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PubMed1990

Selective associations in the observational conditioning of fear in rhesus monkeys.

Three experiments explored the issue of selective associations in the observational conditioning of fear. Experiment 1 results indicated that observer rhesus monkeys acquired a fear of snakes through watching videotapes of model monkeys behaving fearfully with snakes. In Experiment 2, observers watched edited videotapes that showed models reacting either fearfully to toy snakes and nonfearfully to artificial flowers (SN+/FL-) or vice versa (FL+/SN-). SN+/FL- observers acquired a fear of snakes but not of flowers; FL+/SN- observers did not acquire a fear of either stimulus. In Experiment 3, monkeys solved complex appetitive discriminative (PAN) problems at comparable rates regardless of whether the discriminative stimuli were the videotaped snake or the flower stimuli used in Experiment 2. Thus, monkeys appear to selectively associate snakes with fear.

Animals↗
PubMed2003

Dynamics of intracellular dopamine contents in the rat brain during the formation of conditioned contextual fear and extinction of an acoustic startle reaction.

Extracellular dopamine contents in the caudate nucleus, nucleus accumbens, and prefrontal cortex of the rat brain were measured during two sessions of extinction of an acoustic startle reaction--each consisting of ten sound stimuli, the two sessions separated by 24 h--with simultaneous recording of freezing behavior. The results demonstrated a decrease in extracellular dopamine levels in the caudate nucleus and an increase in the nucleus accumbens during both sessions of extinction, with return to initial immediately after sessions ended. During the second session, the amplitude of startle responses and the magnitude of changes in dopamine levels in both structures were significantly smaller than during the first session. Between the sessions, dopamine levels in the caudate nucleus remained constant, while those in the nucleus accumbens decreased. The prefrontal cortex showed increases in dopamine levels during both sessions of extinction, as well as between the two sessions. The amplitude of the startle reaction was found to correlate with dopamine levels in the prefrontal cortex after the end of the corresponding extinction session and with the dopamine level before the start of the second session. The freezing time before the start of sound stimulation in the second session, this being a measure of conditioned fear, correlated with the dopamine level in the caudate nucleus on the training day and with the dopamine level in the nucleus accumbens before the start of the second session. The role of the dopaminergic system in the mechanisms forming and realizing the various components of defensive behavior are discussed.

Acoustic Stimulation↗
PubMed1999

Lasting effect of repeated cocaine administration on acoustic and fear-potentiated startle in rats.

RATIONALE: Following cocaine withdrawal, humans may experience an abstinence syndrome with high levels of anxiety. Studying anxious behavior in animals following repeated cocaine administration may help elucidate important variables that contribute to a withdrawal syndrome. OBJECTIVES: This study investigated whether repeated cocaine pre-exposure produced lasting increases in conditioned fear as measured by fear-potentiated startle responses in rats. METHODS: Startle was measured in response to 50 ms acoustic stimuli of 95, 105 and 115 dB. Cocaine (20 mg/kg, IP) or saline was administered for 7 days and after each injection rats were either placed in startle chambers for 30 min or returned to the home cage. After a 1-week cocaine-free period, most rats were given ten light-footshock pairings in the startle chamber. Fear-potentiated startle was tested by presenting acoustic startle-eliciting stimuli of 95, 105 and 115 dB in the presence or absence of the light. Rats that were not fear conditioned received acoustic stimuli one week after 7 days of 20 mg/kg cocaine. RESULTS: Startle responses, both in the presence and absence of the light CS, were greater in fear-conditioned rats that received cocaine pre-exposure in the startle chamber than in saline pre-exposed rats. Startle responses in the presence of the light CS were further augmented at 115 dB. In contrast, home-cage exposure to cocaine did not enhance startle responses. In rats that were not fear conditioned, cocaine pre-exposure reduced acoustic startle. CONCLUSIONS: Repeated cocaine pre-exposure can increase, decrease or not change acoustic startle depending on whether fear conditioning occurred and whether cocaine was given in the testing chamber. The data suggest that cocaine pre-exposure may act as a contextually conditioned occasion setting stimulus that can facilitate anxious behavior similar to the postulated human cocaine abstinence syndrome.

