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PubMed2004

Consolidation of CS and US representations in associative fear conditioning.

Much attention has been paid to the associative processes that are necessary to fuse together representations of the various components of an episodic memory. In the present study, we focus on the processes involved in the formation of lasting representations of the individual components that make up a fear-conditioning episode. In one-trial contextual fear conditioning experiments, weak conditioning to context occurs if the shock is delivered immediately following placement of the animal in a novel conditioning apparatus, a phenomenon known as the immediate shock deficit. We show that the immediate shock deficit in mice may be alleviated by pre-exposure to either the context or shock. In using this approach to temporally dissect a contextual fear-conditioning task into its constituent representational and associative processes, we are able to examine directly the processes that are important for formation of lasting representations of the context conditioned stimulus (CS) or unconditioned stimulus (US). Our data indicate that the formation of a lasting representation of the context or shock engages protein synthesis-dependent processes. Furthermore, genetic disruption of cAMP-responsive element binding protein (CREB), a transcription factor that regulates the synthesis of new proteins required for long-term memory, disrupts the formation of lasting context memories. We go on to show that the stress hormone epinephrine modulates the consolidation of a context memory, and reverses consolidation deficits in the CREB-deficient mice. Finally we show that disrupting either NMDA or calcium/calmodulin-dependent kinase II (CaMKII) function impairs consolidation of context memories. Together, these data suggest that this approach is particularly suited for the characterization of molecular and cellular processes underlying the formation of stimulus representations.

Animals↗

PubMed2002

Time-dependent inhibition of hippocampal LTP in vitro following contextual fear conditioning in the rat.

The effects of contextual fear-learning on hippocampal synaptic excitability were investigated by means of high frequency tetanic stimulation (HFS) in rat brain slices (hippocampal CA1 region), prepared at different intervals (immediately, 24 h or 7 days) after a one-trial contextual fear conditioning paradigm session. In the latter, rats that had previously received aversive electrical footshocks in the experimental apparatus exhibited freezing (the conditioned response) when placed again in the same apparatus (retrieval test). It was shown that contextual fear-learning affects the hippocampal synaptic response. In fact, the HFS produced a decrease in the amplitude of short-term (STP) and long-term potentiation (LTP) when compared to control "naïve" subject values. This decrease in STP amplitude could be observed only in slices prepared immediately after the training session. A decrease in the amplitude of long-term but not short-term potentiation was also observed at 24 h. At 7 days, no decreases in amplitude were observed. These modifications may be thought of as specifically associated with the learning process as they were not recorded in brain preparations from "shock-only" rats (i.e. those that received the same number of aversive stimuli of equal intensity as the conditioned group but with the shocks compressed temporally so that the shocked subjects could not associate nociceptive stimulation and surroundings - no conditioned freezing during retention testing). In "exploration" preparations (brain slices from rats having only freely explored the experimental apparatus without receiving any adverse stimulation) a decrease in LTP amplitude was recorded only immediately after the training session, and STP was never modified. The synaptic response modifications do not appear to be due to presynaptic events, as they are not associated with paired-pulse facilitation curve (PPF) modifications. The present results show that contextual fear conditioning and exploration of a novel environment (i) reduce the ability to induce synaptic plasticity; (ii) differentially influence STP and LTP and that (iii) the persistence of synaptic modifications depends on an animal's prior experience.

Acoustic Stimulation↗

PubMed2005

Overt behavior and ultrasonic vocalization in a fear conditioning paradigm: a dose-response study in the rat.

