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PubMed1978

Modeling processes in the acquisition of fears: vicarious electrodermal conditioning to fear-relevant stimuli.

Fear-relevant (snakes, spiders, and rats) and fear-irrelevant (flowers, mushrooms, and berries) pictures were compared as conditioned and instigating stimuli in a vicarious classical conditioning paradigm with skin conductance responses as the dependent variable. A female confederate model and subject watched the pictures side by side. A female stimulus presentations, the experimenter interrupted to investigate alleged overreactions of the model to one of the stimulus classes. The model then vividly described a phobia for this object, which was to serve as a vicarious instigating stimulus. The experiment continued for a few conditioning trials, and then the experimenter announced that the disturbing stimulus would be omitted before the second part of the experiment. There was no effect of stimulus content on vicariously instigated responses, although significant overall instigation was observed. However, the responses to the stimulus that was paired with the model's phobic stimulus, that is, the vicariously conditioned responses, failed to extinguish during the second part of the experiment when it was fear-relevant but extinguished immediately when it was fear-irrelevant.

Adult↗
PubMed1998

Distinct regions of the periaqueductal gray are involved in the acquisition and expression of defensive responses.

In fear conditioning, a rat is placed in a distinct environment and delivered footshock. The response to the footshock itself is called an activity burst and includes running, jumping, and vocalization. The fear conditioned to the distinct environment by the footshock elicits complete immobility termed freezing. Lesions of the ventral periaqueductal gray (vPAG) strongly attenuate freezing. However, lesions of the dorsolateral periaqueductal gray (dlPAG) increase the amount of freezing seen to conditional fear cues acquired under conditions in which intact rats do not demonstrate much fear conditioning. To examine the necessity of these regions in the acquisition and expression of fear, we performed five experiments that examined the effects of electrolytic lesions of the dlPAG and the vPAG in learned and unlearned fear. In experiment 1, lesions of the vPAG strongly attenuated, whereas lesions of the dlPAG enhanced, unconditional freezing to a cat. In experiment 2, lesions of the dlPAG made before but not after training enhanced the amount of freezing shown to conditional fear cues acquired via immediate footshock delivery. In experiment 3, vPAG lesions made either before or after training with footshock decreased the level of freezing to conditional fear cues. Neither dlPAG lesions nor vPAG lesions affected footshock sensitivity (experiment 4) or consumption on a conditioned taste aversion test that does not elicit antipredator responses (experiment 5). On the basis of these results, it is proposed that activation of the dlPAG produces inhibition of the vPAG and forebrain structures involved with defense. In contrast, the vPAG seems to be necessary for postencounter freezing defensive behavior.

Animals↗
PubMed2003

Genes and mechanisms in the amygdala involved in the formation of fear memory.

With a combined molecular, electrophysiological, and behavioral approach we have sought to correlate conditioned fear behavior with electrophysiological activities in the lateral amygdala and hippocampal formation in mice and rats and to determine the potential contribution of effector genes that are expressed in the basolateral amygdaloid complex during the late phase of pavlovian fear conditioning. Our data indicate that resonant/oscillatory electrical activity in projection neurons of the lateral amygdala provide an important cellular element of coherent theta activity in amygdalohippocampal pathways, which may represent a nondiscriminating neural correlate of conditioned fear. Correlated activity seems to contribute to the formation of synaptic plasticity in these networks, such as input-specific long-term depression of thalamoamygdaloid signals and consolidation of long-term potentiation in the dentate gyrus. Moreover, associative fear conditioning results in selective gene expression in the basolateral amygdaloid complex, involving molecular factors of structural reorganization and signal transduction, particularly GABA function, supporting the view that the amygdala is a site of neural plasticity and information storage during formation of fear memory.

Amygdala↗
PubMed2004

Pretraining inactivation of the caudal pontine reticular nucleus impairs the acquisition of conditioned fear-potentiated startle to an odor, but not a light.

