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PubMed2005

Fear conditioning following unilateral temporal lobectomy: dissociation of conditioned startle potentiation and autonomic learning.

The present study investigated fear-potentiated startle and autonomic learning in brain-lesioned patients in a classical fear-conditioning paradigm. Startle blink and skin conductance responses of 30 patients who underwent unilateral temporal lobectomy because of drug-resistant epilepsy were compared with those of 32 healthy controls. As expected, temporal lobectomy patients showed a general impairment in fear conditioning relative to controls. This impairment did not differ with respect to the affected hemisphere. Moreover, while fear-conditioned startle potentiation in healthy controls was independent of contingency awareness, skin conductance discrimination was only observed for those participants who correctly recognized the stimulus contingencies. Patients who acquired a declarative memory of the contingencies also showed intact skin conductance discrimination but failed to exhibit fear-potentiated startle. The present findings support a two-levels-of-learning account of human fear conditioning and also demonstrate that the amygdala is crucially involved in fear learning.

Adult↗
PubMed2002

L-type voltage-gated calcium channels are required for extinction, but not for acquisition or expression, of conditional fear in mice.

It has been shown recently that extinction of conditional fear does not depend acutely on NMDA-type glutamate receptors, although other evidence has led to the hypothesis that L-type voltage-gated calcium channels (LVGCCs) play a role in conditional fear. We therefore tested the role of LVGCCs in the acquisition, expression, and extinction of conditional fear of cue and context in mice. Using systemic injections of two LVGCC inhibitors, nifedipine and nimodipine, which both effectively cross the blood-brain barrier, we show that LVGCCs are essential for the extinction, but not for the acquisition or expression, of conditional fear in mice.

Animals↗
PubMed2006

Early life stress impairs fear conditioning in adult male and female rats.

We demonstrated that neonatal isolation (1-h pup isolation; postnatal days 2-9) impairs context-induced fear conditioning in adult male rats and tends to enhance this effect and foot shock sensitivity in females. In this study, we examine the effects of brief (i.e., handling; 15 min) and prolonged (3 h) maternal separations (postnatal days 1-21) on fear conditioning and foot shock sensitivity in adult male and female rats. Identical training and test conditions from our prior study were employed so comparisons of the three early life stressors could be made. Context- and cue-elicited freezing and ultrasonic vocalizations (USVs; 22 kHz) were measured after 10 tone-shock training trials in Experiment 1. In Experiment 2, foot shock responses (flinch, jump, sonic vocalizations) to escalating shock levels were assessed. Brief maternal separation impaired context- and cue-conditioned fear in rats of both sexes as assessed by USVs. Prolonged maternal separation only impaired context fear in female rats. There were no effects on foot shock sensitivity. Results of this and other studies suggest that early life stress impairs fear conditioning in adult rats whereas stress experienced in adulthood has the opposite effect. These opposing effects may reflect developmental differences on stress-induced alterations on hippocampal regulation of the hypothalamic-pituitary-adrenal axis.

Analysis of Variance↗
PubMed2005

Dorsal hippocampus NMDA receptors differentially mediate trace and contextual fear conditioning.

The dorsal hippocampus (DH) is critically involved in the acquisition and expression of trace and contextual fear conditioning. NMDA/glutamate receptor-mediated transmission is thought to be one mechanism mediating the plastic changes that support long-term memories in the DH. However, their precise involvement in acquisition and expression processes has not been defined. To examine this issue, the NMDA receptor antagonist, D,L-2-amino-5-phosphonovaleric acid (APV; 10 microg/microl; 0.5 microl), was infused into the DH prior to conditioning and/or testing, using a trace fear conditioning procedure. All rats were tested for freezing to both tone and context in separate, counterbalanced sessions. The three sessions (1 training and 2 test) were separated by approximately 24 h. Using this design, it was possible to assess the role for DH NMDA receptors in the acquisition versus expression of trace and contextual fear conditioning. APV disrupted acquisition, but not expression, of contextual fear conditioning. By contrast, APV attenuated both acquisition and expression of trace fear memories. Thus, DH NMDA receptors appear to contribute to retrieval of some, but not all, fear memories.

Animals↗
PubMed2005

Expression of cardiovascular and behavioural components of conditioned fear to context in T4 spinally transected rats.