The behavioral analysis of laboratory rats is usually confined to the level of overt behavior, like locomotion, behavioral inhibition, instrumental responses, and others. Apart from such visible outcome, however, behaviorally relevant information can also be obtained when analyzing the animals' ultrasonic vocalization, which is typically emitted in highly motivational situations, like 22-kHz calls in response to acute or conditioned threat. To further investigate such vocalizations and their relationship with overt behavior, we tested male Wistar rats in a paradigm of Pavlovian fear conditioning, where a tone stimulus (CS) was preceding an aversive foot-shock (US) in a distinct environment. Importantly, the shock dose was varied between groups (0-1.1 mA), and its acute and conditioned outcome were determined. The analysis of visible behavior confirms the usefulness of immobility as a measure of fear conditioning, especially when higher shock doses were used. Rearing and grooming, on the other hand, were more useful to detect conditioned effects with lower shock levels. Ultrasonic vocalization occurred less consistently than changes in overt behavior; however, dose-response relationships were also observed during the phase of conditioning, for example, in latency, call rate and lengths, intervals between calls, and sound amplitude. Furthermore, total calling time (and rate) were highly correlated with overt behavior, namely behavioral inhibition as measured through immobility. These correlations were observed during the phase of fear conditioning, and the subsequent tests. Importantly, conditioned effects in overt behavior were observed, both, to the context and to the CS presented in this context, whereas conditioned vocalization to the context was not observed (except for one rat). In support and extent of previous results, the present data show that a detailed analysis of ultrasonic vocalization can substantially broaden and refine the spectrum of analysis in behavioral work with rats, since it can provide information about situational-, state-, and subject-dependent factors which are partly distinct from what is visible to the experimenter.

Acoustic Stimulation↗

PubMed1999

Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy.

This study investigated whether 21 days of restraint stress (6 hr/day) and the subsequent hippocampal dendritic atrophy would affect fear conditioning, a memory task with hippocampal-dependent and hippocampal-independent components. Restraint-stressed rats were injected daily (21 days) with tianeptine (10 mg/kg; to prevent hippocampal atrophy) or vehicle then tested on fear conditioning (Days 23-25, with 2 tone-shock pairings) and open field (Day 25). Restraint stress enhanced freezing to context (hippocampal-dependent behavior) and tone (hippocampal-independent) and decreased open-field exploration, irrespective of whether tianeptine was given. Results confirmed that stress produced CA3 dendritic atrophy and tianeptine prevented it. Moreover, CA3 dendritic atrophy was not permanent but reversed to control levels by 10 days after the cessation of restraint stress. These data argue that different neural substrates underlie spatial recognition memory and fear conditioning.

Animals↗

PubMed2004

Amphetamine injections into the nucleus accumbens affect neither acquisition/expression of conditioned fear nor baseline startle response.

The acoustic startle response is enhanced during states of fear and attenuated during pleasant ones. Our question was whether pharmacological stimulation of the reward system disrupts the learning and retrieval of conditioned fear as measured by fear-potentiated startle. We therefore injected the dopamine agonist amphetamine into the nucleus accumbens (NAC) immediately before either acquisition or expression of conditioned fear and measured the effect of these injections on fear-potentiated startle and baseline startle response. This study clearly showed that amphetamine injections into the NAC had no effect on baseline startle amplitude and acquisition/expression of conditioned fear. In contrast, amphetamine injections into the nucleus accumbens clearly enhanced spontaneous motor activity. These results suggest that dopamine within the NAC is not involved in modulation of fear-potentiated startle and baseline startle.

Amphetamine↗

PubMed1998

Immediate-early gene expression in the amygdala following footshock stress and contextual fear conditioning.

