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Results for “fear conditioning”

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At least 19 recordsLinked to original sources

PubMed2003

L-type voltage-gated calcium channels are involved in the in vivo and in vitro expression of fear conditioning.

Fear conditioning, a behavioral model of fear learning and cue-related anxiety, causes enhanced neuronal transmission in the thalamic to lateral amygdala pathway.(1,2) In the expression phase of learned fear, this increased transmission recorded in vitro is revealed in increased amplitudes of excitatory postsynaptic currents (EPSCs) and occlusion of paired-pulse facilitation (PPF) implicating a presynaptic increase in transmitter release. Here we examined the contribution of L-type calcium channels in fear conditioning. We measured the effect of nimodipine (Nim, 1.5-20 mg/kg), an L-type calcium channel antagonist, on fear-potentiated startle in which startle was assessed in animals receiving paired or unpaired tone and foot shock. Nim administered intraperitoneally blocked fear-potentiated startle but not baseline startle in a dose-dependent manner. We also analyzed the effect of Nim (10 micro M) in vitro on synaptic facilitation of EPSCs and PPF in slices from naïve control, unpaired control, and fear-conditioned animals. In neurons from naïve control animals, Nim had no effect on EPSC amplitude or PPF, but in slices from fear-conditioned rats, Nim reduced EPSC amplitude, suggesting the recruitment of L-type calcium channels within the fear-conditioning pathway. Nim increased PPF in slices from fear-conditioned animals, suggesting that L-type calcium channels may contribute to increased probability of release in fear conditioning. In slices from unpaired animals, Nim decreased synaptic transmission but had little effect on PPF, suggesting that stress or contextual fear learning may induce L-type channel activity in fear-conditioned and unpaired control animal groups. We also analyzed protein expression of the alpha(1C) and alpha(1D) L-type calcium channel subunits isolated from the amygdala and found that alpha(1C) protein was significantly increased in fear-conditioned animals. These findings suggest that L-type calcium channels play a role in the amygdala in cued fear conditioning and have important implications in the treatment of anxiety and in emotional learning and plasticity.

Animals↗

PubMed2005

Effects of pre- or post-training entorhinal cortex AP5 injection on fear conditioning.

Fear conditioning is one of the most studied paradigms to assess the neural basis of emotional memory. The circuitry involves NMDA receptor activation in the amygdala and, in the case of contextual conditioning, in the hippocampus. Entorhinal cortex is one of the major input/output structures to the hippocampus and also projects to the amygdala, both through glutamatergic transmission. Other learning tasks involving hippocampus and amygdala, such as inhibitory avoidance, require entorhinal cortex during acquisition and consolidation. However, the involvement of NMDA receptors mediated transmission in entorhinal cortex in fear conditioning acquisition and consolidation is not clear. To investigate that issue, rats were trained in fear conditioning to both contextual and tone conditioned stimulus. Immediately before, immediately, 30 or 90 min after training they received NMDA antagonist AP5 or saline injections bilaterally in the entorhinal cortex (AP-6.8 mm, L +/-5.0 mm DV-6.8 mm). Contextual fear conditioning was measured 24 h after training, and tone fear conditioning 48 h after training. AP5 injections selectively impaired contextual fear conditioning only when injected pre-training. Post-training injections had no effect. These findings suggest that entorhinal cortex NMDA receptors are necessary for acquisition, but not for consolidation, of contextual fear conditioning. On the other hand, both acquisition and consolidation of tone fear conditioning seem to be independent of NMDA receptors in the entorhinal cortex.

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning.

