR) cortices, two components of the medial temporal lobe memory system, are reciprocally connected with the hippocampus both directly and via the entorhinal cortex. Damage to PER or POR before or shortly after training on a contextual fear conditioning task causes deficits in the subsequent expression of contextual fear, implicating these regions in the acquisition or expression of contextual memory. Here, we examined the contribution of PER and POR to the processing of remotely learned contextual information. Male Long-Evans rats were trained in an unsignaled contextual fear conditioning paradigm. After training, rats received bilateral neurotoxic lesions to PER or POR or sham control surgeries at three different training-to-lesion intervals: 1, 28, or 100 d after training. Two weeks after surgery, lesioned and control rats were returned to the training context to assess contextual fear as measured by freezing. Rats with PER or POR damage froze significantly less in the training context than control rats but were not different from each other. The severity of the deficit did not differ across training-to-lesion intervals for any group. This pattern of deficits differs from that of posttraining hippocampal lesions, for which longer training-to-lesion intervals produce significantly more fear-conditioned contextual freezing than shorter training-to-lesion intervals. In the absence of such a retrograde gradient in the present study, our interpretation is that PER and POR have an ongoing role in the storage or retrieval of representations for context. Alternatively, these regions may be involved in a more extended consolidation process that becomes apparent beyond 100 d after learning. (+info)