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Results for “fear conditioning”

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PubMed2002

Increased conditioned fear response and altered balance of dopamine in the shell and core of the nucleus accumbens during amphetamine withdrawal.

It has been suggested that neuroadaptations within the nucleus accumbens (NAC) dopaminergic (DA) projection contribute to the negative affect associated with psychostimulant withdrawal. The present study assessed the effects of amphetamine (AMPH) withdrawal on behavioral and NAC DA responses to conditioned fear stress. Animals injected with escalating-dose AMPH (1-5mg/kg, three injections/day, 6 days) or saline (SAL) acquired a tone-shock association on withdrawal day 3 and were tested for extinction of conditioned freezing to the tone on withdrawal day 4. Extracellular levels of NAC shell and core DA were monitored using in vivo microdialysis on both days. AMPH-withdrawn animals exhibited more conditioned freezing than SAL animals during both acquisition and extinction. During acquisition, DA increased more in the shell than the core of the NAC in both AMPH and SAL groups. During extinction to the tone, shell DA increased in SAL- but not AMPH-treated animals, whereas core DA activity was greater in AMPH than SAL animals. These data demonstrate that AMPH withdrawal alters the balance between shell and core DA transmission while increasing the behavioral expression of conditioned fear. Such drug-induced neuroadaptations in the NAC stress response may be involved in the exacerbation of negative emotions associated with drug withdrawal and stimulant-induced psychosis.

Amphetamine↗
PubMed2002

Rosmarinic acid and caffeic acid reduce the defensive freezing behavior of mice exposed to conditioned fear stress.

RATIONALE: We previously showed that rosmarinic acid from the leaves of Perilla frutescens Britton var. acuta Kudo (Perillae Herba) and its major metabolite caffeic acid have antidepressive-like activity in the forced swimming test. OBJECTIVE: The present study was designed to examine whether rosmarinic acid and caffeic acid might also be effective in other types of stress model. METHODS: The conditioned fear stress paradigm was used as a stress model for assessing the effects of rosmarinic acid and caffeic acid. RESULTS: Rosmarinic acid (0.25-4 mg/kg, IP) induced a dose-dependent, U-shaped reduction in the duration of the defensive freezing behavior of mice exposed to conditioned fear stress. Caffeic acid (1-8 mg/kg, IP) also dose-dependently reduced this freezing behavior. However, neither substance, at doses that produced a significant reduction in the freezing behavior, affected spontaneous motor activity. CONCLUSIONS: These results confirm that rosmarinic acid and caffeic acid may inhibit the emotional abnormality produced by stress.

Analysis of Variance↗
PubMed2004

A role for prefrontal cortex in memory storage for trace fear conditioning.

The prefrontal cortex has been shown to participate in the association of events separated by time. However, it is not known whether the prefrontal cortex stores the memory for these relationships. Trace conditioning is a form of classical conditioning in which a time gap separates the conditioned stimulus (CS) from the unconditioned stimulus (US), the association of which has been shown to depend on prefrontal activity. Here we demonstrate that inhibition of extracellular signal-regulated kinase (Erk) cascade (a biochemical pathway involved in long-term memory storage) in the rat medial prefrontal cortex did not interfere with memory encoding for trace fear conditioning but impaired memory retention. In addition, animals displayed impaired memory for the irrelevancy of the training context. Hippocampal Erk phosphorylation was found to have a later time course than prefrontal Erk phosphorylation after trace fear conditioning, indicating a direct role for the prefrontal cortex in associative memory storage for temporally separated events as well as in memory storage of relevancy.

Animals↗
PubMedDate not supplied

Context pre-exposure obscures amygdala modulation of contextual-fear conditioning.

We report that post-training inactivation of basolateral amygdala region (BLA) with muscimol impaired memory for contextual-fear conditioning (as measured by freezing) and intra-BLA norepinephrine enhanced this memory. However, pre-exposure to the context eliminated both of these effects. These findings provide a likely explanation of why an earler study failed to observe that the BLA modulates contextual fear conditioning-they pre-exposed their rats to the context. These results also suggest that the amygdala modulates the storage of the context fear memory and may do so by influencing the storage of the representation of the context in which the shock occurred.

Amygdala↗
PubMed2005

Low dose quetiapine reverses deficits in contextual and cued fear conditioning in rats with excitotoxin-induced hippocampal neuropathy.

Previous studies have demonstrated that adult rats with excitotoxic lesions of the hippocampus display deficits in memory-related behaviors similar to the memory deficits associated with schizophrenia. In this study, we assessed the sub-chronic effects of quetiapine, risperidone and haloperidol on performance deficits after intracerebroventricular administration of the excitotoxin, kainic acid, using paradigms for contextual and cued fear conditioning and spatial reversal learning in rats. The effects of three doses of quetiapine (5, 10 and 20 mg/kg) and single doses of risperidone (0.5 mg/kg) and haloperidol (0.15 mg/kg) were compared. Quetiapine administration at the lowest dose (5 mg/kg) reversed deficits in contextual and cued fear conditioning, but not deficits in spatial reversal learning, in kainic acid-treated animals. However, the two higher doses of quetiapine, and the single doses of risperidone and haloperidol, did not reverse any of the kainic acid-induced behavioral deficits. These results may be relevant to the effects of quetiapine and other antipsychotic drugs on memory deficits in patients with schizophrenia.