Fear conditioning is a form of associative learning in which subjects come to express defense responses to a neutral conditioned stimulus (CS) that is paired with an aversive unconditioned stimulus (US). Considerable evidence suggests that critical neural changes mediating the CS-US association occur in the lateral nucleus of the amygdala (LA). Further, recent studies show that associative long-term potentiation (LTP) occurs in pathways that transmit the CS to LA, and that drugs that interfere with this LTP also disrupt behavioral fear conditioning when infused into the LA, suggesting that associative LTP in LA might be a mechanism for storing memories of the CS-US association. Here, we develop a detailed cellular hypothesis to explain how neural responses to the CS and US in LA could induce LTP-like changes that store memories during fear conditioning. Specifically, we propose that the CS evokes EPSPs at sensory input synapses onto LA pyramidal neurons, and that the US strongly depolarizes these same LA neurons. This depolarization, in turn, causes calcium influx through NMDA receptors (NMDARs) and also causes the LA neuron to fire action potentials. The action potentials then back-propagate into the dendrites, where they collide with CS-evoked EPSPs, resulting in calcium entry through voltage-gated calcium channels (VGCCs). Although calcium entry through NMDARs is sufficient to induce synaptic changes that support short-term fear memory, calcium entry through both NMDARs and VGCCs is required to initiate the molecular processes that consolidate synaptic changes into a long-term memory.

Amygdala↗

PubMed2005

Amygdala, long-term potentiation, and fear conditioning.

Fear conditioning, during which emotional significance is attached to an initially biologically insignificant conditioned stimulus, when such neutral stimulus is paired with an aversive unconditioned stimulus, provides an experimental paradigm that is most commonly used to study fear learning. The amygdala, a sub-cortical nuclear group, is a brain structure critically important for fear conditioning. Recent studies indicate that both fear conditioning-induced neuronal plasticity and LTP at the amygdala synapses share common mechanisms of induction and expression. These findings provide the most direct evidence yet available that the mechanisms of LTP are recruited in the experimental animals during behavioral training and that such mechanisms might be utilized for memory storage.

Amygdala↗

PubMed2004

Impact of healthy aging on awareness and fear conditioning.

Fear conditioning has provided a useful model system for studying associative emotional learning, but the impact of healthy aging has gone relatively unexplored. The present study investigated fear conditioning across the adult life span in humans. A delay discrimination task was employed using visual conditioned stimuli and an auditory unconditioned stimulus. Awareness of the reinforcement contingencies was assessed in a postexperimental interview. Compared with young adult participants, middle-aged and older adults displayed reductions in unconditioned responding, discriminant conditioning, and contingency awareness. When awareness and overall arousability were taken into consideration, there were no residual effects of aging on conditioning. These results highlight the importance of considering the influence of declarative knowledge when interpreting age-associated changes in discriminative conditioned learning.

Adolescent↗

PubMed1997

Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats.

Electrolytic lesions of the dorsal hippocampus (DH) produce deficits in both the acquisition and expression of conditional fear to contextual stimuli in rats. To assess whether damage to DH neurons is responsible for these deficits, we performed three experiments to examine the effects of neurotoxic N-methyl-D-aspartate (NMDA) lesions of the DH on the acquisition and expression of fear conditioning. Fear conditioning consisted of the delivery of signaled or unsignaled footshocks in a novel conditioning chamber and freezing served as the measure of conditional fear. In Experiment 1, posttraining DH lesions produced severe retrograde deficits in context fear when made either 1 or 28, but not 100, days following training. Pretraining DH lesions made 1 week before training did not affect contextual fear conditioning. Tone fear was impaired by DH lesions at all training-to-lesion intervals. In Experiment 2, posttraining (1 day), but not pretraining (1 week), DH lesions produced substantial deficits in context fear using an unsignaled shock procedure. In Experiment 3, pretraining electrolytic DH lesions produced modest deficits in context fear using the same signaled and unsignaled shock procedures used in Experiments 1 and 2, respectively. Electrolytic, but not neurotoxic, lesions also increased pre-shock locomotor activity. Collectively, this pattern of results reveals that neurons in the DH are not required for the acquisition of context fear, but have a critical and time-limited role in the expression of context fear. The normal acquisition and expression of context fear in rats with neurotoxic DH lesions made before training may be mediated by conditioning to unimodal cues in the context, a process that may rely less on the hippocampal memory system.

