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PubMed2004

Amygdala and hippocampal activity during acquisition and extinction of human fear conditioning.

Previous functional magnetic resonance imaging (fMRI) studies have characterized brain systems involved in conditional response acquisition during Pavlovian fear conditioning. However, the functional neuroanatomy underlying the extinction of human conditional fear remains largely undetermined. The present study used fMRI to examine brain activity during acquisition and extinction of fear conditioning. During the acquisition phase, participants were either exposed to light (CS) presentations that signaled a brief electrical stimulation (paired group) or received light presentations that did not serve as a warning signal (control group). During the extinction phase, half of the paired group subjects continued to receive the same treatment, whereas the remainder received light alone. Control subjects also received light alone during the extinction phase. Changes in metabolic activity within the amygdala and hippocampus support the involvement of these regions in each of the procedural phases of fear conditioning. Hippocampal activity developed during acquisition of the fear response. Amygdala activity increased whenever experimental contingencies were altered, suggesting that this region is involved in processing changes in environmental relationships. The present data show learning-related amygdala and hippocampal activity during human Pavlovian fear conditioning and suggest that the amygdala is particularly important for forming new associations as relationships between stimuli change.

Adolescent↗
PubMed2005

A different recruitment of the lateral and basolateral amygdala promotes contextual or elemental conditioned association in Pavlovian fear conditioning.

Convergent data suggest dissociated roles for the lateral (LA) and basolateral (BLA) amygdaloid nuclei in fear conditioning, depending on whether a discrete conditioned stimulus (CS)-unconditional stimulus (US) or context-US association is considered. Here, we show that pretraining inactivation of the BLA selectively impaired conditioning to context. In contrast, inactivation of the LA disrupted conditioning to the discrete tone CS, but also either impaired or enhanced contextual conditioning, depending on whether the context was in the foreground or in the background. Hence, these findings refine the current model of the amygdala function in emotional learning by showing that the BLA and the LA not only differentially contribute to elemental and context-US association, but also promote, through their interaction, the most relevant of these two associations.

Acoustic Stimulation↗
PubMed1995

Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli.

The goal of this work was to test the involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning, using auditory and visual conditioned stimuli (CSs). The acoustic startle reflex in rats was used as the behavioral index of conditioning because startle is reliably enhanced in the presence of a conditioned stimulus (CS) previously paired with a footshock. Initially, differential conditioning procedures indicated reliable discrimination between a noise CS and a visual CS. Subsequently, the effects of amygdala lesions were evaluated when both modalities were paired with shocks in the same rats. Electrolytic or ibotenic acid lesions of the central nucleus of the amygdala blocked fear-potentiated startle to both auditory and visual CSs, consistent with the idea that the central nucleus serves as a response independent, final common relay for fear conditioning. Similarly, pre- or post-training electrolytic or NMDA-induced lesions of the basolateral complex of the amygdala, which damaged the lateral nucleus, and most of the basolateral nucleus, disrupted fear-potentiated startle to both CS modalities. This finding is consistent with the suggestion that, in fear conditioning, the basolateral complex of the amygdala serves as an obligatory relay of sensory information from subcortical and cortical sensory areas to the central nucleus of the amygdala.

Acoustic Stimulation↗
PubMed2000

Involvement of NMDA receptors within the amygdala in short- versus long-term memory for fear conditioning as assessed with fear-potentiated startle.

Pretraining intra-amygdala infusions of the NMDA receptor antagonist. D,L-AP5, block fear-potentiated startle in rats tested 24+ hr after training. This may reflect a failure of either acquisition or retention. To evaluate these alternatives, rats were tested for fear-potentiated startle during fear conditioning (30 light-shock pairings [0.6 mA shock]), as well as 1-30 min and 48 hr after fear conditioning. Amygdala lesions abolished fear-potentiated startle at all train-test intervals. Intra-amygdala AP5 infusions (25 nmol/side) abolished fear-potentiated startle during the long-term test and had partial effects at shorter train-test intervals. When the level of fear-potentiated startle during the short-term test was lowered to that of the 48-hr test (i.e., by training rats with a lower, 0.3 mA footshock), AP5 abolished fear-potentiated startle at each timepoint. Thus, amygdala NMDA receptors appear to participate in the initial acquisition of fear memories.

