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Results for “fear conditioning”

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PubMed2003

Memory retrieval after contextual fear conditioning induces c-Fos and JunB expression in CA1 hippocampus.

Using specific polyclonal antisera against c-Fos, JunB, c-Jun and JunD, we tried to identify the candidate transcription factors of the immediate early gene family which may contribute to the molecular processes during contextual memory reconsolidation. For that purpose we analyzed the expression of these proteins in the hippocampus after contextual memory retrieval in a mouse model of fear conditioning. A single exposure to a foot shock of 0.8 mA was sufficient to induce robust contextual fear conditioning in C57BI/6N mice. In these mice context dependent memory retrieval evoked a marked induction of c-Fos and JunB, but not of c-Jun and JunD, in pyramidal CA1 neurons of the dorsal hippocampus. In contrast, mice exposed and re-exposed only to the context, without foot shock, did not show behavioral signs of contextual fear conditioning and exhibited significantly less expression of c-Fos and JunB in CA1 neurons. Mice which received a foot shock but were not re-exposed to the context revealed no immediate early gene induction. These results demonstrate that contextual memory retrieval is associated with de novo synthesis of specific members of the Fos/Jun transcription factor family. Therefore we suggest that these genes may contribute to plasticity and reconsolidation accompanying the retrieval process. The specific activation of CA1 neurons during the retrieval of contextual fear associations supports the postulated concept of a mnemonic role of this hippocampal subsector during the retrieval of contextual informations.

Animals↗
PubMed1998

Effects of sigma receptor ligands on conditioned fear stress.

Mice or rats exhibit a marked suppression of motility when they are replaced in the same environment in which they previously received an electric footshock. To clarify the functional role of sigma receptors in a stressful situation, we investigated the behavioral and neurochemical effects of various sigma receptor ligands on this psychological stress-induced motor suppression, defined as a conditioned fear stress. (+)-SKF-10,047 and dextromethorphan, putative sigma receptor agonists, reversed the conditioned fear stress. However, other sigma receptor ligands, (+)-pentazocine and 1,3-di(2-tolyl)guanidine had no effect. Further, (+)-SKF-10,047, but not (+)-pentazocine, restored the decreased dopamine turnover in the nucleus accumbens in the stressed group to the control level, the effect being consistent with its behavioral effect. We indicated that these controversial results may be due to the presence of multiple types of sigma receptors, and that the activation of phenytoin-sensitive sigma 1 receptors may be involved in the ameliorating effects of sigma receptor agonists on this stress. Our findings suggest that the dysfunction in the mesolimbic dopaminergic neurons is responsible for the development of conditioned fear stress, and that this stress response is restored through phenytoin-sensitive sigma 1 receptors, which are closely connected to the dopaminergic neuronal systems.

Animals↗
PubMed2003

Context fear conditioning inhibits panic-like behavior elicited by electrical stimulation of dorsal periaqueductal gray.

Context fear conditioning has been widely used as an animal model of anxiety whereas electrical stimulation of the dorsal portion of the periaqueductal gray (DPAG) as a model of panic attack. The present study employed these two animal models in order to investigate the influence of anxiety in the occurrence of panic attack. Results indicated that animals exposed to contextual cues that were previously associated with electrical footshocks engaged in robust defensive freezing behavior and were less likely to display flight evoked by electrical stimulation of the DPAG when compared with control animals that were not exposed to the context fear conditioning procedure. These results indicate that activation of the brain mechanisms that underlie anxiety produces an inhibitory effect on panic attack.

Animals↗
PubMedDate not supplied

Involvement of corticotropin-releasing factor in the retrieval process of fear-conditioned ultrasonic vocalization in rats.

The role of the corticotropin-releasing factor (CRF) system in the fear-conditioned ultrasonic vocalizations (USVs) induced by foot shocks in rats was investigated. In the acquisition phase of fear conditioning, the intracerebroventricular administration of CRF receptor antagonist alpha-hCRF attenuated USV responses related to context memory. Even after experiencing eight consecutive days of foot-shock challenges, the alpha-hCRF group emitted similar number of USVs as the control group if they were not given the drug. After the conditioning phase, the groups treated with alpha-hCRF or CRF receptor 1 (CRFR1) antagonist CP-154,526 emitted fewer conditioned USVs than the control group, although there was no difference in the USVs after the shock, which reflected physical stress. These results suggest that the central CRF systems, especially those mediated via CRFR1, are involved in the retrieval process, but not the acquisition or retention processes, of fear-related memory.