Animals↗

PubMed2003

Effects of dorsal striatum lesions in tone fear conditioning and contextual fear conditioning.

It has been suggested that the striatum mediates hippocampus-independent memory tasks. Classical fear conditioning to a discrete stimulus such as a tone is not affected by hippocampal lesion, whereas contextual fear conditioning is an hippocampus dependent task. The purpose of the present study was to verify the effect of dorsal striatal lesions on tone and contextual fear conditioning. The lesioned rats were not impaired in contextual fear conditioning but in tone fear conditioning both electrolytically and neurotoxically lesioned animals showed less freezing compared with controls. The lesion effect was observed after a postoperative recovery period of 14 days but not after 2 months. The results support the hypothesis that the dorsal striatum is involved in hippocampus-independent memory tasks, but, in spite of this involvement, it does not seem to be a critical structure.

Acoustic Stimulation↗

PubMed2005

Amygdalar unit activity during three learning tasks: eyeblink classical conditioning, Pavlovian fear conditioning, and signaled avoidance conditioning.

Neural activity in central and basolateral amygdala nuclei (CeA and BLA, respectively) was recorded during delay eyeblink conditioning, Pavlovian fear conditioning, and signaled barpress avoidance. During paired training, the CeA exhibited robust learning-related excitatory activity during all 3 tasks. By contrast, the BLA exhibited minimal activity during eyeblink conditioning, while demonstrating pronounced increases in learning-related excitatory responsiveness during fear conditioning and barpress avoidance. In addition, the relative amount of amygdalar activation observed appeared to be related to the relative intensity of the unconditioned stimulus and somatic requirements of the task. Results suggest the CeA mediates the Pavlovian association between sensory stimuli and the BLA mediates the modulation of instrumental responding through the assignment of motivational value to the unconditioned stimulus.

Action Potentials↗

PubMed1998

Hippocampectomy disrupts auditory trace fear conditioning and contextual fear conditioning in the rat.

The hippocampus is believed to be an important structure for learning tasks that require temporal processing of information. The trace classical conditioning paradigm requires temporal processing because the conditioned stimulus (CS) and the unconditioned stimulus (US) are temporally separated by an empty trace interval. The present study sought to determine whether the hippocampus was necessary for rats to perform a classical trace fear conditioning task in which each of 10 trials consisted of an auditory tone CS (1 5-s duration) followed by an empty 30-s trace interval and then a fear-producing floor-shock US (0.5-s duration). Several weeks prior to training, animals were anesthetized and given aspiration lesions of the neocortex (NEO; n = 6), hippocampus and overlying neocortex (HIPP; n = 7), or no lesions at all (control; n = 6). Approximately 24 h after trace conditioning, NEO and control animals showed a significant decrease in movement to a CS-alone presentation that was indicative of a conditioned fear response. Animals in the HIPP group did not show conditioned fear responses to the CS alone, nor did a pseudoconditioning group (n = 7) that was trained with unpaired CSs and USs. Furthermore, all groups except the HIPP group showed conditioned fear responses to the original context in which they received shock USs. One week later, HIPP, NEO, and control animals received delay fear-conditioning trials with no trace interval separating the CS and US. Six of seven HIPP animals could perform the delay version, but none could perform the trace version. This result suggests that the trace fear task is a reliable and useful model for examining the neural mechanisms of hippocampally dependent learning.

Acoustic Stimulation↗

PubMed2004

Corticosterone facilitates retention of contextually conditioned fear and increases CRH mRNA expression in the amygdala.