Amygdala↗
PubMed2003

Hippocampal place cells acquire location-specific responses to the conditioned stimulus during auditory fear conditioning.

We recorded neurons from the hippocampus of freely behaving rats during an auditory fear conditioning task. Rats received either paired or unpaired presentations of an auditory conditioned stimulus (CS) and an electric shock unconditioned stimulus (US). Hippocampal neurons (place and theta cells) acquired responses to the auditory CS in the paired but not in the unpaired group. After CS-US pairing, rhythmic firing of theta cells became synchronized to the onset of the CS. Conditioned responses of place cells were gated by their location-specific firing, so that after CS-US pairing, place cells responded to the CS only when the rat was within the cell's place field. These findings may help to elucidate how the hippocampus contributes to context-specific memory formation during associative learning.

Acoustic Stimulation↗
PubMed2004

Fear, conditioning, and aging: theoretical comment on LaBar et al. (2004).

Age-related impairments in associative learning have been found in studies using classical conditioning of motor responses. However, it is as yet unclear whether conditioning of fear responses is similarly affected by aging. K. S. La Bar et al. (2004) aimed to address this issue by studying age effects on fear conditioning applying a discrimination paradigm. Considering these results, this commentary discusses methodological issues in investigating fear conditioning as well as similarities and differences between associative learning of motor and autonomic responses with respect to neuronal substrates, susceptibility to aging, and the role of awareness of stimulus contingencies in mediating aging effects.

Aging↗
PubMed1995

Involvement of subcortical and cortical afferents to the lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli.

The goal of this work was to test the involvement, in fear conditioning, of afferents to the lateral nucleus of the amygdala originating from the auditory thalamus, auditory cortex, and perirhinal area. The acoustic startle reflex was used as the behavioral index of conditioning because it is reliably enhanced in the presence of a conditioned stimulus (CS) previously paired with a footshock. Auditory and visual CSs were used to assess the modality specificity of lesions to the above brain areas. Pre- or posttraining lesions of the entire auditory thalamus including the ventral, dorsal, and medial divisions of the medial geniculate body, the posterior intralaminar nucleus, and the suprageniculate nucleus, completely blocked fear-potentiated startle to the auditory CS, but had no effect on fear-potentiated startle to the visual CS. Posttraining lesions mostly restricted to the ventral and dorsal divisions of the medial geniculate body specifically disrupted fear-potentiated startle to the auditory CS. However, retraining in rats sustaining ventral and dorsal medial geniculate body lesions led to reliable fear-potentiated startle to the auditory CS. Posttraining lesions mostly restricted to the medial division of the medial geniculate body, posterior intralaminar, and suprageniculate nuclei did not disrupt fear-potentiated startle. These results indicate that the auditory thalamus is specifically involved, through either its direct or indirect amygdaloid afferents, in fear conditioning to auditory CSs. Pre- or posttraining lesions mostly restricted to the primary auditory cortex did not reliably attenuate fear-potentiated startle to the auditory or visual CSs. Extensive posttraining lesions of the perirhinal area (including secondary auditory cortices), but not its rostral aspect alone, blocked fear-potentiated startle to both CSs. However, reliable potentiated startle was observed to both CSs following similarly extensive pretraining lesions of the perirhinal area. Because post- but not pretraining lesions of the perirhinal area blocked fear-potentiated startle nonspecifically, at least with regard to auditory and visual CSs, the results are consistent with the involvement of the perirhinal area in general memory functions such as information storage or retrieval. Alternatively, the secondary auditory and/or perirhinal cortices might function as multimodal sensory relays to the amygdala.

Acoustic Stimulation↗
PubMed2003

Pretraining NMDA receptor blockade in the basolateral complex, but not the central nucleus, of the amygdala prevents savings of conditional fear.