This study investigated the increase in expression in the amygdala of 2 immediate-early genes, c-fos and NGFI-A, following contextual fear conditioning. The immediate-shock freezing deficit paradigm was used to compare rats that received footshock after exploring a context to rats that received footshock immediately after placement in the chamber. The former procedure produces contextual fear conditioning while the latter does not. Rats were either handled (handled group), placed in a test chamber without receiving footshock (context-no-footshock group), received footshock immediately upon being placed in the chamber (immediate-footshock group), or received footshock after a 1 min delay (delayed-footshock group). Only the delayed-footshock group displayed a fear response (freezing behavior). Rats were sacrificed either 15 min after the experience or after a retention test 24 h later. The c-fos mRNA was increased in the medial nucleus of the amygdala in all of the groups that were placed in the test chamber. However, rats that received footshock (immediate- and delayed-footshock groups) had greater levels of c-fos mRNA expression than rats of the context-no-footshock group. The c-fos mRNA expression in the immediate- and delayed-footshock groups did not differ. However, after the retention test, the expression of c-fos mRNA in the medial nucleus of the amygdala did not differ between groups. In contrast to c-fos, NGFI-A mRNA expression in the lateral nucleus of the amygdala was greater in the delayed-footshock group than the handled and context-no-footshock groups 15 min after the footshock. This elevation in NGFI-A mRNA was not seen in the immediate-footshock group. This suggests that NGFI-A mRNA in the lateral nucleus of the amygdala may play a role in contextual fear conditioning.

Amygdala↗

PubMed2004

Inhibition of mitogen-activated protein kinase-extracellular signal-regulated kinase disrupts latent inhibition of cued fear conditioning in C57BL/6 mice.

The mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) cascade has been implicated in a variety of associative conditioning tasks. However, the role of the MAPK-ERK cascades in modulating conditioning is less clear. The authors examined the effect of the potent and selective MAPK-ERK inhibitor SL327 on latent inhibition of cued fear conditioning. The results demonstrate that 50 mg/kg and 100 mg/kg SL327 disrupt latent inhibition of cued fear conditioning. These data provide evidence for an essential role of the MAPK-ERK cascade in tasks that modulate the strength of associative conditioning. The results are discussed in relation to the molecular mechanisms that support latent inhibition of cued fear conditioning.

Acoustic Stimulation↗

PubMed1999

Effects of mild traumatic brain injury on immunoreactivity for the inducible transcription factors c-Fos, c-Jun, JunB, and Krox-24 in cerebral regions associated with conditioned fear responding.

We have previously demonstrated that mild traumatic brain injury (TBI) of the right parietal cortex results in a relatively selective deficit in conditioned fear responding. However, this behavioural deficit is very consistent and unrelated to the extent of the cortical necrotic lesion. We were therefore interested in determining if other brain regions might show a consistent response to mild TBI, and therefore, more reliably relate to the behavioural change. Increased expression of inducible transcription factors (ITFs) has been used to study which brain regions respond to a variety of events. In the present study, we examined the expression patterns of immunoreactivity (IR) for four ITFs (c-Fos, c-Jun, JunB, and Krox-24) at 3 h after mild fluid percussion TBI. Changes in ITF expression were only observed ipsilateral to the side of TBI. The clearest changes were observed in brain regions known to be involved in conditioned fear responding, such as the amygdala complex and hippocampal formation and several cortical regions. In contrast, no changes in IR for any of the ITFs were observed in the striatum, nucleus accumbens, nucleus basalis magnocellularis, septum or periacqueductal grey. Unlike the extent of visible damage to the cortex at the site of impact, the overexpression of ITFs showed a notable consistency between animals subjected to TBI. This consistency in regions known to be involved in conditioned fear responding (i.e., amygdala complex and hippocampal formation) lead us to suggest that it is these changes, rather than the more variable cortical necrotic lesion, that is responsible for the behavioural deficits we observe following mild TBI. Importantly, our results demonstrate that like the hippocampus, the amygdala is a sub-cortical structure particularly sensitive to the effects of mild brain trauma and underline the fact that cerebral regions distant from the location of the fluid impact can be affected.

Amygdala↗

PubMed2006

Involvement of medial prefrontal cortex neurons in behavioral and cardiovascular responses to contextual fear conditioning.