The present study examined the effects of glucocorticoid administration on emotional memory and on corticotropin-releasing hormone (CRH) mRNA expression in the central nucleus of the amygdala (CeA) and the paraventricular nucleus of the hypothalamus (PVN). This was tested by administering repeated corticosterone (CORT) within a contextual fear conditioning paradigm. Rats received 2.5 mg/kg (s.c.) CORT or placebo twice a day for five and a half days and, 2 h after the last injection, rats were given one-trial contextual fear conditioning. When tested for retention of conditioned fear 6 days later, the CORT-treated rats displayed more fear-conditioned freezing in the retention test than vehicle-treated rats, which was not accounted for by an increase in footshock responsivity nor elevated plasma CORT. Another group of rats was fear conditioned prior to CORT administration, followed 24 h later by the five and a half days of CORT, and tested 6 days later; conditioned fear was not enhanced in these rats. Finally, CORT administration produced an increase of CRH mRNA in the CeA and a decrease in the PVN. The data suggest that repeated administration of CORT given before fear conditioning facilitates the acquisition of emotional memory, whereas CORT given after consolidation does not increase emotional memory.

Amygdala↗

PubMed2004

NMDA receptors are essential for the acquisition, but not expression, of conditional fear and associative spike firing in the lateral amygdala.

We examined the contribution of N-methyl-D-aspartate (NMDA) receptors (NMDARs) to the acquisition and expression of amygdaloid plasticity and Pavlovian fear conditioning using single-unit recording techniques in behaving rats. We demonstrate that NMDARs are essential for the acquisition of both behavioral and neuronal correlates of conditional fear, but play a comparatively limited role in their expression. Administration of the competitive NMDAR antagonist +/--3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) prior to auditory fear conditioning completely abolished the acquisition of conditional freezing and conditional single-unit activity in the lateral amygdala (LA). In contrast, CPP given prior to extinction testing did not affect the expression of conditional single-unit activity in LA, despite producing deficits in conditional freezing. Administration of CPP also blocked the induction of long-term potentiation in the amygdala. Together, these data suggest that NMDARs are essential for the acquisition of conditioning-related plasticity in the amygdala, and that NMDARs are more critical for regulating synaptic plasticity and learning than routine synaptic transmission in the circuitry supporting fear conditioning.

Action Potentials↗

PubMed2002

Prefrontocortical dopamine loss in rats delays long-term extinction of contextual conditioned fear, and reduces social interaction without affecting short-term social interaction memory.

Prefrontal dopamine loss delays extinction of cued fear conditioning responses, but its role in contextual fear conditioning has not been explored. Medial prefrontal lesions also enhance social interaction in rats, but the role of prefrontal dopamine loss on social interaction memory is not known. Besides, a role for subcortical accumbal dopamine on mnesic changes after prefrontal dopamine manipulation has been proposed but not explored. The objective was to study the involvement of dopaminergic neurotransmission in the medial prefrontal cortex (mPFC) and nucleus accumbens in two mnesic tasks: contextual fear conditioning and social interaction memory. For contextual fear conditioning, short- and long-term freezing responses after an electric shock were studied, as well as extinction retention. Regarding social interaction memory, the recognition of a juvenile, a very sensitive short-term memory test, was used. Dopamine loss was carried out by injection of 6-hydroxydopamine, and postmortem catecholamine levels were analyzed by high-performance liquid chromatography. Prefrontocortical dopamine loss (>76%) led to a reactive enhancement of accumbal dopamine content (p<0.01), supporting the hypothesis that a hyperdopaminergic tone emerges in the nucleus accumbens after prefrontocortical dopamine loss. In lesioned rats, long-term extinction of contextual fear conditioning was significantly delayed and extinction retention was impaired without changes in acquisition and short-term contextual fear conditioning and, on the other hand, acquisition and short-term social interaction memory were not affected, although time spent on social interaction was significantly reduced. Added dopamine loss in the nucleus accumbens (>76%) did not alter these behavioral changes. In summary, the results of the present study indicate that the dopaminergic network in the mPFC (but not in the nucleus accumbens) coordinates the normal long-term extinction of contextual fear conditioning responses without affecting their acquisition, and it is involved in time spent on social interaction, but not acquisition and short-term social interaction memory.

Animals↗

PubMedDate not supplied

The L-Type voltage-gated calcium channel Cav1.3 mediates consolidation, but not extinction, of contextually conditioned fear in mice.