Recent data from developing rats suggest that structures downstream from the amygdala are involved in the acquisition of conditioned fear-potentiated startle (FPS). The authors tested this idea in adult rats by temporarily inactivating the structure critical for FPS, the caudal pontine reticular nucleus (PnC), during fear conditioning. When the conditioned stimulus (CS) was an odor, rats displayed freezing, but not FPS, at test. This effect was not due to a decrease in footshock sensitivity. Further, no savings were evident on retraining. When the CS was a light, inactivation of the PnC had no effect on the acquisition of FPS. Thus, the PnC may be crucial for the acquisition of conditioned FPS to an odor, but not a light.

Animals↗
PubMed2004

Differential regulation of the expression of contextual freezing and fear-potentiated startle by 5-HT mechanisms of the median raphe nucleus.

It has previously been shown that the median raphe nucleus (MR) is one of the main sources of projections to the septum and hippocampus. 5-HT projections from this nucleus to the hippocampus are implicated in the acquisition and expression of contextual fear (background stimuli), as assessed by freezing. It has also been reported that amygdala is involved in the acquisition of conditioned fear to foreground cues such as light, used as CS. As the MR projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to contextual and classical fear conditioning remains to be elucidated. The present study examined the involvement of the MR serotonergic mechanisms in the expression of two distinct types of conditioned fear responses: contextual freezing and fear conditioning to explicit cue (light) measured in a fear-potentiated startle (FPS) procedure. Animals received MR electrolytic lesions of or microinjections of 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino tetralin) (1 microg/0.2 microl) into the MR, 1 or 7 days after two consecutive training sessions in which they received 10 pairings of the CS (light, 4 s)-US (foot-shocks 0.6 mA, 1s) and were tested in a contextual fear paradigm and in a FPS procedure. The startle was clearly potentiated in the presence of light-CS in animals bearing lesions of or microinjected with 8-OH-DPAT into MR at 1 or 7 days post-training. However, animals bearing MR electrolytic lesions or microinjections of 8-OH-DPAT into the MR at 1 day, but not at 7 days post-training, showed a significant decrease in time spent in freezing than control ones. Thus, the memory for contextual conditioned fear seems to be formed during a time-window shorter than 1 week. As FPS may be produced in lesioned rats unable to freeze to fear contextual stimuli, dissociable systems seem to be recruited in each condition. Thus, the production of contextual freezing and fear-potentiated startle are conveyed by distinct 5-HT-mediated circuits of the MRN.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Injections of the NMDA receptor antagonist aminophosphonopentanoic acid into the lateral nucleus of the amygdala block the expression of fear-potentiated startle and freezing.

NMDA receptors within the amygdala play an important role in the acquisition and expression of conditioned fear. Because amygdaloid injections of NMDA receptor antagonists did not block the expression of every behavioral sign of fear, a discussion arose as to whether amygdaloid NMDA receptors play different roles in different kinds of fear-conditioning tasks. To clarify the exact role of amygdaloid NMDA receptors, the present study measured the effects of amygdaloid NMDA receptor blockade on the two major animal models of conditioned fear. An experimental design was used that allowed simultaneous measurement of fear-potentiated startle and freezing during the same test session after animals had undergone identical training procedures. The present study clearly demonstrates that injections of the NMDA receptor antagonist AP-5 into the lateral nucleus of the amygdala significantly attenuated both behavioral fear responses (i.e., the amygdaloid NMDA receptors are necessary for the expression of fear-potentiated startle and freezing). The present results together with others from the literature indicate that NMDA receptors within the lateral amygdala are critically involved in normal synaptic transmission. It appears then that NMDA receptor antagonists may block the acquisition of fear conditioning by directly interfering with normal synaptic transmissions in the amygdala. Possible reasons for some discrepant results in earlier studies are also discussed.

2-Amino-5-phosphonovalerate↗
PubMed1999

An antisense oligonucleotide reverses the footshock-induced expression of fos in the rat medial prefrontal cortex and the subsequent expression of conditioned fear-induced immobility.