To explore the ventral medial prefrontal cortex (vMPFC) involvement in behavioral and autonomic fear-conditioned responses to context, vMPFC synaptic transmission was temporarily inhibited by bilateral microinjections of 200 nL of the nonselective synapse blocker CoCl(2) (1 mM). Behavioral activity (freezing, motor activity and rearing) as well as evoked cardiovascular responses (arterial pressure and heart rate) was analyzed. Rats were pre-exposed to the footshock chamber (context) and shock stimulus was used unconditioned stimulus. During re-exposure to context, conditioned rats spent 80% of the session in freezing while non-conditioned rats (no shock group) spent less than 15% of the session time in freezing. Conditioned rats had significantly lower activity scores than non-conditioned animals. Exposure to context increased mean arterial pressure (MAP) and heart rate (HR) of both groups. MAP and HR of the conditioned animals were markedly increased and remained at a high and stable level, whereas MAP and HR increases in non-conditioned animals were less pronounced and declined during the session. CoCl(2) microinjected in the vMPFC significantly reduced freezing and attenuated MAP and HR increase of the conditioned group. Cobalt-induced vMPFC inhibition also significantly reduced MAP and HR increase observed in non-conditioned animals, without any behavioral changes. The effect of vMPFC acute ablation on MAP and HR did not seem to be specific to the fear response because they were also evident in non-conditioned animals. The results indicate that vMPFC integrity is crucial for expression of fear-conditioned responses to context, such as freezing and cardiovascular changes, suggesting that fear-conditioned responses to context involve cortical processing prior to amygdalar output. They also indicate a cardiovascular response observed during re-exposure of non-conditioned rats to the context is completely dependent on vMPFC integrity.

Analysis of Variance↗

PubMed1989

Temporal specificity of fear conditioning: effects of different conditioned stimulus-unconditioned stimulus intervals on the fear-potentiated startle effect.

Separate groups of rats were given 30 pairings of a light (conditioned stimulus, CS) and 500-ms shock (unconditioned stimulus, US) at CS-US intervals of 0, 25, 50, 100, 200, 800, 3,200, 12,800, or 51,200 ms. Other groups had lights and shocks inconsistently paired. The startle reflex was elicited 2-4 days later with a noise burst alone or 25-51,200 ms after light onset. After CS-US pairings over a wide range of intervals (25-51,200 ms), startle was potentiated in testing, sometimes as rapidly as 50 ms after light onset. Magnitude of potentiation and resistance to extinction were generally greater with longer CS-US intervals. In several groups, potentiation was maximal at a test interval that matched the CS-US interval used in training. This temporal specificity sharpened with increasing numbers of training trials but even occurred with a single training trial in which a 51,200-ms CS-US interval was used. The data indicate that even during simple fear conditioning, animals rapidly learn a temporal CS-US relationship. This has important implications for understanding the neural mechanisms of fear conditioning.

Animals↗

PubMed2006

Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats.

Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic-like effects similar to diazepam in animal models of innate aversive behavior. However, the effects of CBD contextual conditioned fear have not been studied. Therefore, the aim of this work was to compare the behavioral and cardiovascular effects of CBD and diazepam, a prototype anxiolytic, in animals submitted to a contextual conditioned fear paradigm. Male Wistar rats were submitted to a 10min conditioning session (six footshocks, 2.5 mA, 3s, delivered at pseudo-random intervals). The behavioral and cardiovascular responses to the context were measured 24h later in a 10 min test session. Diazepam (2.5 mg/kg), FG-7142 (8 mg/kg), a benzodiazepine inverse agonist, or CBD (10 mg/kg) were administered i.p. before the test session. Conditioned rats submitted to the aversive context exhibited more freezing behavior and a larger increase in blood pressure and heart rate as compared to non-conditioned animals. These effects were attenuated by CBD and diazepam in the conditioned animals. These drugs did not have any effect in non-conditioned rats. FG-7142 treatment failed to change the behavioral and cardiovascular responses to the aversive context. In conclusion, the results suggest that CBD has anxiolytic-like properties similar to those of diazepam in a rat model of conditioned fear to context.