Using pharmacological techniques, it has been demonstrated that both consolidation and extinction of Pavlovian fear conditioning are dependent to some extent upon L-type voltage-gated calcium channels (LVGCCs). Although these studies have successfully implicated LVGCCs in Pavlovian fear conditioning, they do not provide information about the specific LVGCC isoform involved. Both of the major LVGCC subtypes found in the brain (Cav1.2 and Cav1.3) are targets of the pharmacological manipulations used in earlier work. In this study, we used mice in which the gene for the pore-forming subunit (alpha1D) Cav1.3 was deleted (Cav1.3 knockout mice) to elucidate its contribution to consolidation and extinction of conditioned fear. We find that Cav1.3 knockout mice exhibit significant impairments in consolidation of contextual fear conditioning. However, once sufficiently overtrained, the Cav1.3 knockout mice exhibit rates of extinction that are identical to that observed in wild-type mice. We also find that Cav1.3 knockout mice perform as well as wild-type mice on the hidden platform version of the Morris water maze, suggesting that the consolidation deficit in conditioned fear observed in the Cav1.3 knockout mice is not likely the result of an inability to encode the context, but may reflect an inability to make the association between the context and the unconditioned stimulus.

Analysis of Variance↗

PubMed1998

Time of conditioning selectively influences contextual fear conditioning: further support for a multiple-memory systems view of fear conditioning.

Time of conditioning influences long-term retention of contextual but not auditory-cue fear conditioning. Long-Evans rats (Rattus norvegicus) conditioned at 12 noon displayed reduced contextual fear conditioning compared to rats conditioned at 8 a.m. or 4 p.m. This effect was eliminated by exposure to the context 24 hr prior to conditioning and by a posttrial injection of corticosterone (1.0 mg/kg). Time of conditioning did not influence short-term retention of contextual fear. These results suggest that time of conditioning influences the posttrial processes that construct a memory representation of the context. They also support the view that contextual and auditory-cue fear conditioning depend on different processes. These results are discussed in relation to the concept of memory storage modulators.

Animals↗

PubMedDate not supplied

A mutant mouse with a highly specific contextual fear-conditioning deficit found in an N-ethyl-N-nitrosourea (ENU) mutagenesis screen.

Targeted mutagenesis in mice has shown that genes from a wide variety of gene families are involved in memory formation. The efficient identification of genes involved in learning and memory could be achieved by random mutagenesis combined with high-throughput phenotyping. Here, we provide the first report of a mutagenesis screen that has generated memory mutants in the mouse. We tested a group of N-ethyl-N-nitrosourea (ENU) mutagenized mice in the conditioned fear paradigm. We screened for both dominant and recessive mutations that caused impairments in contextual or tone fear conditioning. Heritability testing confirmed three fear conditioning mutants, i.e., Forgetful, Slowlearner, and Scatterbrain. All three have a learning or short-term memory deficit in contextual fear conditioning. Forgetful was further characterized and showed a highly specific phenotype. The contextual fear-conditioning deficit was apparent when Forgetful was trained with tone-shock pairings, but not when trained with shock alone. The deficit was not due to changes in shock sensitivity or anxiety. Forgetful was not impaired in two other memory tests (hidden platform version of Morris water maze and object recognition). Our data show that a mutagenesis screen can generate mutant mice with highly specific memory phenotypes that can supplement existing mice with targeted mutations. Mapping of Slowlearner found linkage to a region of chromosome 12 (LOD score of 6.5 close to D12Mit171), which suggests that ENU mutants should enable the positional cloning of genes involved in memory formation.

Animals↗

PubMed2004

Nicotine enhances trace cued fear conditioning but not delay cued fear conditioning in C57BL/6 mice.