The acquisition of conditional freezing is abolished by N-methyl-D-aspartate (NMDA) receptor antagonism in the basolateral complex of the amygdala (BLA) during fear conditioning, suggesting that memory formation is prevented. The present study examined whether there is residual memory, or "savings," for fear conditioning in rats trained under amygdaloid NMDA receptor blockade. Rats infused with D,L-2-amino-5-phosphonovalerate (APV) into the BLA or central nucleus of the amygdala (CEA) during fear conditioning did not acquire either auditory or contextual fear conditioning. However, savings of conditional fear was exhibited by rats infused with APV into the CEA but not the BLA. These results suggest that both the BLA and CEA play a critical role in the acquisition of conditional fear but that the BLA is able to process and retain some aspects of aversive memories in the absence of the CEA.

Amygdala↗
PubMedDate not supplied

Nicotine produces a within-subject enhancement of contextual fear conditioning in C57BL/6 mice independent of sex.

Nicotine enhances learning including contextual fear conditioning. The present study extends previous work on nicotine and conditioned fear to examine the nature of nicotine's enhancement of contextual fear conditioning and sex differences in contextual fear conditioning in C57BL/6 mice using a within-subjects design. Mice were trained by pairing of an auditory stimulus of 80 dB, 6 cps train of broad-band clicks conditioned stimulus (CS) with a 2 sec., 0.35 mA shock unconditioned stimulus (US). Twenty-four hours later mice were tested for freezing in the original context, and one hour later mice were retested in the same context. A 0.5 mg/kg dose of nicotine was given either for three conditions: (1) before training, testing, and retesting; (2) before training and retesting; and (3) before retesting only. The use of a within-subjects design allowed for testing if nicotine would produce state-dependent deficits in contextual fear conditioning. Nicotine did enhance contextual fear conditioning in the groups that received nicotine for both training and testing. Nicotine, however, did not alter freezing when given on training but not testing or testing but not training. No sex differences, however, existed for conditioning or for nicotine's effects on conditioning. These results suggest that nicotine enhanced acquisition and retrieval processes but did not produce state-dependent deficits when administered just for training or just for testing.

Acoustic Stimulation↗
PubMed2003

Effect of dorsal periaqueductal gray lesion on cardiovascular and behavioural responses to contextual conditioned fear in rats.

Contextual conditioned fear in the rat is characterized by a freezing immobility associated with a marked increase in blood pressure, a slow increase in heart rate, and ultrasonic vocalizations. A previous Fos study also revealed a marked activation of the ventrolateral part of the periaqueductal gray (VLPAG) and a much smaller activation of its dorsal part (DPAG). Recent chemical blockade experiments indicate that the main role of the VLPAG in the response is to impose the immobility necessary for the expression of the freezing component. We now test the role of the DPAG to see if its small activation (as revealed by Fos) is of any functional significance in the contextual fear response. Large N-methyl-D-aspartate (NMDA) excitotoxic lesions that destroyed most of the DPAG were made in 10 rats. Another group of 10 rats had sham lesions with saline. The animals were then implanted with blood pressure telemetric probes, fear conditioned, and finally tested. There was no significant difference in the amount of freezing and in the blood pressure response between the two groups. However, there was a complete abolition of ultrasonic vocalizations and a significantly greater increase in heart rate in the DPAG-lesioned group. The effect on vocalization and heart rate may be explained by lesion of adjacent structures: the lateral PAG and the superior colliculus (baroreflex alteration), respectively. Thus, most of DPAG appears to play little role in the expression of the contextual fear response.

Animals↗
PubMed2004

Have no fear, erythropoietin is here: erythropoietin protects fear conditioning performances after functional inactivation of the amygdala.