Acoustic Stimulation↗
PubMed1999

Acquisition and severity of driving-related fears.

Rachman's theory of fear acquisition proposes that directly-conditioned fears will differ from indirectly-conditioned fears in magnitude and anxiety response patterns, however the theory has received inconsistent empirical support. The aim of the present study was to describe the fear acquisition pathways for a community sample who reported driving-related fears, and to test Rachman's theory of fear acquisition. One hundred and ninety participants completed a questionnaire which assessed a variety of driving-related situations, reactions to motor vehicle accidents (MVAs), and anxiety response patterns. Professional psychological helpseeking and perceived need for treatment for driving-related fears were also assessed. Results failed to support Rachman's predictions. However, it was confirmed that respondents who had been involved in an MVA were more likely to ascribe their fears to a directly-conditioned pathway. The theoretical and methodological implications of the findings are discussed, along with suggestions for assessment of those with driving-related fears.

Accidents, Traffic↗
PubMed2002

The anxiolytic action of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated startle model in rats is mechanistically distinct from diazepam.

The fear-potentiated startle paradigm has been characterized for drugs that act via ionotropic (NMDA and AMPA/kainate receptor) glutamate receptor mechanisms. Previous studies have shown that the potent systemically active mGlu2/3 receptor agonist, LY354740, effectively reduced the expression of fear-potentiated startle responses in rats. The present study examined the effects of LY354740 in a pre- versus post-fear conditioning paradigm and compared the effects to diazepam. Diazepam (0.3, 0.6, and 1.0 mg/kg ip) attenuated both pre- and post-fear conditioning startle responses in a dose-related manner. In contrast, LY354740 (0.03, 0.3, and 3.0 mg/kg ip) did not disrupt preconditioning startle responses at doses that attenuated post-fear conditioning responses. The benzodiazepine antagonist, flumazenil, at a dose (2 mg/kg sc) that did not alter fear-potentiated startle per se, selectively reversed suppression of fear responses to diazepam (0.6 mg/kg ip) while not affecting fear suppression induced by LY354740 (0.3 mg/kg ip). At a dose of 1 mg/kg ip, the mGlu2/3 receptor antagonist, LY341495, did not disrupt fear-enhanced startle per se, but completely reversed the postconditioning anxiolytic effects of LY354740 in this model. This dose of LY341495 had no effect on fear suppression by diazepam. These results demonstrate that fear suppression by diazepam and LY354740 involves different neuronal mechanisms. While diazepam acts via the facilitation of GABAergic transmission, LY354740 induces its actions via the glutamatergic system, specifically mGlu2/3 receptor activation. Furthermore, in contrast to disruption of fear conditioning as well as fear suppression by diazepam, LY354740 had selective effects on fear expression, suggesting anxiolytic actions without the associated memory impairment.

Acoustic Stimulation↗
PubMed2005

Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala.

In experiments designed to investigate the relationship between stress and the acquisition of new fear memories, it was found that previous exposure to a restraint session increased fear conditioning in a contextual fear paradigm. Moreover, the infusion of bicuculline, a competitive antagonist of GABAA receptors, into the basolateral amygdala complex (BLA), but not into the central amygdaloid nucleus, induced the same behavioral effect. Pretreatment with midazolam (MDZ), a positive modulator of GABAA sites, prevented the facilitating influence on fear memory of both stress and GABAA receptor blockade in the BLA. These data suggest that facilitation of fear conditioning could be causally related to increased neuronal excitability attributable to depressed GABAergic inhibition in the BLA. To test this hypothesis, evoked potentials were studied in brain slices from stressed animals. Potentials evoked in the BLA by single stimuli applied to the external capsule showed multispike responses, suggestive of GABAergic disinhibition. These multiple responses were no longer evident after the slices were perfused with diazepam or if the stressed animals were pretreated with MDZ. In slices from stressed rats, paired-pulse inhibition (GABA dependent) was suppressed. Also, in stressed animals, long-term potentiation (LTP) was induced with a single train of high-frequency stimulation, which did not induce LTP in control rats. Moreover, MDZ pretreatment prevented the facilitating influence of stress on LTP induction. All of these findings support the hypothesis that previous stress attenuates inhibitory GABAergic control in the BLA, leading to neuronal hyperexcitability and increased plasticity that facilitates fear learning.