Nicotine facilitates hippocampus-dependent contextual but not hippocampus-independent cued delay fear conditioning. To test if the effects of nicotine are specific to contextual fear conditioning or would extend to another hippocampus-dependent version of fear conditioning, we compared the effects of nicotine on cued delay and cued trace fear conditioning in male and female C57BL/6 mice. Unlike cued delay fear conditioning, cued trace fear conditioning is hippocampus dependent. Thus, if nicotine enhances hippocampus-dependent fear conditioning, nicotine should enhance trace fear conditioning. For both trace and delay conditioning, five 30 s, 85 dB white noise conditioned stimuli (CS) were paired with five 2 s, 0.5 mA footshock unconditioned stimuli (US). In the trace paradigm, a 30-s period was inserted between CS offset and US onset. The CS and US co-terminated in the delay paradigm. Testing occurred 24 h later. The data indicate that nicotine (given on training and testing day) enhances trace but not delay cued fear conditioning. No sex differences were found. For delay cued fear conditioning a high level of freezing to the CS was found. Thus, a second experiment examined if the lack of enhancement of delay cued fear conditioning by nicotine was due to a ceiling effect. The CS duration was decreased to 15 s and only one CS-US pairing was used for delay and trace cued fear conditioning. Although overall levels of freezing to the cue were lower in the second experiment, nicotine still enhanced trace fear conditioning but did not enhance delay fear conditioning. Taken together, the results of the present experiments suggest that nicotine enhances hippocampus-dependent versions of fear conditioning.

Analysis of Variance↗

PubMedDate not supplied

Coantagonism of glutamate receptors and nicotinic acetylcholinergic receptors disrupts fear conditioning and latent inhibition of fear conditioning.

The present study investigated the hypothesis that both nicotinic acetylcholinergic receptors (nAChRs) and glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) and N-methyl-d-aspartate glutamate receptors (NMDARs)) are involved in fear conditioning, and may modulate similar processes. The effects of the nAChR antagonist mecamylamine administered alone, the AMPAR antagonist NBQX administered alone, and the NMDAR antagonist MK-801 administered alone on cued fear conditioning, contextual fear conditioning, and latent inhibition of cued fear conditioning were examined. In addition, the effects of coadministration of either mecamylamine and NBQX or mecamylamine and MK-801 on these behaviors were examined. Consistent with previous studies, neither mecamylamine nor NBQX administered alone disrupted any of the tasks. However, coadministration of mecamylamine and NBQX disrupted both contextual fear conditioning and latent inhibition of cued fear conditioning. In addition, coadministration of mecamylamine with a dose of MK-801 subthreshold for disrupting either task disrupted both contextual fear conditioning and latent inhibition of cued fear conditioning. Coadministration of mecamylamine and NBQX, and coadministration of mecamylamine with a dose of MK-801 subthreshold for disrupting fear conditioning had little effect on cued fear conditioning. These results suggest that nAChRs and glutamate receptors may support similar processes mediating acquisition of contextual fear conditioning and latent inhibition of fear conditioning.

Animals↗

PubMed2004

Effect of MS-153 on the acquisition and expression of conditioned fear in rats.

Pavlovian fear conditioning is one of the most extensively studied and reliable behavioral paradigms used to investigate the mechanisms involved in fear and anxiety. Increased glutamatergic neurotransmission may play an important role in mediating fear conditioning. The present study assessed whether (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), a novel cerebroprotective agent that inhibits the release of glutamate and enhances glutamate uptake, affects the acquisition and expression of conditioned fear. The rats received administration of MS-153 (i.p.) at 3, 10, and 30 mg/kg, 30 min before footshock and 24 h after footshock. Freezing behavior was measured in the chamber where they had previously received footshock for the acquisition experiments. For the expression experiments, the rats received MS-153 (i.p.) at the same doses 23.5 h after footshock and 30 min before expression testing. MS-153 significantly attenuated the acquisition and expression of freezing behavior. In addition, MS-153 administration did not affect locomotor activity. The present results suggest that extracellular glutamate is involved in fear conditioning, and that MS-153 has an anxiolytic effect by decreasing endogenous glutamate neurotransmission.

Analysis of Variance↗