Animals↗
PubMedDate not supplied

Deficits in trace cued fear conditioning in galanin-treated rats and galanin-overexpressing transgenic mice.

Galanin inhibits the release of several neurotransmitters and produces performance deficits in a variety of spatial and aversive learning and memory tasks. The experiments in this study investigated the role galanin has in emotional learning and memory using a standard delay cued and contextual fear conditioning task. Rats were administered galanin into the lateral ventricles before training, and scored for freezing behavior in the same context and in a novel context with and without an auditory cue (CS) that had been paired previously with an aversive stimulus (US). Galanin-overexpressing transgenic mice were tested in an identical behavioral protocol. The galanin-administered rats and the transgenic mice were not significantly different from their respective controls on this task. A more challenging trace cued and contextual fear conditioning procedure was administered to separate groups of galanin-treated rats and galanin-overexpressing transgenic mice. Subjects were trained with the same CS and US, however, a 2.5-sec delay was inserted between CS offset and US onset. Following the trace conditioning, rats administered galanin and mice overexpressing galanin both exhibited significantly less freezing to the CS in the novel context as compared with their control groups. These results indicate that the observed disruption of cued fear conditioning was specific to the more difficult trace conditioning task. These findings are the first demonstration that galanin impairs performance on an emotional memory task and support the hypothesis that galanin-induced deficits are specific to more difficult cognitive tasks.

Acoustic Stimulation↗
PubMed2000

Deficits of spatial and non-spatial memory and of auditory fear conditioning following anterior thalamic lesions in mice: comparison with chronic alcohol consumption.

This study was aimed at determining (i) whether or not bilateral subtotal lesions of the anterior thalamic nuclei (ATH) in rodents produced memory deficits for spatial and/or non-spatial information and of auditory fear conditioning, and (ii) if these eventual deficits resemble those produced by chronic alcohol consumption (CAC). Working memory was assessed using both spatial (spontaneous alternation) and non-spatial (temporal alternation) delayed response tasks. Results showed that ATH lesions induced delay-dependent memory impairments in both spatial and non-spatial alternation tasks, as well as a decreased level of auditory and background contextual fear conditioning compared with respective controls. CAC did not induce accelerated rate of forgetting in the spatial and non-spatial tasks, but increased the vulnerability to interference in the spatial task. CAC impaired only background contextual fear conditioning. We conclude that ATH nuclei are involved in the maintenance of information over time, regardless of the nature (spatial vs. non-spatial) of the information, and play a role in associative processes for both unimodal (the tone) and polymodal (contextual) information. In contrast, ATH dysfunction does not account for the memory disorders induced by the CAC treatment. Our results contribute to showing that the functional overlap between the structures comprising the hippocampo-mamillo-thalamic pathway is only partial.

Acoustic Stimulation↗
PubMed1998

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.

Amygdala↗
PubMed1992

Contribution of the amygdala to learning and performance of conditional fear.

The amygdaloid complex appears to be an essential component in the neural systems mediating some forms of aversive Pavlovian conditioning. The relative contribution of this structure to acquisition and performance during fear conditioning was assessed by making temporary lesions in the amygdala prior to training or retention testing in a single-trial Pavlovian conditioning preparation. Microinjection of lidocaine HCl (5.0%, 1.0 microliters) into the amygdala prior to the presentation of a CS signalling footshock resulted in a significant attenuation of the performance of conditional fear, as indexed by the amount of time rats spent engaged in defensive freezing behavior during the retention session. However, similar treatment with lidocaine prior to the training session, during which the CS and UCS were paired, resulted in only a weak reduction in subsequent responding. Thus, while both acquisition- and performance-related processes take place within the amygdala, it appears that the latter are more sensitive to disruption using the present procedures. These results are discussed in terms of the general role played by this structure in aversive learning and motivational processes.

Amygdala↗
PubMed1996

(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated sigma 1 sites.