The immediate-early genes, including c-fos, have been proposed to be involved in learning and memory. In this report, we examine stress-induced Fos-like immunoreactivity (Fos-li) in subregions of the prefrontal cortex during a conditioned fear paradigm. During the acquisition phase, the rats were conditioned to fear a formerly neutral tone by pairing the tone with a mild footshock. The rats were then tested for fearful behavior by reexposure to the tone without additional footshock. During acquisition, Fos-li was increased in the medial prefrontal cortex (infralimbic and prelimbic) but not the anterior cingulate and M1 motor cortex. However, during the extinction phase, no significant increase in Fos-li was observed in any region. These findings indicate that acquisition, but not extinction, of conditioned fear is associated with an increase in Fos-li in subregions of the medial prefrontal cortex. In other animals, an antisense oligonucleotide directed against the c-fos mRNA was injected into the infralimbic/prelimbic cortex 12 or 72 hr before the acquisition session. Antisense treatment given 12, but not 72, hr earlier suppressed Fos production without altering behavior during the acquisition session. Three days after the acquisition session, rats were tested for fearful behavior as before. The antisense oligonucleotide blockade of Fos production during acquisition was associated with a significantly less fearful response during the extinction session. These results support a role for Fos in the medial prefrontal cortex during the acquisition of aversive learning.

Acoustic Stimulation↗
PubMed1983

Strain differences in fear between spontaneously hypertensive and normotensive rats.

The purpose of this study was to determine whether the reduced conditioned fear response in spontaneously hypertensive rats (SHRs) relative to Wistar-Kyoto controls (WKYs); (a) reflects a decrease in fear in SHRs or an increase in fear in WKYs, relative to other strains; (b) is secondary to strain differences in cardiovascular regulation; (c) represents a weaker conditioned response or a weaker memory trace; and (d) generalizes beyond tests of conditioned fear. SHRs, WKYs and Sprague-Dawley (SD) rats were subjected to classical fear conditioning (30 trials) involving the pairing of a tone conditioned emotional stimulus (CES: 800 Hz, 82 dB, 10 s) with an electric footshock unconditioned stimulus (US: 1.5 mA, 0.5 s). Cardiovascular responses elicited by the CES (without the US) were assessed through computer assisted techniques in chronically instrumented animals. Conditioned fear behavior was assessed as the proportion of time accounted for by crouching or freezing during a 300 s presentation of the CES without the US. Unconditioned fear reactivity was examined using the open field test. Conditioned fear reactivity (% freezing during 300 s CES) was reduced (P less than 0.01) in SHRs relative to both WKYs and SDs, which did not differ (SHR: 57% +/- 5; WKY 85% +/- 3; SD: 93% +/- 4). Young (7 week) and mature (14 week) animals within each strain differed in resting mean arterial pressure (MAP, in mm Hg) (WKY: young , 102 +/- 1; mature, 133 +/- 2; P less than 0.01; SHR: young, 124 +/- 3; mature, 153 +/- 5; P less than 0.01) but did not differ in conditioned fear reactivity (WKY: young, 91% +/- 3; mature, 93% +/- 3; SHR: young, 47% +/- 3; mature, 62% +/- 8.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Automated assessment of conditioning parameters for context and cued fear in mice.

A behavioral technique often used to evaluate the cognitive performance of rats and mice is the fear conditioning paradigm. During conditioned fear experiments, freezing responses shown by rodents after exposure to environmental stimuli previously paired to an aversive experience provide a behavioral index of the animal's associative abilities. The present study examined the ability of a computer-controlled automated Freeze Monitor system for recording immobility behavior in mice. The sensitivity of the automated procedure to detect group differences caused by the application of various training protocols was also evaluated. Statistical analyses revealed significant positive correlations between immobility scores obtained with the automated apparatus and hand-scored data collected by a continuous or a time-sampling method. Behavioral patterns recorded by the computerized system were very similar to those obtained by the hand-scoring methods adopted. In particular, during context testing, exposure to environmental stimuli previously paired with a mild foot shock (unconditioned stimulus [US]) evoked increased immobility behavior in mice conditioned with the US compared with levels of immobility displayed by mice previously confined to the same contextual stimuli without receiving the US. Moreover, although during conditioned stimulus (CS) testing, mice previously exposed to the US displayed high levels of immobility when confined to environmental cues much different from those paired with the US (contextual fear generalization), both hand-scored and automated results revealed the effect of CS-US pairing (increased immobility) only in mice trained to associate the two stimuli (paired group) but not in mice exposed to both CS and US separated by a 40-sec time interval (unpaired group) or in mice receiving only the US (US group) during conditioning sessions. Overall, the results show associative conditioning measured in an automated apparatus and highlight the utility of obtaining both latency as well as beam interruption parameters.