Animals↗
PubMed1999

Lesions of the medial or lateral perforant path have different effects on hippocampal contributions to place learning and on fear conditioning to context.

The axons of the neurons in the medial and lateral components of the entorhinal cortex (MEC and LEC) form the medial and lateral perforant paths (MPP and LPP) which represent the major source of cortical input to the hippocampus. Anatomical, physiological, and pharmacological studies have shown that MPP and LPP are distinct. Unfortunately, assessment of the functional significance of damage to either of these pathways has not used tasks known to be sensitive to hippocampal function in the rodent. In this study, we performed dissociated lesions of MPP and LPP using a combined physiological and anatomical method. Rats with lesions of either the MPP or the LPP were tested on place learning in the water task and on a discriminative fear conditioning to context task. The results indicated that the MPP, but not LPP, lesions resulted in impaired place learning. The context discrimination data revealed an amygdala-like, reduced fear effect of MPP lesions and an enhanced discriminative fear conditioning to context effect of LPP lesions. Consistent with a two-stage model of spatial learning proposed by Buzsaki (Buzsaki G. Two-stage model of memory trace formation: a role for 'noisy' brain states. Neuroscience 1989;31(3):551-570), the impairment in the water task can be interpreted as reflecting the higher efficiency of the MPP synapses in activating hippocampal neurons. The context discrimination results can be explained by either a dissociation of sensory information that reaches the MEC and LEC, or alternatively, by a dissociation between the limbic nature of the MEC and the sensory nature of the LEC.

Animals↗
PubMed2006

Extinction in human fear conditioning.

Although most extinction research is conducted in animal laboratories, the study of extinction learning in human fear conditioning has gained increasing attention over the last decade. The most important findings from human fear extinction are reviewed in this article. Specifically, we review experimental investigations of the impact of conditioned inhibitors, conditioned exciters, context renewal, and reinstatement on fear extinction in human samples. We discuss data from laboratory studies of the extinction of aversively conditioned stimuli, as well as results from experimental clinical work with fearful or anxious individuals. We present directions for future research, in particular the need for further investigation of differences between animal and human conditioning outcomes, and research examining the role of both automatic and higher-order cognitive processes in human conditioning and extinction.

Animals↗
PubMed1993

[Effects of conditioned fear stress on monoaminergic systems in the rat brain].

The effects of conditioned fear stress (CFS), an animal model of anxiety, on brain dopamine (DA) and serotonin (5-HT) metabolism and behavior were investigated in rats. CFS (exposure to an environment paired previously with footshock) after single footshock stress increased plasma corticosterone levels and defecation, and induced freezing behavior. It also increased 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the medial prefrontal cortex (mPFC), paraventricular nucleus of the hypothalamus (PVH) and lateral hypothalamus, increased homovanillic acid (HVA) levels in the mPFC and amygdala, and increased 5-hydroxyindoleacetic acid (5-HIAA) level in the mPFC. Rats exposed to the stress for 10 days displayed enhanced freezing induced by CFS compared to rats given only one footshock session, according to the augmentation of fear. CFS after repeated footshock increased DOPAC levels in all seven brain regions and HVA levels in the mPFC, nucleus accumbens, amygdala and hippocampus. It also increased 5-HIAA levels in the mPFC and PVH. Thus, it was deduced that CFS after repeated footshock activated DA and 5-HT metabolism not only in the mPFC but also in other various brain regions, whereas increased metabolism of both DA and 5-HT was marked in the mPFC after CFS following a single footshock. In behavioral pharmacological experiments, the effects of various serotonergic agents and diazepam on CFS-induced freezing behavior were examined. The benzodiazepine diazepam (1mg/kg) and the selective 5-HT1A agonist ipsapirone (0.5-10mg/kg) significantly reduced freezing. The augmentation of 5-HT activity by the 5-HT precursor (L-5-HTP) and the selective 5-HT reuptake inhibitor (citalopram) also attenuated freezing. The 5-HT synthesis inhibitor PCPA failed to change freezing. In conclusion, these results suggest that the anxiolytic effect of ipsapirone results from the activation of postsynaptic 5-HT1A receptors and the facilitation of 5-HT neurotransmission decreases anxiety. This model may be useful for detecting the anxiolytic potential for drugs and examining the relationship of 5-HT to anxiety.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Intrahippocampal scopolamine impairs both acquisition and consolidation of contextual fear conditioning.

Lesions of the dorsal hippocampus have been shown to disrupt both the acquisition and the consolidation of memories associated with contextual fear (fear of the place of conditioning), but do not affect fear conditioning to discrete cues (e.g., a tone). Blockade of central muscarinic cholinergic receptor activation results in selective acquisition deficits of contextual fear conditioning, but reportedly has little effect on consolidation. Here we show for the first time that direct infusion of the muscarinic cholinergic receptor antagonist, scopolamine, into the dorsal hippocampus produces a dose-dependent deficit in both acquisition and consolidation of contextual fear conditioning, while having no impact on simple tone conditioning.