Mice exhibited a marked suppression of motility when they were replaced in the same environment in which they had previously received an electric footshock. This psychological stress-induced motor suppression, known as conditioned fear stress, was dose dependently attenuated by (+)-N-allylnormetazocine ((+)-SKF-10,047) and by dextromethorphan, putative sigma receptor agonists, but not by other sigma receptor ligands, (+)-pentazocine and 1,3-di-(2-tolyl)guanidine (DTG). Unlike (+)-SKF-10,047 and dextromethorphan, the non-competitive NMDA receptor antagonists, phencyclidine and dizocilpine, attenuated the conditioned fear stress only at high doses that induced marked hypermotility in non-stressed mice. The effects of (+)-SKF-10,047 and dextromethorphan, but not phencyclidine and dizocilpine, on the conditioned fear stress were antagonized by the sigma receptor antagonists, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2- phenylethoxy)phenyl]-ethylamine monohydrochloride) and BMY-14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine- butanol hydrochloride). Interestingly, the effects of (+)-SKF-10,047 and dextromethorphan on the stress response were enhanced by combination with phenytoin, an anticonvulsant drug, whereas those of (+)- pentazocine, DTG, phencyclidine, and dizocilpine were not. These results suggest that activation of phenytoin-regulated type sigma 1 receptors, but not of phencyclidine receptors, is involved in the ameliorating effects of (+)-SKF-10,047 and dextromethorphan on stress-induced motor suppression.

Animals↗
PubMed2003

Regulation of contextual fear conditioning by baseline and inducible septo-hippocampal cyclin-dependent kinase 5.

In this work, we confirm the novel role of cyclin-dependent kinase (Cdk) 5 in associative learning by demonstrating that injection of the Cdk5 inhibitor butyrolactone I into the lateral septum or hippocampus profoundly impaired context-dependent fear conditioning of C57BL/6J mice. However, unlike the inducible up-regulation of Cdk5 and its regulator p35 observed in Balb/c mice, high baseline levels, which were not affected by fear conditioning, were found in C57BL/6J mice. Surprisingly, microinjections of butyrolactone I into the lateral septum or hippocampus significantly decreased baseline Cdk5 activity within the entire septo-hippocampal circuitry, suggesting a functional link between septal and hippocampal Cdk5 activity. Significantly higher levels of the transcription factor Sp4 in the septo-hippocampal system of C57BL/6J mice may account for the high baseline Cdk5/p35 production. On the other hand, the stronger cFos production observed in the lateral septum of fear conditioned Balb/c mice may be responsible, at least in part, for the inducible up-regulation of Cdk5 in this strain. These results suggest that the role of Cdk5 in memory consolidation is strain independent and functionally related to the septo-hippocampal circuitry. However, the molecular regulation of baseline and inducible Cdk5 protein might be different among individual mouse strains and possibly other species.

4-Butyrolactone↗
PubMed2004

Automated measurement of freezing time to contextual and auditory cues in fear conditioning as a simple screening method to assess learning and memory abilities in rats.

In fear-conditioning paradigms, rats display a freezing response not only upon presentation of a conditioned stimulus (usually tone), but also when returned to a conditioning chamber (context) in which they received an unconditioned stimulus (usually a foot shock). These paradigms have intrinsic advantages for screening effects of chemicals on learning and memory, although the time-consuming monitoring of freezing time by human observers may be problematic. In this study, an automated apparatus was developed to optimize a fear-conditioning paradigm for screening. We developed an apparatus that records freezing time measured from body movements detected by passive infrared (PIR) sensors. The apparatus detected freezing time as accurately as the human scoring method, and these data were used to determine learning parameters (freezing time to context or to tone) and a non-learning parameter (freezing time to novel context) in the rats. Rats orally administered the neurotoxic compound trimethyltin (TMT) exhibited decreased freezing levels to context, but not to tone or to novel context. These results suggest that this automated method can be an effective part of a screening program.

Animals↗
PubMed1996

Serotonergic activation reduces defensive freezing in the conditioned fear paradigm.

