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PubMed2000

Contextual fear, gestalt memories, and the hippocampus.

This review examines the relationship between exploration and contextual fear conditioning. The fear acquired to places or contexts associated with aversive events is a form of Pavlovian conditioning. However, an initial period of exploration is necessary to allow the animal to form an integrated memory of the features of the context before conditioning can take place. The hippocampal formation plays a critical role in this process. Cells within the dorsal hippocampus are involved in the formation, storage and consolidation of this integrated representation of context. Projections from the subiculum to the nucleus accumbens regulate the exploration necessary for the acquisition of information about the features of the context. This model explains why electrolytic but not excitotoxic lesions of the dorsal hippocampus cause enhanced exploratory activity but both cause deficits in contextual fear. It also explains why retrograde amnesia of contextual fear is greater than anterograde amnesia.

Animals↗
PubMed1998

[Behavioral and neurochemical study on the role of the brain cholecystokinin system in anxiety].

In order to elucidate the involvement of cholecystokinin (CCK) in the regulation of anxiety, the author examined the effects of the selective non-peptide CCKB receptor antagonist LY288513 on freezing behavior induced by conditioned fear stress, an animal model of anxiety. 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. Subcutaneous administration of LY288513 30 min before footshock (0.3 mg/kg) and 30 min before conditioned fear stress (0.03-0.3 mg/kg) reduced conditioned freezing. This indicates that LY288513 blocked both the acquisition and expression of conditioned fear. The relatively selective non-peptide CCKA receptor antagonist, lorglumide, blocked the expression of conditioned fear, but only at a high dose (1.0 mg/kg). The peripheral non-peptide CCKA/B receptor antagonist, loxiglumide, failed to do so. Subcutaneous administration of LY288513 (3 mg/kg) enhanced the conditioned fear-induced in 3, 4-dihydroxy-phenylacetic acid (DOPAC) contents in the medial prefrontal cortex, which was assayed by high performance liquid chromatography with electrochemical detection. Thirty min of inescapable electric footshock decreased CCK8S contents in the amygdala, which was assayed by radioimmunoassay. These results suggest that the brain CCKB receptors are involved in the regulation of anxiety, and that the anxiolytic effects of CCKB receptor antagonists are mediated by increasing dopamine activity in the medial prefrontal cortex. Furthermore, it is possible that the CCK neurons in the amygdala are also associated with anxiety.

Animals↗
PubMed1979

Effect of autoanalgesia on CNS enkephalin receptors.

Fear conditioning to foot shock (15 sec/day, 12 days) elicited autoanalgesia in 10 male (Sprague-Dawley) rats, while 17 non-shock control rats exhibited no analgesia as measured by the tail-flick assay. The binding of 3H-leu-enkephalin to synaptosomal preparations isolated from fear conditioned (experimental) and control animals was analyzed. At leu-enkephalin concentrations of 10(-9) M or less, both synaptosomal preparations demonstrated high affinity binding with dissociation constants on the order of 10(-10). Binding of leu-enkephalin could not be displaced by a hundred-fold excess of naloxone at leu-enkephalin concentrations less than 10(-9) M. However, the ability of naloxone to compete with leu-enkephalin for binding sites progressively increased at concentrations greater than 10(-9) M leu-enkephalin. At these ligand concentrations, the competition of naloxone for leu-enkephalin binding sites was more dramatic in the control than in the experimental animals. These data support the existence of two classes of receptors for leu-enkephalin, one of which is not blocked by opiate antagonists. Furthermore, changes in binding capacity associated with autoanalgesia produced by conditioned fear are consistent with the hypothesis of endogenous release of opiate-like peptides in response to stress.

Analgesia↗
PubMed1996

The psychobiological basis of posttraumatic stress disorder.

Posttraumatic stress disorder is a disorder with an identifiable etiological factor (exposure to a traumatic event) and with a complex symptomatology (i.e. intrusive memories, avoidance, hyperarousal) that suggests dysfunction in multiple psychobiological systems. This review considers studies of the neurobiological consequences of acute and chronic stress showing that traumatic experiences can produce long-lasting alterations in multiple neurochemical systems. The role of the locus coeruleus noradrenergic system, prefrontal cortex dopaminergic system, endogenous opiates, hypothalamic-pituitary-adrenal axis, and cortico-releasing factors are reviewed. Several models of PTSD are highlighted, including fear conditioning, kindling, and sensitization. In particular, fear conditioning to explicit and contextual cues is proposed as a model for intrusive memories reactivated by trauma-related stimuli and hyperarousal, respectively. It is argued that the amygdala plays a crucial role in the encoding and retrieval of fear memories activated by specific stimuli that have been associated with aversive events. Association involving more complex environmental stimuli and aversive events may require the involvement of the hippocampus and the bed nucleus of the stria terminalis. Repeated activation of conditioned fear memories may produce a kindling-like process which results in spontaneous intrusive memories.