Analysis of Variance↗

PubMed2006

Dorsal hippocampal administration of triiodothyronine enhances long-term memory for trace cued and delay contextual fear conditioning in rats.

Thyroid hormones play critical roles in brain maturation and cognitive functions. The present study investigated the role of thyroid hormone in emotional learning and memory using trace and delay contextual and cued fear conditioning tasks, respectively. Rats were administered triiodothyronine (T3) into the dorsal hippocampal area 10 min before training or immediately after training, and were scored for freezing behaviour in the same context and in a novel context with and without an auditory cue that had been paired previously with an aversive stimulus, a foot shock. Rats administered T3 before and after training both exhibited significantly increased long-term fear memory in the trace cued and the delay contextual fear conditioning procedures compared to their control groups. The T3-administered rats were not significantly different from their respective controls on the acquisition and short-term fear memory in the trace and delay fear conditioning tasks. No significant difference on long-term trace contextual and delay cued fear memory, respectively, was found. These results indicate that the observed T3-induced enhancement of long-term contextual and cued fear memory was specific to the hippocampus-dependent conditioning tasks. These findings are the first to demonstrate that infusion of T3 into the dorsal hippocampus can improve performance on an emotional memory task.

Animals↗

PubMed1998

Production of the Fos protein after contextual fear conditioning of C57BL/6N mice.

Male C57BL/6N mice were chosen to determine Fos production during acquisition of context-dependent fear and after re-exposure to the conditioning context. Fear-conditioning was induced by a single exposure of mice to a context followed by an electric shock. Control groups consisted of mice exposed to context only (Context group) or to an immediate electric shock. When contextual retention was measured 24 h after conditioning (retention test 1), significant contextual generalization was observed. However, when animals were exposed to a different context from days 2-5 after conditioning and then tested for retention on day 6 (retention test 2), generalization was markedly reduced. After the training, the fear-conditioned mice produced higher Fos levels than mice exposed to an immediate shock in the hippocampus, medial amygdaloid nucleus and parietal somatosensory cortex. Both shock groups produced significantly more Fos than the Context group in the central nucleus of the amygdala. After retention test 1, fear-conditioned mice generated more Fos in the hippocampus and central amygdaloid nucleus than the two control groups. However, all groups exhibited similarly low Fos production after retention test 2. The results demonstrated that simultaneous Fos production in the hippocampus, central and medial nuclei of amygdala and somatosensory parietal cortex closely paralleled the ability of mice to acquire conditioned fear. In contrast, Fos production after the retention tests did not correlate with the expression of conditioned fear.

Amygdala↗

PubMed1999

Differential impairment of auditory and contextual fear conditioning by protein synthesis inhibition in C57BL/6N mice.

A 1-trial fear conditioning was used to investigate the temporal development of fear responses expressed as increase of freezing or heart rate and its impairment by the protein synthesis inhibitor cycloheximide (CHX) in male C57BL/6N mice. Heart rate was measured with an implanted transmitter. In the memory tests, mice were exposed to tone and context provided either as foreground or background stimulus during training. The fear responses developed differently from 0 to 24 hr after training under these 3 conditions. A single pretraining CHX injection impaired both memory forms, whereas a single posttraining CHX injection impaired tone- but not context-dependent memory, with the context provided as background stimulus. It was concluded that consolidation of tone-, foreground context-, and background context-dependent fear conditioning may be mediated by partly different neuronal or partly different biochemical pathways, or both.

Acoustic Stimulation↗

PubMed2002

Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors.