A spinal cord transection at the fourth thoracic level (T4) results in paraplegia. It also removes supraspinal control of sympathetic outflow to most viscera and their blood vessels but spares the heart. We studied the effects of such a transection on the expression of the conditioned fear response to context, which includes freezing, 22 kHz ultrasonic vocalisations, a marked pressor response and a slowly rising tachycardia. Rats implanted with radiotelemetric probes were fear conditioned, tested, then transected at T4 and finally re-tested 4 weeks after transection. Baseline blood pressure in transected animals was the same as in intact animals but baseline heart rate was 127 bpm higher. There were clear signs of fear in the transected animals: although freezing occurred in the upper part of the body only, there was a 3 fold increase in the number of ultrasonic vocalisations, most probably due to paralysis of abdominal muscles that made expirations shorter and therefore more frequent. The pressor response of fear was initially the same as in intact animals but controls revealed that this was due to handling during transfer to the aversive context. The rest of the pressor response was markedly reduced (70%) confirming that it depends in large part on a sympathetically mediated increase in vascular resistance in the lower part of the body. The cardiac response was characterized by an initial bradycardia followed by a marked tachycardia, which is consistent with a baroreceptor-mediated reflex response to the altered pressor changes. Finally, none of these changes was observed when the same experiment was repeated in sham transected animals. Thus, the pressor response of fear is in large part mediated by the thoracic cord below T4 and the baroreflex is not inhibited but maintained during conditioned fear.

Animals↗
PubMed2004

Putting fear in its place: remapping of hippocampal place cells during fear conditioning.

We recorded hippocampal place cells in two spatial environments: a training environment in which rats underwent fear conditioning and a neutral control environment. Fear conditioning caused many place cells to alter (or remap) their preferred firing locations in the training environment, whereas most cells remained stable in the control environment. This finding indicates that aversive reinforcement can induce place cell remapping even when the environment itself remains unchanged. Furthermore, contextual fear conditioning caused significantly more remapping of place cells than auditory fear conditioning, suggesting that place cell remapping was related to the rat's learned fear of the environment. These results suggest that one possible function of place cell remapping may be to generate new spatial representations of a single environment, which could help the animal to discriminate among different motivational contexts within that environment.

Animals↗
PubMed2000

Induction of NGFI-B mRNA following contextual fear conditioning and its blockade by diazepam.

Expression of the immediate-early gene, NGFI-B (nerve growth factor inducible gene B), was examined in the amygdala, hippocampus, and neocortex following contextual fear conditioning. Rats were either handled, placed within the testing context without receiving the footshock, received a footshock immediately upon placement within the context, or received a footshock after a 3-min delay (delayed-shock). Only the delayed-shock group displayed a fear response (freezing) in the post-shock period and in a retention test 24 h after fear conditioning. Expression of NGFI-B mRNA was increased in the dorsolateral part of the lateral nucleus of the amygdala (LaDL) and the neocortex 30 min following conditioning in the delayed-shock group compared to the other three groups. In addition, following a retention test conducted 24 h after fear conditioning, NGFI-B mRNA expression was increased in the neocortex of the delayed-shock group compared to the handled group. In a subsequent experiment, the effects of pretreatment with the anxiolytic drug, diazepam, on fear conditioning and the concomitant increases in NGFI-B mRNA were investigated. Rats administered a 2.5 mg/kg, i.p. dose of diazepam before fear conditioning did not acquire contextual fear as demonstrated by a lack of freezing in a retention test. Although diazepam blocked fear conditioning while the 40% propylene glycol, 10% ethanol vehicle solution did not, both diazepam and the vehicle reduced the conditioning-induced increase in NGFI-B expression in the LaDL. In contrast, the fear-conditioning-induced NGFI-B increase in the neocortex was blocked by diazepam, but not by the vehicle. The data suggest that the transcriptional factor NGFI-B in the LaDL and neocortex may play a functional role in learning and memory of contextual fear, but blocking the increase in NGFI-B expression in the LaDL is not essential for diazepam to interfere with fear conditioning.

Amygdala↗
PubMed1997

Electrolytic lesions of the fimbria/fornix, dorsal hippocampus, or entorhinal cortex produce anterograde deficits in contextual fear conditioning in rats.