Amygdala↗
PubMed1997

Effects of small amygdala lesions on fear, but not aggression, in the rat.

The effects of amygdala lesions on passive avoidance of drinking (dPA) and social interactions in a resident-intruder test were examined in two experiments that utilized different lines of Long-Evans hooded rats. The lesions were fairly well restricted to the rostral half of the central nucleus (rACe), or the cholinergically richly innervated basolateral nucleus (ABL) or the medial nucleus (AMe) of the amygdala. In both experiments, dPA deficits indicating disturbances in fear conditioning or fear expression were found with ABL and rACe lesions. The rACe lesions produced a greater deficit. AMe lesions caused no dPA deficit at all, which contrasts with the mild PA deficits reported by others employing larger lesions extending to the cortical nucleus and, perhaps, damaging the central nucleus. Social behavior was not affected by the lesions in any clear manner. In rats from a long-standing home colony, rACe lesions increased a behavior of plowing and kicking the wood-chip cage bedding during social encounters, and AMe lesions increased lateral defense behaviors. Both effects are paradoxical, suggesting increased anxiety in the fear-deficient rACe rats and increased defense with AMe lesions, despite several previous reports of decreased defense. In the second experiment, rats purchased from a supplier showed no lesion effects during social interactions; like the control group, all three lesion groups exhibited increases in offense associated with cohabitation with a female. The ABL lesions, particularly, had no effect comparable to the decreased offense recently reported to occur following neurotoxin lesions.

Aggression↗
PubMed2005

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning.

The amygdala is centrally involved in formation of emotional memory and response to fear or risk. We have demonstrated that the lateral and basolateral amygdala nuclei fail to form in neuroD2 null mice and neuroD2 heterozygotes have fewer neurons in this region. NeuroD2 heterozygous mice show profound deficits in emotional learning as assessed by fear conditioning. Unconditioned fear was also diminished in neuroD2 heterozygotes compared to wild-type controls. Several key molecular regulators of emotional learning were diminished in the brains of neuroD2 heterozygotes including Ulip1, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and GABA(A) receptor. Thus, neuroD2 is essential for amygdala development and genes involved in amygdala function are altered in neuroD2-deficient mice.

Amygdala↗
PubMed2002

Protein kinase signal transduction cascades in mammalian associative conditioning.

One of the most intriguing and intensely studied questions facing contemporary neuroscientists involves the elucidation of the physiological mechanisms that underlie learning and memory. Recent advances have given us a much more detailed understanding of the signal transduction mechanisms subserving learning in the intact animal. One fact that has become clear is that activation of protein kinases and phosphorylation of their downstream effectors play a critical role. Four protein kinase cascades have garnered considerable attention in the study of information storage at both the synaptic and behavioral levels: Ca++/phospholipid-dependent protein kinase (PKC), Ca++/calmodulin-dependent protein kinase II (CaMKII), cAMP-dependent protein kinase (PKA), and extracellular signal-regulated kinase (ERK). This review will concentrate on studies of two behavioral tasks, conditioned fear and conditioned taste aversion, that provide evidence for the involvement of these kinase systems in associative learning. The authors will also examine a number of potential kinase substrates and how each could participate in the formation of long-term memories.

Animals↗
PubMed2004

Multimodal classical conditioning of fear: contributions of direct, observational, and verbal experiences to current fears.

The authors propose that a multimodal classical conditioning model be considered when clinicians or clinical researchers study the etiology of fears and anxieties learned by human beings. They argue that fears can be built through the combined effects of direct, observed, and verbally presented classical conditioning trials. Multimodal classical conditioning is offered as an alternative to the three pathways to fear argument prominent in the human fear literature. In contrast to the three pathways position, the authors present theoretical arguments for why "learning by observation" and "learning through the receipt of verbal information" should be considered classical conditioning through observational and verbal modes. The paper includes a demonstration of how data, commonly collected in research on the three pathways to fear, would be studied differently using a multimodal classical conditioning perspective. Finally, the authors discuss implications for assessment, treatment, and prevention of learned fears in humans.