Humans↗
PubMed1989

Observational conditioning of fear to fear-relevant versus fear-irrelevant stimuli in rhesus monkeys.

Two experiments examined whether superior observational conditioning of fear occurs in observer rhesus monkeys that watch model monkeys exhibit an intense fear of fear-relevant, as compared with fear-irrelevant, stimuli. In both experiments, videotapes of model monkeys behaving fearfully were spliced so that it appeared that the models were reacting fearfully either to fear-relevant stimuli (toy snakes or a toy crocodile), or to fear-irrelevant stimuli (flowers or a toy rabbit). Observer groups watched one of four kinds of videotapes for 12 sessions. Results indicated that observers acquired a fear of fear-relevant stimuli (toy snakes and toy crocodile), but not of fear-irrelevant stimuli (flowers and toy rabbit). Implications of the present results for the preparedness theory of phobias are discussed.

Animals↗
PubMed2002

Metabotropic glutamate receptors are involved in amygdaloid plasticity.

The amygdala plays an important role in emotional learning. Synaptic plasticity underlying the acquisition of conditioned fear occurs in the lateral nucleus of the amygdala: long-term potentiation (LTP) of synapses in the pathway of the conditioned stimulus (CS) has shown to be a neural correlate of this kind of emotional learning. The present study is based on previous results of our laboratory showing an important role of the metabotropic glutamate receptor subtype 5 (mGluR5) in fear conditioning. Here, we explored whether mGlu5 receptors within the lateral nucleus of the amygdala are involved in the plasticity underlying fear conditioning. We used an in vivo approach investigating the acquisition, consolidation and expression of conditioned fear by the fear-potentiated startle paradigm and by the inhibition of motor activity during CS presentation. Additionally, we used an in vitro approach inducing LTP in the lateral amygdala by patch-clamp recordings in rat brain slices. Acquisition of conditioned fear, but not consolidation and expression, was blocked by intra-amygdaloid injections of the specific mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) in vivo. Furthermore, induction of amygdaloid LTP but not synaptic transmission was disrupted by MPEP application in vitro. These experiments show for the first time in vivo and in vitro that mGluR5 receptors are necessary for plasticity in the amygdala.

Amygdala↗
PubMed2004

The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are efficacious in the treatment of a variety of fear or anxiety disorders. Although they inhibit the reuptake of serotonin within hours of administration, therapeutic improvement only occurs after several weeks. In this study, we used fear conditioning to begin to understand how acute and chronic SSRI treatment might differentially affect well-characterized fear circuits. METHODS: We evaluated the effects of acute and chronic treatment with the SSRI citalopram on the acquisition of auditory fear conditioning. To further understand the role of serotonin in modulating fear circuits, we compared these effects with those of acute and chronic administration of the antidepressant tianeptine, a purported serotonin reuptake enhancer. RESULTS: We found that acute administration of the SSRI citalopram enhanced acquisition, whereas chronic treatment reduced the acquisition of auditory fear conditioning. In comparison, treatment with tianeptine had no effect acutely but also reduced the acquisition of tone conditioning when administered chronically. CONCLUSIONS: Our findings with citalopram are consistent with the clinical effects of SSRI treatment seen in patients with anxiety disorders, in which anxiety is often increased during early stages of treatment and decreased after several weeks of treatment. The findings also indicate that auditory fear conditioning can be a useful tool in understanding differences in the effects of short-term and long-term antidepressant treatment with serotonergic medications.

Acoustic Stimulation↗
PubMed2004

Molecular mechanisms underlying emotional learning and memory in the lateral amygdala.