Our previous study showed that conditioned fear stress (CFS) increased serotonin (5-HT) metabolism in the medial prefrontal cortex and induced freezing behavior. Although these results could support the 5-HT hypothesis of anxiety, the functional significance of the 5-HT response to stress is unclear. In this study, the effects of 5-HT reuptake inhibitors, agonists, antagonists, and diazepam on freezing behavior induced by CFS were examined using a time-sampling procedure. Various doses of test compounds were administered subcutaneously to rats 24 h after the last session of repeated foot-shock for 5 days. Rats were again placed in the shock chamber without shocks 20 min after injections of drugs, and observed. Diazepam (1 mg/kg) and the 5-HT1A agonist ipsapirone (0.5-10 mg/kg) significantly inhibited freezing behavior. L-5-Hydroxytryptophan (with benserazide) and the selective 5-HT reuptake inhibitor citalopram (10 mg/kg) reduced freezing behavior. The 5-HT2 antagonists ICI169,369 and ketanserin failed to change freezing behavior. p-Chlorophenylalanine (200 mg/kg) administered 15 h before the test did not affect freezing. The effect of ipsapirone was not modified in rats with lesions of 5-HT neurons, produced by p-chloroamphetamine (2 x 10 mg/kg). In conclusion, these results suggest the anxiolytic potential of ipsapirone and citalopram, and support the hypothesis that the facilitation of 5-HT neurotransmission decreases anxiety.

Animals↗
PubMed2006

Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala.

Whereas the neuronal substrates underlying the acquisition of auditory fear conditioning have been widely studied, the substrates and mechanisms mediating the acquisition of fear extinction remain largely elusive. Previous reports indicate that consolidation of fear extinction depends on the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) signalling pathway and on protein synthesis in the medial prefrontal cortex (mPFC). Based on experiments using the fear-potentiated startle paradigm suggesting a role for neuronal plasticity in the basolateral amygdala (BLA) during fear extinction, we directly addressed whether MAPK/ERK signalling in the basolateral amygdala is necessary for the acquisition of fear extinction using conditioned freezing as a read-out. First, we investigated the regional and temporal pattern of MAPK/ERK activation in the BLA following extinction learning in C57Bl/6J mice. Our results indicate that acquisition of extinction is associated with an increase of phosphorylated MAPK/ERK in the BLA. Moreover, we found that inhibition of the MAPK/ERK signalling pathway by intrabasolateral amygdala infusion of the MEK inhibitor, U0126, completely blocks acquisition of extinction. Thus, our results indicate that the MAPK/ERK signalling pathway is required for extinction of auditory fear conditioning in the BLA, and support a role for neuronal plasticity in the BLA during the acquisition of fear extinction.

Acoustic Stimulation↗
PubMed1998

Effects of 7-nitroindazole, a neuronal nitric oxide synthase (nNOS) inhibitor, on locomotor activity and contextual fear conditioning in rats.

The effect of 7-nitroindazole (7-NI), a selective neuronal nitric oxide synthase (nNOS) inhibitor, on contextual fear conditioning in rats was examined. Systemic administration of 7-NI did not affect the acquisition of contextual fear (measured as freezing), but it did reduce locomotor activity and cause a corresponding increase in the expression of contextual freezing. It is concluded that nNOS activity is not required for either the acquisition or expression of contextual fear conditioning.

Animals↗
PubMedDate not supplied

ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning.

Long-term memory formation is regulated by many distinct molecular mechanisms that control gene expression. An emerging model for effecting a stable, coordinated pattern of gene transcription involves epigenetic tagging through modifications of histones or DNA. In this study, we investigated the regulation of histone phosphorylation in the hippocampus by the ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway. We found that activation of ERK/MAPK in vitro significantly increased histone H3 phosphorylation in hippocampal area CA1. Furthermore, we found that contextual fear conditioning in vivo leads to a rapid time-dependent increase in histone H3 phosphorylation in area CA1. This increase paralleled the time course of contextual fear-dependent activation of ERK, and was inhibited in vivo by a latent inhibition paradigm as well as by injection of an N-methyl-d-aspartic acid receptor (NMDA-R) antagonist. Finally, injection of an inhibitor of MEK (MAP kinase/ERK kinase), the unique dual-specificity kinase upstream of ERK, blocked the increase in histone H3 phosphorylation seen after contextual fear conditioning. These results demonstrate that changes in histone phosphorylation in the hippocampus are regulated by ERK/MAPK following a behavioral fear conditioning paradigm.