Adolescent↗
PubMed2001

Prolonged fear responses in mice lacking dopamine D1 receptor.

Dopamine is an important neurotransmitter involved in learning and memory including emotional memory. The involvement of dopamine in conditioned fear has been widely documented. However, little is known about the molecular mechanisms that underlie contextual fear conditioning and memory consolidation. To address this issue, we used dopamine D1-deficient mice (D1-/-) and their wild-type (D1+/+) and heterozygote (D1+/-) siblings to assess aversive learning and memory. We quantified two different aspects of fear responses to an environment where the mice have previously received unsignaled footshocks. Using one-trial step-through passive avoidance and conditioned freezing paradigms, mice were conditioned to receive mild inescapable footshocks then tested for acquisition, retention and extinction of conditioned fear responses 5 min after and up to 45-90 days post-training. No differences were observed among any of the genotypes in the acquisition of passive avoidance response or fear-induced freezing behavior. However, with extended testing, D1-/- mice exhibited prolonged retention and delayed extinction of conditioned fear responses in both tasks, suggesting that D1-/- mice are capable of acquiring aversive learning normally. These findings demonstrate that the dopamine D1 receptor is not important for acquisition or consolidation of aversive learning and memory but has an important role in modulating the extinction of fear memory.

Animals↗
PubMed1997

Amygdala and bed nucleus of the stria terminalis: differential roles in fear and anxiety measured with the acoustic startle reflex.

Neural stimuli associated with traumatic events can readily become conditioned so as to reinstate the memory of the original trauma. These conditioned fear responses can last a lifetime and may be especially resistant to extinction. A large amount of data from many different laboratories indicate that the amygdala plays a crucial role in conditioned fear. The amygdala receives information from all sensory modalities and projects to a variety of hypothalamic and brainstem target areas known to be critically involved in specific signs that are used to define fear and anxiety. Electrical stimulation of the amygdala elicits a pattern of behaviours that mimic natural or conditioned states of fear. Lesions of the amygdala block innate or conditioned fear and local infusion of drugs into the amygdala have anxiolytic effects in several behavioural tests. Excitatory amino acid receptors in the amygdala are critical for the acquisition, expression and extinction of conditioned fear.

Amygdala↗
PubMed2003

Amygdalar and hippocampal theta rhythm synchronization during fear memory retrieval.

The amygdalohippocampal circuit plays a pivotal role in Pavlovian fear memory. We simultaneously recorded electrical activity in the lateral amygdala (LA) and the CA1 area of the hippocampus in freely behaving fear-conditioned mice. Patterns of activity were related to fear behavior evoked by conditioned and indifferent sensory stimuli and contexts. Rhythmically synchronized activity at theta frequencies increased between the LA and the CA1 after fear conditioning and became significant during confrontation with conditioned fear stimuli and expression of freezing behavior. Synchronization of theta activities in the amygdalohippocampal network represents a neuronal correlate of conditioned fear, apt to improve neuronal communication during memory retrieval.

Amygdala↗
PubMed1996

Chlordiazepoxide discriminates between the neural circuits mediating neuroendocrine responses to fear- and anxiety-producing stimuli in the rat.

Effects of a benzodiazepine, chlordiazepoxide (CDP), on neuroendocrine responses to emotional stimuli were studied in male rats. In the experiments with conditioned fear stimuli, rats received a pure tone paired with footshocks in the training session and were tested on the following day with the same environmental stimuli. CDP injected i.p. 30 min before training impaired the suppressive vasopressin and the augmentative oxytocin or adrenocorticotrophic hormone (ACTH) responses to the conditioned fear stimuli. However, the drug, administered 30 min after the training, did not significantly alter the hormonal responses to conditioned fear stimuli. CDP administered 30 min before testing also abolished the hormonal responses to conditioned fear stimuli. The stimuli which were identical to those used for training or unconditioned fear stimuli (intermittent footshocks) also produced the vasopressin, oxytocin and ACTH responses, and CDP prevented these hormonal responses. The drug, however, did not prevent the hormonal responses to novel environmental stimuli. Novel stimuli are known to produce a state of anxiety. Thus the present experiments demonstrate that CDP discriminates between the neural circuits mediating fear- and anxiety-producing stimuli in the rat.