The heterogeneity of gamma-aminobutyric acid type A (GABA(A)) receptors contributes to the diversity of neuronal inhibition in the regulation of information processing. Although most GABA(A) receptors are located synaptically, the small population of alpha5GABA(A) receptors is largely expressed extrasynaptically. To clarify the role of the alpha5GABA(A) receptors in the control of behavior, a histidine-to-arginine point mutation was introduced in position 105 of the murine alpha5 subunit gene, which rendered the alpha5GABA(A) receptors diazepam-insensitive. Apart from an incomplete muscle relaxing effect, neither the sedative, anticonvulsant, nor anxiolytic-like activity of diazepam was impaired in alpha5(H105R) mice. However, in hippocampal pyramidal cells, the point mutation resulted in a selective reduction of alpha5GABA(A) receptors, which altered the drug-independent behavior. In line with the role of the hippocampus in certain forms of associative learning, trace fear conditioning, but not delay conditioning or contextual conditioning, was facilitated in the mutant mice. Trace fear conditioning differs from delay conditioning in that the conditioned and unconditioned stimulus are separated by a time interval. Thus, the largely extrasynaptic alpha5GABA(A) receptors in hippocampal pyramidal cells are implicated as control elements of the temporal association of threat cues in trace fear conditioning.

Animals↗

PubMed1996

Effect of repeated methamphetamine pretreatment on freezing behavior induced by conditioned fear stress.

The present study examined the effect of methamphetamine (MA) pretreatment on conditioned fear stress in male Wistar-King rats. Rats received MA or the vehicle according to the repeated escalating dose schedule (1.25, 2.5, 3.75, and 5 mg/kg s.c. x 2/every other day for a week). After a 5-day drug abstinent period, the rats were exposed to conditioned fear stress (exposure to an environment paired previously with foot shock). Repeated but not single MA pretreatment significantly increased conditioned freezing behavior, suggesting that rats previously exposed to chronic MA are hypersensitive to subsequent stress than control rats. Repeated MA treatment did not decrease basal dopamine or serotonin concentrations in the brain. Furthermore, coadministration of MK-801 (noncompetitive NMDA antagonist), amfonelic acid (dopamine reuptake inhibitor), or fluoxetine (serotonin reuptake inhibitor) with MA did not alter the enhanced freezing behavior. Taken together, it seems that MA-induced hypersensitivity to stress is not due to the neurotoxic effect of MA. Coadministration of nemonapride (D2/3/4 antagonist) with MA prevented the MA-induced increase in freezing. These results suggest that D2/3/4 receptors play an important role for MA-induced enhancement of fear or anxiety.

Animals↗

PubMed1991

Efferent pathway of the amygdala involved in conditioned fear as measured with the fear-potentiated startle paradigm.

Fear-potentiated startle in the rat is a measure of conditioned fear that is blocked by lesions of the central nucleus of the amygdala. In a companion study, Rosen, Hitchcock, Sananes, Miserendino, and Davis (1991) demonstrated a direct anatomical projection from the central nucleus to the brainstem startle reflex circuit. In the present study, fear-potentiated startle was blocked by lesions that interrupted this pathway at 3 different levels or by a crossed lesion that interrupted the pathway at its source on one side and at a more caudal level on the other side. Although synaptic relays have not been ruled out entirely, the data suggest that the direct projection from the central nucleus of the amygdala to the startle circuit mediates the expression of fear-potentiated startle. These findings are consistent with the literature indicating that efferent projections from the central nucleus to various brainstem structures are involved in the expression of several conditioned fear responses.

Amygdala↗

PubMed2004

Fischer 344 rats display age-related memory deficits in trace fear conditioning.

A functional hippocampus is required for trace fear conditioning, which involves learning the association of a tone and shock that are separated over time. Young and aged rats received 10 trace conditioning trials. Twenty-four hours later, rats were tested for fear to the tone in a novel chamber by measuring freezing. The results showed significantly lower levels of freezing in aged rats as compared with young rats, which provides evidence of age-related memory impairments. Pseudorandom conditioning groups showed low levels of freezing, indicative of no associative memory. Age-related memory deficits were not found with delay conditioning, which suggests no age-related sensory-motor deficits. These data suggest that aging hinders the ability of the hippocampus to process information separated over time.

Age Factors↗