Fear conditioning is a valuable behavioral paradigm for studying the neural basis of emotional learning and memory. The lateral nucleus of the amygdala (LA) is a crucial site of neural changes that occur during fear conditioning. Pharmacological manipulations of the LA, strategically timed with respect to training and testing, have shed light on the molecular events that mediate the acquisition of fear associations and the formation and maintenance of long-term memories of those associations. Similar mechanisms have been found to underlie long-term potentiation (LTP) in LA, an artificial means of inducing synaptic plasticity and a physiological model of learning and memory. Thus, LTP-like changes in synaptic plasticity may underlie fear conditioning. Given that the neural circuit underlying fear conditioning has been implicated in emotional disorders in humans, the molecular mechanisms of fear conditioning are potential targets for psychotherapeutic drug development.

Amygdala↗
PubMed2005

Early handling, but not maternal separation, decreases emotional responses in two paradigms of fear without changes in mesolimbic dopamine.

This study aimed at identifying the effects of neonatal handling (H) and maternal separation (MS) on two paradigms of fear, learned and innate, and on the tyrosine hydroxylase (TH) immunoreactive cells in adult life. Wistar rats were daily handled with a brief maternal separation, maternal separated for 3 h or left undisturbed during the first 10 days of life. Behavioural responses in the open-field (innate fear) and conditioned fear (learned fear) were evaluated. Moreover, a semi-quantitative analysis of TH immunoreactivity in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) was performed using optical densitometry and confirmed by planar measurements of neuronal density. Early handling decreased behaviour responses of innate and learned fear in adult life, while maternal separation had no significant long-lasting effect on these responses compared to the non-handled group. The behavioural effects of early handling could not be explained by changes in the density of midbrain dopaminergic cells, which were not affected by handling or maternal separation.

Animals↗
PubMed1993

Mechanisms involved in the observational conditioning of fear.

Three experiments support the hypothesis that mechanisms involved in observational conditioning (OC) of fear are similar to those of direct classical conditioning and involve the organism attempting to detect the causal structure of its environment. Experiment 1, a correlational analysis, shows that model monkeys' fear behaviors on snake trials (unconditioned stimulus [US]) were highly correlated with observer monkeys' fear (unconditioned response) while watching the models' fear. In Experiment 2, all observers showed distress while watching the model's fear during Session 1 of OC, but only observers who could see the snake to which the model was reacting continued to show fear during subsequent OC sessions, suggesting that the model's fear is an easily habituable US. In Experiment 3, observers acquired significant fear of snakes after 1 OC session, indicating that the continued fear of those Experiment 2 observers that could see the snake may reflect their own acquired fear of snakes.

Animals↗
PubMed2006

The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats.

RATIONALE: Previous studies demonstrated that pharmacological blockade of CB1 cannabinoid receptors decreases the extinction of conditioned fear and spatial memory in rodents. However, the effects of CB1 cannabinoid receptor activation in this response remain unclear. OBJECTIVES: To evaluate the effects of the cannabinoid agonist WIN 55,212-2 (WIN) and the cannabinoid antagonist SR 147778 (SR) on the extinction of contextual fear memory in rats 24 h or 30 days after fear conditioning. METHODS: For fear conditioning, rats were placed in the conditioning chamber for 3 min and received a 1-s electric foot shock (1.5 mA). Retrieval testing consisted of a 3-min exposure to the conditioning chamber and extinction training consisted of successive 9-min exposures at 24-h intervals. Rats were also evaluated in the open field and water maze reversal task. RESULTS: The administration of SR (1.0 mg/kg, i.p.) and WIN (0.25 mg/kg, i.p.) before extinction training disrupted and facilitated, respectively, the extinction of 24 h contextual fear memory. These effects were not related to any disturbance in memory retrieval, unconditioned freezing expression, or locomotor activity. WIN (0.25 mg/kg, i.p.) also facilitated the extinction of 30-day-old contextual fear memory, while the prior administration of SR (0.2 mg/kg, i.p.) antagonized this response. The facilitative effect of WIN on memory extinction does not seem to be specific for contextual fear memory because it was also observed in the water maze reversal task. CONCLUSIONS: These results suggest cannabinoid receptor agonists as potential drugs to treat anxiety disorders related to the retrieval of aversive memories.

Animals↗
PubMed2002

Associative learning deficits increase symptoms of anxiety in humans.