Adrenocorticotropic Hormone↗
PubMed2005

Development of a rat model to assess the efficacy of the somatosensory-evoked potential as indicator of analgesia.

Drug-induced changes in somatosensory-evoked potentials (SEPs) are considered to reflect an altered nociceptive state. Therefore, the SEP is proposed to be a parameter of analgesic efficacy. However, at present, SEPs have not been studied in relation to animal pain. The present study aims to develop a rat model in which this relationship can be studied based on Pavlovian fear conditioning. Therefore, rats, implanted with epidural electro-encephalogram recording electrodes, were randomly assigned to either a paired or random-control group and subjected to an aversive-to-appetitive transfer paradigm. During the aversive phase, the SEP-stimulation paradigm (5 mA square wave pulses, n = 72, of 2 ms duration each, with a stimulus frequency of 0.5 Hz; total duration 144 s) was used as the unconditioned stimulus (US), while a tone (40 s, 1500 Hz, 85 dB sound pressure level) was used as the conditioned stimulus (CS). During the appetitive phase, the CS was presented paired to the presentation of a sugar pellet. When compared to the random-control group, the paired group showed significantly more freezing behavior and significantly less reward-directed behavior in response to the CS in the appetitive phase. In addition, SEPs were not significantly affected by fear conditioning. Based on these results, we conclude that the SEP-stimulation paradigm can be successfully employed as a US in fear conditioning. In future studies, fear conditioning can be carried out under different levels of an analgesic regimen to allow the changes in SEP parameters to be compared to changes in fear-induced behavior making this model potentially useful to validate SEP parameters as indicators of analgesia.

Analgesia↗
PubMed1998

Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala.

Fear conditioning is a paradigm that has been used as a model for emotional learning in animals. The cellular correlate of fear conditioning is thought to be associative N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity within the amygdala. Here we show that glutamatergic synaptic transmission to inhibitory interneurons in the basolateral amygdala is mediated solely by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast to AMPA receptors at inputs to pyramidal neurons, these receptors have an inwardly rectifying current-voltage relationship, indicative of a high permeability to calcium. Tetanic stimulation of inputs to interneurons caused an immediate and sustained increase in the efficacy of these synapses. This potentiation required a rise in postsynaptic calcium, but was independent of NMDA receptor activation. The potentiation of excitatory inputs to interneurons was reflected as an increase in the amplitude of the GABA(A)-mediated inhibitory synaptic current in pyramidal neurons. These results demonstrate that excitatory synapses onto interneurons within a fear conditioning circuit show NMDA-receptor independent long-term potentiation. This plasticity might underlie the increased synchronization of activity between neurons in the basolateral amygdala after fear conditioning.

Amygdala↗
PubMed2002

Behavioral profiles of inbred strains on novel olfactory, spatial and emotional tests for reference memory in mice.

Studying the behavior of genetic background strains provides important information for the design and interpretation of cognitive phenotypes in mutant mice. Our experiments examined the performance of three commonly used strains (C57BL/6J, 129S6, DBA/2J) on three behavioral tests for learning and memory that measure very different forms of memory, and for which there is a lack of data on strain differences. In the social transmission of food preference test (STFP) all three strains demonstrated intact memory for an odor-cued food that had been sampled on the breath of a cagemate 24 hours previously. While C57BL/6J and 129S6 mice showed good trace fear conditioning, DBA/2J mice showed a profound deficit on trace fear conditioning. In the Barnes maze test for spatial memory, the 129S6 strain showed poor probe trial performance, relative to C57BL/6J mice. Comparison of strains for open field exploratory activity and anxiety-like behavior suggests that poor Barnes maze performance reflects low exploratory behavior, rather than a true spatial memory deficit, in 129S6 mice. This interpretation is supported by good Morris water maze performance in 129S6 mice. These data support the use of a C57BL/6J background for studying memory deficits in mutant mice using any of these tasks, and the use of a 129S6 background in all but the Barnes maze. A DBA/2J background may be particularly useful for investigating the genetic basis of emotional memory using fear conditioning.

Animals↗