Animals↗
PubMed2006

Posttraining lesions of the auditory thalamus, but not cortex, disrupt the inhibition of fear conditioned to an auditory stimulus.

The purpose of this study was to examine the effects of lesions within the auditory system in an effort to disrupt the processing of the noise stimulus conditioned to inhibit fear. To accomplish this, three experiments were conducted in which rats were first given feature-negative discrimination training in which a noise was conditioned to inhibit fear to a light that signals danger. Following training, rats were given lesions of the medial geniculate body (MGB), auditory thalamus (ADT), or auditory cortex (CTX). Next, rats were tested for the ability to inhibit fear in the presence of the noise safety signal. The results of these experiments indicated that bilateral lesions of ADT disrupted the ability of the noise inhibitor to inhibit fear. In contrast, lesions largely restricted to the MGB or CTX did not disrupt the inhibition of fear. Along with past studies, these results suggest that an auditory pathway(s), which includes projections from the tectum to the ADT, is used to detect the safety properties previously conditioned to an auditory stimulus.

Acoustic Stimulation↗
PubMed2006

Influence of the stress hormone cortisol on fear conditioning in humans: evidence for sex differences in the response of the prefrontal cortex.

The stress hormone cortisol is known to influence declarative memory and associative learning. In animals, stress has often been reported to have opposing effects on memory and learning in males and females. In humans, the effects of cortisol have mainly been studied at the behavioral level. The aim of the present experiment was to characterize the effects of a single cortisol dose (30 mg) on the hemodynamic correlates of fear conditioning. In a double-blind group comparison study subjects (17 females and 17 males) received 30 mg cortisol or placebo orally before participating in a discriminative fear conditioning paradigm. Results revealed that cortisol impaired electrodermal signs of learning (the first interval response) in males, while no conditioned SCRs emerged for the females independent of treatment. fMRI results showed that cortisol reduced activity for the CS+ > CS- comparison in the anterior cingulate, the lateral orbitofrontal cortex and the medial prefrontal cortex in males. Opposite findings (increase in these regions under cortisol) were detected in females. In addition, cortisol reduced the habituation in the CS+ > CS- contrast in the dorsolateral prefrontal cortex independent of sex. Finally, cortisol also modified the response to the electric shock (the UCS) by enhancing the activity of the anterior as well as the posterior cingulate. In sum, these findings demonstrate that in humans cortisol mostly influences prefrontal brain activation during fear conditioning and that these effects appear to be modulated by sex.

Adult↗
PubMed2000

Antisense DNA against calcineurin facilitates memory in contextual fear conditioning by lowering the threshold for hippocampal long-term potentiation induction.

In the previous study, we demonstrated that the antisense oligodeoxynucleotides against calcineurin Aalpha and Abeta, catalytic subunits of Ca(2+)/calmodulin-dependent protein phosphatase, produce a facilitatory effect on long-term potentiation induction in the hippocampal CA1 region in rats anesthetized with urethane. Here, we have studied how animals, in which the hippocampal long-term potentiation induction is enhanced by antisense oligodeoxynucleotides against calcineurin, perform in learning tasks that depend on hippocampal function. The rats received antisense oligodeoxynucleotides by bilateral ventricular administration via miniosmotic pumps. We tested four groups of rats, three infused with either antisense oligodeoxynucleotides, scramble oligodeoxynucleotides, or saline, and untreated rats, for two types of hippocampus-dependent learning, water maze and contextual fear conditioning. After the behavioral tests, we conducted a long-term potentiation induction test to determine whether long-term potentiation induction was enhanced. In contextual fear conditioning, rats in which long-term potentiation induction was enhanced by antisense oligodeoxynucleotides displayed significantly more conditioned freezing response than control rats. Rats with enhanced long-term potentiation induction showed no differences in shock sensitivity, general activity, or light-dark choice from control rats. In contrast with contextual fear conditioning, rats with enhanced long-term potentiation induction showed no difference in spatial learning performance on the water maze compared with control rats. These results demonstrate that an enhancement in long-term potentiation induction produced by the inhibition of calcineurin leads to an increase in memory strength in specific forms of hippocampus-dependent learning.

Animals↗