BACKGROUND: Unpredictability has been postulated to be fundamental to anxiety and mood disorders. The origin of this unpredictability remains obscure. Because classical conditioning promotes predictability, this study investigated whether failure to learn conditioned stimulus (CS)-unconditioned stimulus (US) relationship during fear conditioning increased anxiety and avoidance. METHODS: Healthy subjects participated in two similar differential fear conditioning sessions separated by 1 week (n = 72) or a month (n = 61) in which one of two conditioned stimuli was associated with a shock/US. Following initial acquisition, subjects' awareness of CS-US relationship was assessed. Conditioned responses (CR) to the CS and to the experimental context were examined using the startle reflex and the skin conductance. Avoidance was operationally defined as failure to return for the second session. RESULTS: Only aware subjects showed differential CR. In the unaware subjects, the deficit in differential conditioning was associated with increased signs of anxiety during the first and second sessions. In addition, there was greater avoidance in the unaware subjects. CONCLUSIONS: Deficits in explicit cue fear conditioning can enhance anxiety. These findings are consistent with theories that associate anxiety and mood disorders with perceived unpredictability. Contextual conditioning models may be relevant to study chronic forms of anxiety.

Adolescent↗
PubMed1990

The influence of conditioned fear-induced stress on the opioid systems in the rat.

In this study the rats were repeatedly placed in a conditioning box, and 30 min later were subjected to a mild foot-shock. Anticipation of painful stimuli resulted in development of antinociception before a painful stimulus was applied. This conditioned fear-induced antinociception was antagonized by naloxone (1 mg/kg IP), as well as by ipsapirone (10 mg/kg IP), as measured by a tail-flick test. Stressed rats were hypersensitive to the analgesic action of morphine (1 mg/kg SC), but not to the specific kappa agonist U69,593 (0.1 mg/kg SC). In order to determine the involvement of the proopiomelanocortin and prodynorphin systems in stress we measured levels of their represenative peptides beta-endorphin and alpha-neoendorphin using selective RIAs. Biochemical data showed that conditioned stress evoked a marked decrease in the beta-endorphin level in the hypothalamus and both lobes of the pituitary, together with a three-fold increase in the peptide level in the plasma. In contrast, the level of alpha-neoendorphin in the hypothalamus, pituitary and spinal cord remained unchanged. Only in the plasma a decrease in that peptide content was found. Furthermore, in vitro studies showed that the spontaneous and K(+)-stimulated release of beta-endorphin from the hypothalamus of rats which had been exposed to a conditioned stimulus was enhanced, whereas the release of alpha-neoendorphin from that tissue was attenuated. These results suggest a major role of the proopiomelanocortin system and, to the lesser extent, of the prodynorphin one in the mechanism of a conditioned fear-induced stress.

Analgesia↗
PubMed2005

Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder.

BACKGROUND: In the conditioned fear paradigm, repeated pairing of an aversive unconditioned stimulus (US) (e.g. electric shock) with a neutral conditioned stimulus (CS) (e.g. bright light) results in a conditioned fear response to the light alone. Animal studies have shown that the amygdala plays a critical role in acquisition of conditioned fear responses, while the medial prefrontal cortex (including anterior cingulate), through inhibition of amygdala responsiveness, has been hypothesized to play a role in extinction of fear responses. No studies have examined neural correlates of fear conditioning and extinction in patients with post-traumatic stress disorder (PTSD). METHOD: Women with early childhood sexual-abuse-related PTSD (n = 8) and women without abuse or PTSD (n = 11) underwent measurement of psychophysiological (skin conductance) responding as well as positron emission tomographic (PET) measurement of cerebral blood flow during habituation, acquisition and extinction conditions. During habituation subjects were repeatedly exposed to a blue square on a screen. During acquisition, exposure to the blue square (CS) was paired with an electric shock to the forearm (US). With extinction, subjects were again exposed to the blue squares without shock. On a different day subjects went through the same procedure with electric shocks administered randomly in the absence of the blue square. RESULTS: Skin conductance responding to the CS was consistent with the development of conditioned responses with this paradigm. PTSD patients had increased left amygdala activation with fear acquisition, and decreased anterior cingulate function during extinction, relative to controls. CONCLUSIONS: These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.

Adult↗
PubMedDate not supplied

Different mechanisms of fear extinction dependent on length of time since fear acquisition.