Recent data indicate that dorsal hippocampal (DH) lesions disrupt Pavlovian fear conditioning to contextual cues in rats. In the present study, we examined the effects of electrolytic lesions of the fimbria/fornix (FX) or entorhinal cortex (EC), the primary afferent projection systems to the DH, on contextual fear conditioning in rats. Conditioning consisted of the delivery of unsignaled footshocks in a novel observation chamber, and freezing served as the measure of conditional fear. Electrolytic lesions of the FX, DH, or EC made 1 week before training produced anterograde impairments in both immediate postshock freezing on the conditioning day and freezing during the context extinction test 24 h following training. The deficits in conditional freezing produced by FX, DH, and EC lesions were not statistically different, although the deficits in rats with FX or EC lesions tended to be more severe than those in rats with DH lesions. In addition to producing deficits in conditional freezing, FX, DH, or EC lesions produced a pronounced locomotor hyperactivity. Within the lesion and sham groups, however, locomotor activity was not significantly correlated with conditional freezing. These results indicate that contextual fear deficits in rats with hippocampal formation damage are equivalent following either FX, DH, or EC lesions. The relationship of freezing deficits and locomotor hyperactivity in rats with hippocampal formation lesions is discussed.

Animals↗
PubMed1994

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

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

Aging↗
PubMed2003

Facilitative role of prolactin-releasing peptide neurons in oxytocin cell activation after conditioned-fear stimuli.

Emotional stress activates oxytocin neurons in the hypothalamic supraoptic and paraventricular nuclei and stimulates oxytocin release from the posterior pituitary. Oxytocin neurons in the hypothalamus have synaptic contact with prolactin-releasing peptide (PrRP) neurons. Intracerebroventricular administration of PrRP stimulates oxytocin release from the pituitary. These observations raise the possibility that PrRP neurons play a role in oxytocin response to emotional stress. To test this hypothesis, we first examined expression of Fos protein, an immediate early gene product, in the PrRP neurons in the medulla oblongata after conditioned-fear stimuli. Conditioned-fear stimuli increased the number of PrRP cells expressing Fos protein especially in the dorsomedial medulla. In order to determine whether PrRP cells projecting to the supraoptic nucleus are activated after conditioned-fear stimuli, we injected retrograde tracers into the supraoptic nucleus. Conditioned-fear stimuli induced expression of Fos protein in retrogradely labeled PrRP cells in the dorsomedial medulla. Finally we investigated whether immunoneutralization of endogenous PrRP impairs oxytocin release after emotional stimuli. An i.c.v. injection of a mouse monoclonal anti-PrRP antibody impaired release of oxytocin but not of adrenocorticotrophic hormone or prolactin and did not significantly change freezing behavior in response to conditioned-fear stimuli. From these data, we conclude that PrRP neurons in the dorsomedial medulla that project to the hypothalamus play a facilitative role in oxytocin release after emotional stimuli in rats.

Adrenocorticotropic Hormone↗
PubMed1985

Effects of conditioned fear on responsiveness to pain: long-term retention and reversibility by naloxone.

The effect of a conditioned fear stimulus (CS) on responsiveness to pain was examined in three experiments. In Experiment 1, a CS that signaled shock attenuated freezing in response to shock, with the attenuation occurring several minutes after the shock. Naloxone blocked the effect of the CS. The effect of the CS, including its reversibility by naloxone, was retained over an interval of 90 days. Experiment 2 showed that this effect on freezing is due to associative fear conditioning, rather than blocking of conditioning to context by a novel cue. In Experiment 3, presenting a fear CS just prior to administering a tail-flick (radiant heat) test of nociception increased the tail-flick latencies; that is, the fear CS apparently induced hyperalgesia rather than analgesia. Because this result makes it difficult to interpret the change in freezing seen in the first experiment as reflecting antinociception, it raises questions about how pain might differentially affect different measures of pain responsiveness. A memory hypothesis is advanced to resolve the different effects obtained with the freezing and tail-flick tests.

Animals↗
PubMed2005

Dorsal hippocampus involvement in trace fear conditioning with long, but not short, trace intervals in mice.

Placing a "trace" interval between a warning signal and an aversive shock makes consolidation of the memory for trace conditioning hippocampus dependent. To determine the trace at which memory consolidation requires the hippocampus, mice were trained with 0-s, 1-s, 3-s, or 20-s trace intervals and tested for freezing to context and tone. Posttraining dorsal hippocampus (DH) lesions decreased context conditioning regardless of trace interval. However, DH lesions attenuated only the 20-s trace tone freezing. Like eyeblink conditioning, the DH is necessary for trace fear conditioning only at long trace intervals, but the time scale for the effective interval in fear conditioning is about 40 times longer. Manipulations that alter trace fear conditioning with short trace intervals probably do not reflect altered DH function. Given this difference in time scale along with the use of posttraining DH lesions, hippocampus dependency of trace conditioning is not related to a bridging function or response timing.