This study investigated the capacity of erythropoietin (EPO) to protect fear conditioning performances against functional inactivation of the amygdala. We infused an excitotoxic dose of glutamate in the lateral nucleus of the amygdala (LA) of adult rats in order to block the output projections to brainstem areas controlling the expression of conditioned fear responses. Subsequently, animals with excitotoxic lesions in the LA displayed altered short and long-term fear conditioned responses, but the integrity of their general emotional reactivity was preserved, as indicated by their open-field behavior. EPO infused immediately after glutamate succeeded to protect the conditioned fear performances of rats. This effect was reliably represented on both short, and long-term memory tests of conditioned fear. This and other studies have supported the potent neuroprotective activity of EPO, discriminable both morphologically, and behaviorally.

Amygdala↗
PubMed2003

Repeated withdrawal from ethanol impairs acquisition but not expression of conditioned fear.

Repeated withdrawal from ethanol impairs acquisition of conditioned fear [Stephens, D.N., Brown, G., Duka, T. & Ripley, T.L. (2001) Eur. J. Neurosci., 14, 2023-2031]. This study further examined the effect of repeated withdrawal from ethanol on the expression and acquisition of fear conditioning. Following training, presentation of a cue associated with footshock (CS+) resulted in a suppression of operant responding for food reinforcement. In different groups, shock thresholds were manipulated to give weak or severe behavioural suppression. Rats were subsequently chronically treated with ethanol-containing liquid diet either continuously (single withdrawal) or with three withdrawal periods (repeated withdrawal). Ethanol treatment and withdrawal had no effect on conditioned suppression of responding tested 2 weeks after the final withdrawal, at either shock intensity. Nevertheless, extinction of conditioned fear was impaired in the repeated withdrawal group exposed to the higher shock intensity. In the high intensity group, the stimulus-shock association was then reversed, so that the previously neutral conditioned stimulus (CS-) became the CS+. Acquisition of suppression to the new CS+ was significantly less in the animals previously given repeated experience of withdrawal, confirming our previous finding. Thus, repeated withdrawal from ethanol lead to disruption in the acquisition of fear conditioning but had no effect on retrieval of an association formed prior to the ethanol-withdrawal experiences.

Animals↗
PubMed2000

A role for amygdaloid PKA and PKC in the acquisition of long-term conditional fear memories in rats.

Although there is great interest in the cellular mechanisms underlying Pavlovian conditioning, few studies have directly examined the contribution of intracellular signaling pathways in the amygdala to the acquisition and expression of conditional fear memories. In the present study, we examined this issue by infusing 1-(5'-isoquinolinesulfonyl)-2-methylpiperazine (H7), a potent inhibitor of both protein kinase C (PKC) and cAMP-dependent protein kinase (PKA), directly into the amygdala prior to fear conditioning or retention testing. We found that infusion of H7 prior to training attenuated long-term conditional fear in a dose-dependent manner (Experiment 1), but short-term fear memories were spared. The contribution of protein kinases to conditional fear was region-specific within the amygdala: infusion of H7 into the basolateral amygdala (BLA) but not the central nucleus of the amygdala (CEA) resulted in attenuated freezing (Experiment 2). Moreover, the deficits in fear conditioning produced by PKA/PKC inhibition were not modality-specific, insofar as intra-BLA H7 reduced both contextual and auditory fear. The effects of H7 on conditional freezing were not attributable to either state-dependency or performance deficits (Experiment 3). Together, these experiments suggest that amygdaloid PKA and PKC play an important role in the acquisition of fear memories.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

Impaired fear conditioning in Alzheimer's disease.

Classical conditioning of the fear response is a basic form of nondeclarative (nonconscious) memory that mediates both normal and pathological responses to aversive stimuli. Because fear conditioning critically depends on the amygdala, a medial temporal lobe structure that frequently undergoes significant pathological changes early in the course of Alzheimer's disease (AD), we hypothesized that fear conditioning would be impaired in patients with mild to moderate AD. We examined simple classical fear conditioning in a group of 10 patients with probable AD and 14 demographically matched, neurologically intact elderly controls. During conditioning, one stimulus (e.g. a green rectangle, the conditioned stimulus (CS+)), was paired with an aversive stimulus (a loud noise, the unconditioned stimulus (US)) using a partial reinforcement conditioning schedule. The opponent color (e.g. red rectangle), the CS-, was never paired with the US. The elderly controls acquired robust fear responses as demonstrated by their differential skin-conductance responses to the CS+ and CS-. In contrast, the AD group showed a marked impairment in conditioning, failing to exhibit significant conditioned fear responses. This failure to acquire conditioned responses could not be attributed to diminished responding by patients, relative to controls, to the aversive US. The results indicate that fear conditioning, an amygdala-dependent form of memory, is impaired in AD. These findings complement previous reports of impairments in declarative emotional memory in AD by demonstrating that a basic form of nondeclarative emotional memory is also impaired in AD.