Fear extinction is defined as a decline in conditioned fear responses (CRs) following nonreinforced exposure to a feared conditioned stimulus (CS). Behavioral evidence indicates that extinction is a form of inhibitory learning: Extinguished fear responses reappear with the passage of time (spontaneous recovery), a shift of context (renewal), and unsignaled presentations of the unconditioned stimulus (reinstatement). However, there also is evidence to suggest that extinction is an "unlearning" process corresponding to depotentiation of potentiated synapses within the amygdala. Because depotentiation is induced more readily at short intervals following LTP induction and is not inducible at all at a sufficient delay, it may be that extinction initiated shortly following fear acquisition preferentially engages depotentiation/"unlearning," whereas extinction initiated at longer delays recruits a different mechanism. We investigated this possibility through a series of behavioral experiments examining the recoverability of conditioned fear following extinction. Consistent with an inhibitory learning mechanism of extinction, rats extinguished 24-72 h following acquisition exhibited moderate to strong reinstatement, renewal, and spontaneous recovery. In contrast, and consistent with an erasure mechanism, rats extinguished 10 min to 1 h after acquisition exhibited little or no reinstatement, renewal, or spontaneous recovery. These data support a model in which different neural mechanisms are recruited depending on the temporal delay of fear extinction.

Animals↗
PubMed2006

Inhibition of neurogenesis interferes with hippocampus-dependent memory function.

Rats treated with low dose irradiation, to inhibit adult hippocampal neurogenesis, and control rats were administered a non-matching-to-sample (NMTS) task, which measured conditional rule learning and memory for specific events, and a test of fear conditioning in which a discrete CS was paired with an aversive US in a complex environment. Irradiated rats were impaired on the NMTS task when the intervals between sample and test trials were relatively long, and in associating the shock-induced fear with contextual cues in the fear conditioning task. Irradiated rats were not impaired in learning the basic NMTS rule or in performing that task when the intervals between the sample and test trials were short. Nor were there group differences in conditioning the fear response to the CS in the fear conditioning task. The results, which extend the range of hippocampus-dependent tasks that can be said to be vulnerable to the effects of neurogenesis suppression, support the hypothesis that new hippocampal cells generated in adulthood participate in a broad range of hippocampal functions.

Animals↗
PubMed2000

Contributions of postrhinal and perirhinal cortex to contextual information processing.

The role of the postrhinal cortex (POR) and the perirhinal cortex (PER) in processing relational or contextual information was examined with Pavlovian fear conditioning. Rats with electrolytic or neurotoxic lesions of the POR or PER were tested in 2 contextual fear conditioning paradigms. In Experiment 1, electrolytic lesions of the POR or PER produced impairments in contextual fear conditioning but not in conditioning to a phasic auditory conditioned stimulus. Neurotoxic lesions of the POR or PER likewise resulted in anterograde (Experiment 2) and retrograde (Experiment 3) deficits in fear conditioning to the training context in an unsignaled shock paradigm. The results suggest that operations performed on sensory information by the POR and PER are necessary to support contextual learning.

Animals↗
PubMed2005

Cortisol and DHEA-S are associated with startle potentiation during aversive conditioning in humans.

RATIONALE: Fear conditioning reliably increases the startle reflex and stress hormones, yet very little is known about the effect of stress hormones on fear-potentiated startle. Cortisol and the sulfate ester of dehydroepiandrosterone (DHEA-S) are involved in stress and anxiety. Evidence suggests that low cortisol/DHEA-S ratio has a buffering effect on stress and anxiety in preclinical and clinical studies, suggesting that there may be a relationship between fear-potentiated startle and cortisol and DHEA-S activity. OBJECTIVE: The aim of the study was to examine whether there is a relationship between cortisol/DHEA-S ratio and fear-potentiated startle. METHODS: Thirty healthy subjects participated in a differential aversive conditioning experiment during which one of two stimuli (CS+) was paired with a shock, and the other was not (CS-). Conditioned responses were assessed with the startle reflex, defined as startle potentiation during CS+ compared to CS-. DHEA-S and cortisol levels were assayed from blood samples collected in both a baseline and an aversive conditioning session. Subjective state anxiety, arousal, and valence were assessed at various times during testing. RESULTS: Fear-potentiated startle was larger in individuals with high compared to low cortisol/DHEA-S ratio. Multiple regression analyses revealed that fear-potentiated startle was positively associated with cortisol and negatively associated with DHEA-S. There was no significant correlation between DHEA-S and cortisol levels. CONCLUSION: These data suggest that cortisol and DHEA-S are involved in fear conditioning.

Adult↗