Acoustic Stimulation↗
PubMed2000

Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning.

Although much has been learned about the neurobiological mechanisms underlying Pavlovian fear conditioning at the systems and cellular levels, relatively little is known about the molecular mechanisms underlying fear memory consolidation. The present experiments evaluated the role of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade in the amygdala during Pavlovian fear conditioning. We first show that ERK/MAPK is transiently activated-phosphorylated in the amygdala, specifically the lateral nucleus (LA), at 60 min, but not 15, 30, or 180 min, after conditioning, and that this activation is attributable to paired presentations of tone and shock rather than to nonassociative auditory stimulation, foot shock sensitization, or unpaired tone-shock presentations. We next show that infusions of U0126, an inhibitor of ERK/MAPK activation, aimed at the LA, dose-dependently impair long-term memory of Pavlovian fear conditioning but leaves short-term memory intact. Finally, we show that bath application of U0126 impairs long-term potentiation in the LA in vitro. Collectively, these results demonstrate that ERK/MAPK activation is necessary for both memory consolidation of Pavlovian fear conditioning and synaptic plasticity in the amygdala.

Acoustic Stimulation↗
PubMed2004

Subregion-specific differences in hippocampal activity between Delay and Trace fear conditioning: an immunohistochemical analysis.

Lesions of the hippocampus attenuate acquisition of the tone-shock contingency in Trace, but not in Delay fear conditioning. These findings suggest that hippocampal regions are differentially involved in these two forms of fear conditioning. The present study was aimed at testing the hypothesis that hippocampal neurons are differentially activated during acquisition and retrieval of Delay versus Trace fear conditioning. Male C57BL/6J mice were exposed to eight tone-shock pairings (in Trace conditioning the shock came 30 s after the tone), and tested for immobility upon reexposure to contextual stimuli or to one tone presentation. Ten brain regions were analyzed by immunohistochemistry for inducible transcription factors (ITF) c-Fos and Zif268 1.5 h after training, context test or tone test. Acquisition of both Delay and Trace fear conditioning produced significant induction of c-Fos in the majority of brain regions analyzed compared to naive control animals. Importantly, Delay fear conditioning caused a higher increase of c-Fos expression in the CA3 region of the hippocampus compared to Trace-trained animals. After cue reexposure, Zif268 levels in the dentate gyrus of the hippocampus were higher in Trace-conditioned than in Delay-conditioned animals. In addition, reexposure-related c-Fos expression in the anterior cingulate cortex was significantly higher in Delay-conditioned animals than in Trace-conditioned animals. The present study confirms differential activation of hippocampal subregions in Delay and Trace fear conditioning.

Animals↗
PubMed2004

Auditory-conditioned-fear-dependent c-Fos expression is altered in the emotion-related brain structures of Fyn-deficient mice.

Fyn-tyrosine-kinase-deficient mice exhibit increased fearfulness. To elucidate the neural mechanisms of their emotional defects, we compared fyn(-/-) and fyn(+/-) mice by behavioral analysis of conditioned fear and by functional neuroanatomical analysis of the distribution of highly responsive neurons associated with conditioned fear. The mice were exposed to the auditory conditioned stimulus paired with electric shock as the unconditioned stimulus. After the fear conditioning, auditory stimulus-induced freezing behavior was enhanced in fyn(-/-) mice. When the occurrence of c-Fos-immunoreactive neurons in the brain of fear-conditioned mice was examined following exposure to the auditory stimulus, a significant increase in immunoreactive neurons was found in the amygdala, hypothalamus, and midbrain of both genotypes. The occurrence of conditioned-fear-dependent c-Fos-immunoreactive neurons was enhanced in the central, medial, cortical, and basomedial amygdaloid subdivisions, the hypothalamic nuclei, and the midbrain periaqueductal gray of the fyn(-/-) mice in comparison with the fyn(+/-) mice. However, remarkably, the occurrence of conditioned-fear-dependent c-Fos-immunoreactive neurons was very low in the basolateral and lateral amygdaloid subdivisions of the fyn(-/-) mice, in striking contrast to a significant increase in c-Fos-immunoreactive neurons in these subdivisions in the fyn(+/-) mice. These findings suggest that the increased excitability of the specific amygdaloid subdivisions including the central nucleus, and of the projection targets such as the hypothalamus and midbrain in fyn(-/-) mice, is directly related to the enhanced fear response, and that the decreased excitability in the basolateral and lateral amygdaloid subdivisions is involved in the defective control of the neural circuit for emotional expression in this mutant.