Animals↗
PubMed1996

Forebrain pathways mediating stress-induced renin secretion.

1. All stressors tested so far increase plasma renin levels; among these are exposure to foot-shock, immobilization, forced swimming, head-up tilt, exercise, hypotension haemorrhage and conditioned fear. 2. In old rats (22 months old), conditioned fear stress fails to increase plasma renin concentrations to the same level as in young rats (7 months old). 3. Destruction of cells in the paraventricular hypothalamic nucleus (PVH), either electrolytically or with the cell-selective neurotoxin ibotenic acid, prevents the effect of conditioned fear stress, but not of immobilization, on plasma renin concentration. 4. Ibotenic acid-induced lesions in the central amygdaloid nucleus inhibit conditioned fear stress-induced increases in plasma renin concentrations, but do not reduce the renin response to immobilization. Lesions in lateral amygdaloid nuclei do not reduce the renin response to stressors. 5. Although lesions in the bed nucleus of the stria terminalis (BNST) reduce the adrenocortical response to conditioned fear stress, they do not reduce the effect of stress on plasma renin concentration. 6. Destruction of catecholaminergic terminals in the PVH prevents the effect of conditioned fear stress on plasma renin concentration. 7. Electrolytic lesions in the dorsal raphe nucleus, which is a major site of origin of ascending serotonergic pathways, also inhibit the effect of conditioned fear stress on plasma renin concentration. 8. Activation of serotonin1A (5HT1A) receptors with the anti-anxiety drugs buspirone and ipsapirone reduces the firing rate of serotonergic neurons in the dorsal raphe nucleus in the midbrain and decreases the effect of stress on plasma renin concentrations. In contrast, the benzodiazepine anxiolytic drugs, chlordiazepoxide and midazolam, are ineffective in inhibiting the renin response to stress. 9. Chemical sympathectomy combined with adrenal medullectomy does not prevent the effect of conditioned fear stress on plasma renin concentration, suggesting that the sympathetic system is not the sole mediator of the message from the brain to the kidneys. 10. Combined, these observations suggest that aversive information from the cortex is transmitted via the amygdala to catecholaminergic cells in the medulla and to serotonergic cells in the dorsal raphe that stimulate the PVH to increase the release of renin.

Adrenergic beta-Agonists↗
PubMed1990

Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala.

Receptors for N-methyl-D-aspartate (NMDA) seem to have a critical role in synaptic plasticity. NMDA antagonists (such as AP5) prevent induction of long-term potentiation, an activity-dependent enhancement of synaptic efficacy mediated by neural mechanisms that might also underlie learning and memory. They also attenuate memory formation in several behavioural tasks; there are few data, however, implicating an NMDA-sensitive measure of conditioning based on local infusion of antagonists into a brain area tightly coupled to the behavioural response used to assess conditioning. We now show that NMDA antagonists infused into the amygdala block the acquisition, but not the expression, of fear conditioning measured with a behavioural assay mediated by a defined neural circuit (fear-potentiation of the acoustic startle reflex). This effect showed anatomical and pharmacological specificity, and was not attributable to reduced salience of the stimuli of light or shock used in training. The data indicate that an NMDA-dependent process in the amygdala subserves associative fear conditioning.

2-Amino-5-phosphonovalerate↗
PubMed1987

Effects of naltrexone on learning and performance of conditional fear-induced freezing and opioid analgesia.

In the presence of Pavlovian conditional aversive stimuli rats engage in defensive freezing and exhibit a decreased sensitivity to painful stimulation. Administration of the opioid antagonist naltrexone (7 mg/ml/kg) prior to training in a context fear conditioning procedure using footshock caused an increase in freezing but did not affect suppression of formalin-induced recuperative behaviors relative to controls during a test session 24 hr later. The same dose of naltrexone given during the test session reversed conditional analgesia without altering the level of freezing. These results suggest that full expression of endogenous opioid analgesia during training is not necessary for conditional responding.