Aged↗
PubMed1998

Role of adrenoceptors in vasopressin, oxytocin and prolactin responses to conditioned fear stimuli in the rat.

Conditioned fear or novel environmental stimuli suppress vasopressin (VP) and augment oxytocin (OT) and prolactin (PRL) release in rats. We examined the effects of intracerebroventricular (i.c.v.) injections of adrenoceptor antagonists on these neuroendocrine responses to conditioned fear or novel environmental stimuli in male rats. A beta1 antagonist, metoprolol, blocked the VP but not the OT or PRL response to conditioned fear stimuli, but did not abolish neuroendocrine responses to novel environmental stimuli. A beta2 antagonist, ICI118551, impaired the PRL but not the VP or OT response to fear or novel environmental stimuli. In rats injected with a alpha1 adrenoceptor antagonist, benoxathian, conditioned fear stimuli did not significantly induce the VP, OT or PRL responses. The effects of benoxathian were not due to a general reduction of arousal, since benoxathian did not prevent the VP, OT or PRL response to novel environmental stimuli. These data suggest that beta1 adrenoceptors play a selective role in the VP response to conditioned fear stimuli, as do beta2 adrenoceptors in the prolactin response to conditioned fear and novel environmental stimuli. We conclude that alpha1 adrenoceptors play a facilitative role in VP, OT, PRL responses to conditioned fear stimuli.

Adrenergic Antagonists↗
PubMed2005

Effects of Pavlovian fear conditioning on septohippocampal metabolism in rats.

The effects of classical fear conditioning in different regions of the limbic system were analysed using cytochrome oxidase (CO) histochemistry. Wistar rats were submitted to different conditions. Rats in the group Paired received tone-shock pairing, to elicit conditioned suppression of lever pressing (i.e., tone will evoke conditioned fear responses). The group Unpaired underwent random presentations of these stimuli and developed no conditioned fear. Untrained animals were also included as a control group. A significant decrease in CO activity was found in the medial septal area and the dorsal hippocampus (CA3 subfield and dentate gyrus) in the group Paired as compared with the group Unpaired. Furthermore there was greater metabolic activity in the control group as compared with the other two groups. No differences in CO labelling of the basolateral amygdala were detected among all groups. These findings suggest that the septohippocampal system plays an important role in controlling conditioned fear behaviour.

Animals↗
PubMed2005

Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review.

Pavlovian or classical fear conditioning is recognized as a model system to investigate the neurobiological mechanisms of learning and memory in the mammalian brain and to understand the root of fear-related disorders in humans. In recent decades, important progress has been made in delineating the essential neural circuitry and cellular-molecular mechanisms of fear conditioning. Converging lines of evidence indicate that the amygdala is necessarily involved in the acquisition, storage and expression of conditioned fear memory, and long-term potentiation (LTP) in the lateral nucleus of the amygdala is often proposed as the underlying synaptic mechanism of associative fear memory. Recent studies further implicate the prefrontal cortex-amygdala interaction in the extinction (or inhibition) of conditioned fear. Despite these advances, there are unresolved issues and findings that challenge the validity and sufficiency of the current amygdalar LTP hypothesis of fear conditioning. The purpose of this review is to critically evaluate the strengths and weaknesses of evidence indicating that fear conditioning depend crucially upon the amygdalar circuit and plasticity.

Amygdala↗