Acoustic Stimulation↗
PubMed1999

Effects of the benzodiazepine antagonist flumazenil on conditioned fear stress in rats.

1. The authors investigated the effect of the benzodiazepine receptor antagonist flumazenil on freezing behavior induced by conditioned fear stress and used a time-sampling procedure. 2. Rats were individually subjected to 5 min of inescapable electric footshock in a shock chamber. Twenty-four hours after the footshock, the rats were again placed in the shock chamber and observed for 5 min without shocks: this procedure is termed conditioned fear stress. 3. Subcutaneous administration of flumazenil (10 mg/kg) 30 min before conditioned fear stress reduced conditioned freezing, while flumazenil (1-10 mg/kg) 30 min before footshock did not. This indicates that flumazenil reduced the expression of conditioned fear, suggesting an anxiolytic effect of flumazenil. 4. This effect may be attributable to antagonism by flumazenil to endogenous inverse agonist-like ligands for benzodiazepine receptors. It is suggested that endogenous inverse agonist-like ligands for benzodiazepine receptors are involved in the expression of conditioned fear stress.

Animals↗
PubMed2003

Influence of shock training and explicit fear-conditioned cues on sleep architecture in mice: strain comparison.

Fear conditioning is thought to model anticipatory anxiety. Inbred mouse strains exhibit different levels of reactivity to aversive environmental stimuli, which may reflect anxiety. We examined the effects of fear conditioning on sleep in mouse strains that differ on behavioral measures of anxiety. Mice (BALB/cJ [C], C57BL/6J [B6], CB6F1/J [CB6], n = 7-10 per strain) were implanted with transmitters for recording sleep by telemetry. Baseline sleep was recorded, and the mice were trained to associate a cue (tone) with footshock (15 cue-shock pairings on 4 consecutive days). Sleep was recorded after shock training and again 4 to 5 days later after presentation of the cue alone. Shock training produced a relatively selective suppression of rapid eye movement sleep (REM) that was greater in the C strain compared to the B6 and CB6 mice. Post-training exposure to the cue alone suppressed REM in all strains. The C strain exhibited a relatively greater immediate suppression of REM, and the CB6 hybrid mice showed the greatest overall suppression of REM. These data demonstrate that stimuli associated with an aversive event can alter sleep and suppress REM in much the same way as exposure to the event itself. Fear conditioning may provide a model for examining genetic and neural mechanisms underlying the influence of anxiety on sleep.

Analysis of Variance↗
PubMed2004

Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus.

The bed nucleus of the stria terminalis (BNST) is believed to be a critical relay between the central nucleus of the amygdala (CE) and the paraventricular nucleus of the hypothalamus in the control of hypothalamic-pituitary-adrenal (HPA) responses elicited by conditioned fear stimuli. If correct, lesions of CE or BNST should block expression of HPA responses elicited by either a specific conditioned fear cue or a conditioned context. To test this, rats were subjected to cued (tone) or contextual classical fear conditioning. Two days later, electrolytic or sham lesions were placed in CE or BNST. After 5 days, the rats were tested for both behavioral (freezing) and neuroendocrine (corticosterone) responses to tone or contextual cues. CE lesions attenuated conditioned freezing and corticosterone responses to both tone and context. In contrast, BNST lesions attenuated these responses to contextual but not tone stimuli. These results suggest CE is indeed an essential output of the amygdala for the expression of conditioned fear responses, including HPA responses, regardless of the nature of the conditioned stimulus. However, because lesions of BNST only affected behavioral and endocrine responses to contextual stimuli, the results do not support the notion that BNST is critical for HPA responses elicited by conditioned fear stimuli in general. Instead, the BNST may be essential specifically for contextual conditioned fear responses, including both behavioral and HPA responses, by virtue of its connections with the hippocampus, a structure essential to contextual conditioning. The results are also not consistent with the hypothesis that BNST is only involved in unconditioned aspects of fear and anxiety.

Animals↗