Animals↗
PubMed1989

Blockade by diazepam of conditioned fear-induced activation of rat mesoprefrontal dopamine neurons.

The effect of diazepam on activation of the mesoprefrontal dopamine (DA) system by an emotional stress model without direct physical stimuli was examined. Environmental stimuli previously paired with inescapable footshock (conditioned fear) elicited increases in levels of the DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the medial prefrontal cortex and of plasma corticosterone in rats. The increases in both levels were blocked by pretreatment with diazepam (5 mg/kg, IP); such blocking effects were reversed by Ro 15-1788 (15 mg/kg, IP), the benzodiazepine (BZD) receptor antagonist. These data suggest that diazepam can block activation of mesoprefrontal DA neurons as well as hypothalamo-pituitary-adrenocortical system elicited by the conditioned fear paradigm. This action appears to be a specific action of BZDs mediated through BZD receptors. We suggest that blocking effects of BZDs on the hyperactivity of the mesoprefrontal DA neurons may be one neural mechanism of their anxiolytic actions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Conditioned suppression and freezing as measures of aversive Pavlovian conditioning: effects of discrete amygdala lesions and overtraining.

Freezing and suppression are measures of conditioned fear that correlate in unlesioned animals. Both the basolateral (BLA) and central (CeN) nuclei of the amygdala are required for conditioned freezing, though there can be recovery with overtraining. The neuroanatomical substrates of conditioned suppression are less clear, with evidence both for a specific requirement of the CeN and for disruption by BLA lesions. The present study investigated the impact of selective excitotoxic lesions of the BLA and CeN upon the acquisition and expression of conditioned fear, measured by freezing and both on-baseline and off-baseline conditioned suppression in the same rats. BLA and CeN lesions both abolished all measures of conditioned fear after 9 trials of fear conditioning. However, when conditioning was extended to 33 trials, whereas rats with combined lesions of both the BLA and CeN continued to show no conditioned fear responses, there was a pattern of recovery observed after selective lesions. There was a partial recovery of freezing with both lesions, and full recovery of conditioned suppression, except for off-baseline suppression in CeN lesioned rats. These results indicate that with few conditioning trials, both the BLA and CeN are required in a serial manner for conditioned fear responses, but that overtraining can mitigate such impairments, likely involving parallel pathways in and through the amygdala.

Amygdala↗
PubMed2001

Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle.

Previous results indicate that intra-amygdala infusions of NMDA receptor antagonists block the extinction of conditioned fear. Mitogen-activated protein kinase (MAPK) can be activated by NMDA receptor stimulation and is involved in excitatory fear conditioning. Here, we evaluate the role of MAPK within the basolateral amygdala in the extinction of conditioned fear. Rats received 10 light-shock pairings. After 24 hr, fear was assessed by eliciting the acoustic startle reflex in the presence of the conditioned stimulus (CS) (CS-noise trials) and also in its absence (noise-alone trials). Rats subsequently received an intra-amygdala or intrahippocampal infusion of either 20% DMSO or the MAPK inhibitor PD98059 (500 ng/side) followed 10 min later by 30 presentations of the light CS without shock (extinction training). After 24 hr, they were again tested for fear-potentiated startle. PD98059 infusions into the basolateral amygdala but not the hippocampus significantly reduced extinction, which was otherwise evident in DMSO-infused rats. Control experiments indicated that the effect of intra-amygdala PD98059 could not be attributed to lasting damage to the amygdala or to state dependency. These results suggest that a MAPK-dependent signaling cascade within or very near the basolateral amygdala plays an important role in the extinction of conditioned fear.

Amygdala↗
PubMed2001

Sex differences in relation to conditioned fear-induced enhancement of morphine analgesia.

A number of studies have reported that both the immediate and proactive effects of exposure to a shock stressor are less pronounced in female than in male rats. A separate area of research has demonstrated that female rats are less sensitive to the analgesic effects of morphine than males. Experiments from our laboratory, as well as others, have found that exposure to a context associated with shock (i.e., conditioned fear context) at the time of morphine administration, enhances the analgesic effects of morphine. Since previous studies have exclusively employed male rats, the purpose of Experiment 1 was to determine if a sex difference exists to this context conditioned fear-induced enhancement of morphine-induced analgesia. The findings of Experiment 1 showed that females do not appear to exhibit conditioned fear-induced enhancement of morphine analgesia as compared to males. Experiment 2 demonstrated that females exhibited higher levels of conditioned fear-induced enhancement of morphine analgesia during diestrus I than estrous. Experiment 3 demonstrated that females exhibited lower levels of conditioned analgesia compared to males, while both groups exhibited similar freezing levels. The findings of the present experiments suggest that the sex difference observed in Experiment 1 may be due to differences in conditioned analgesia.

Analgesics, Opioid↗
PubMedDate not supplied

[Neurobiological hypothesis relating to connections between psychopathy and childhood maltreatment].

INTRODUCTION: This article aims to closely link maltreatment subjected in childhood with the psychopathy, which is characterised by 2 factors: factor one: callousness, lack of guilt, emotional shallowness; factor two: antisocial behaviour, violence and impulsivity. If the parental education system seems to have an effect on the development of "factor two", "factor one" is for the authors of unknown aetiology. I will try to theorize that harsh and chronic maltreatment could be responsible for this emotional impairment which characterizes psychopathic individuals. LITERATURE FINDINGS: There's a wealth of literature on the consequences of maltreatment on the brain's development in childhood, which are considered from a stress point of view, some individuals developing a syndrome called "post-traumatic stress disorder": PTSD (Perry, Shore, Van der Kolk, Teicher, Bremner, Carrion, De Bellis, Lanius, Nutt...). With prolonged chronic stress, the hypothalamic-pituitary-adrenal (HPA) axis is hyper-activated, with the resulting release in adrenocorticotropin and cortisol, which involves structural changes, cell atrophy and neuronal loss. According to the authors, there are 2 responses to harsh or chronic stress: dissociation (numbing) which involves the parasympathetic system, and hyperarousal which involves the sympathetic system. One of the worst neurobiological effects of repeated stress is amygdala kindling. Many laboratory studies on physiological alterations of amygdala in rats show that kindling interferes with the acquisition of fear conditioning. CONCLUSION: Now, fear conditioning is the model on which the abusive education system is based. If this cannot develop, the child lives in the present, reacting to the unconditioned stimulus (US) like blows (with autonomic reactions), but the emotional association between this and the conditioned stimulus (CS) -- like hostile glances or shouting -- could not be registered in the orbital frontal cortex and the conditioned stimulus would not provoke autonomic responses which enable the anticipation of a danger connected with an interdict. Thus, psychopathic tendencies can develop.

Adult↗
PubMed2002

Galanin peptide levels in hippocampus and cortex of galanin-overexpressing transgenic mice evaluated for cognitive performance.

Galanin-overexpressing transgenic mice (GAL-tg) generated on a dopamine beta-hydroxylase promoter were previously shown to express high levels of galanin mRNA in the locus coeruleus, and to perform poorly on challenging cognitive tasks. The present study employed radioimmunoassay to quantitate the level of galanin peptide overexpression in two brain regions relevant to learning and memory, the hippocampus and cerebral cortex. Approximately 4-fold higher levels of galanin were detected in the hippocampus of GAL-tg as compared to WT. Approximately 10-fold higher levels of galanin were detected in the frontal cortex of GAL-tg as compared to WT. A second cohort of GAL-tg and WT again showed high levels of galanin overexpression in GAL-tg as compared to WT in both brain regions. Correlation analyses were conducted between galanin peptide concentrations and behavioral scores on four learning and memory tasks: the Morris water maze, social transmission of food preference, standard delay fear conditioning, and trace fear conditioning. While some significant correlations were detected, neither hippocampal nor cortical galanin levels in the two cohorts of GAL-tg consistently correlated with performance across these diverse cognitive tasks. Several interpretations of these findings are discussed, including the possibility that a threshold level of galanin overexpression is sufficient to impair performance on learning and memory tasks in mice.

Animals↗