Animals↗
PubMed1994

Dissociated paradoxical sleep deprivation effects on inhibitory avoidance and conditioned fear.

Rats were submitted to paradoxical sleep deprivation (PSD) for 24, 72, or 96 h and were trained on a double aversively motivated task, encompassing a step-through inhibitory avoidance and a classical conditioning of fear to a brief tone serving as conditional stimulus. Retention test of the inhibitory avoidance was performed at the same apparatus of training (without tone presentation). Retention of conditioned fear was assessed in an open field apparatus, where the freezing reaction to the tone was measured. PSD for 24 and 72 h preceding the training session had no effect on either task. However, PSD during the 96 h preceding the training session impaired acquisition of inhibitory avoidance, but had no effect on classically conditioned fear. It is concluded that PSD had differential effects on the two tasks, both aversively motivated and trained at the same time and conditions.

Acoustic Stimulation↗
PubMed2002

Cerebellar role in fear-conditioning consolidation.

Some cerebellar structures are known to be involved in the memorization of several conditioned responses. The role of the interpositus nucleus (IN) and the vermis (VE) in fear-conditioning consolidation was investigated by means of a combined behavioral and neurophysiological technique. The IN and VE were subjected to fully reversible tetrodotoxin (TTX) inactivation during consolidation in adult male Wistar rats that underwent acoustic conditioned stimulus (CS) and context fear training. TTX was injected in different groups of rats at increasing intervals after the acquisition session. Memory was assessed as conditioned freezing duration measured during retention testing, always performed 72 and 96 h after the stereotaxic TTX administration. This schedule ensures that there is no interference with normal cerebellar function during either the acquisition or the retrieval phase so that any amnesic effect may be due only to consolidation disruption. Our results show that IN functional integrity is necessary for acoustic CS fear response memory formation up to the 96-h after-acquisition delay. VE functional integrity was shown to be necessary for memory formation of both context (up to the 96-h after-acquisition delay) and acoustic CS (up to the 192-h after-acquisition delay) fear responses. The present findings help to elucidate the role of the cerebellum in memory consolidation and better define the neural circuits involved in fear memories.

Acoustic Stimulation↗
PubMed2006

Spatiotemporal asymmetry of associative synaptic plasticity in fear conditioning pathways.

Input-specific long-term potentiation (LTP) in afferent inputs to the amygdala serves an essential function in the acquisition of fear memory. Factors underlying input specificity of synaptic modifications implicated in information transfer in fear conditioning pathways remain unclear. Here we show that the strength of naive synapses in two auditory inputs converging on a single neuron in the lateral nucleus of the amygdala (LA) is only modified when a postsynaptic action potential closely follows a synaptic response. The stronger inhibitory drive in thalamic pathway, as compared with cortical input, hampers the induction of LTP at thalamo-amygdala synapses, contributing to the spatial specificity of LTP in convergent inputs. These results indicate that spike timing-dependent synaptic plasticity in afferent projections to the LA is both temporarily and spatially asymmetric, thus providing a mechanism for the conditioned stimulus discrimination during fear behavior.

Action Potentials↗
PubMed2007

Atomoxetine reverses nicotine withdrawal-associated deficits in contextual fear conditioning.

Recent evidence suggests that the cognitive symptoms of nicotine withdrawal and the cognitive symptoms of attention deficit hyperactivity disorder (ADHD) may share neural correlates. Thus, therapeutics that ameliorate ADHD symptoms may also ameliorate nicotine-withdrawal symptoms. The present research tested this hypothesis in an animal model of nicotine withdrawal-associated cognitive deficits using atomoxetine, a norepinephrine reuptake inhibitor that is approved by the FDA to treat the symptoms of ADHD. C57BL/6 mice were prepared with osmotic minipumps that administered 6.3 mg/kg/day of nicotine or saline, and the minipumps were removed after 12 days of continuous treatment. Twenty-four hours later, mice were trained in delay fear conditioning using two paired presentations of an auditory conditioned stimulus (CS) with a footshock unconditioned stimulus. Testing for freezing in response to the training context and for freezing in response to the CS occurred the next day. Nicotine-withdrawn mice and their saline-treated counterparts received either saline or atomoxetine before training and the context test. Consistent with previous research, the results indicate that mice withdrawn from chronic nicotine demonstrated lower levels of contextual fear conditioning than mice that were not withdrawn from chronic nicotine. Atomoxetine dose-dependently reversed the deficit, suggesting that nicotine withdrawal may be associated with changes in noradrenergic function, acetylcholinergic function, and/or with changes in cell signaling cascades that are activated by both nicotine and norepinephrine. These data suggest that atomoxetine may be efficacious for treating nicotine withdrawal-associated cognitive deficits that promote relapse in abstinent smokers.

Adrenergic Uptake Inhibitors↗
PubMed2001

Treatments that weaken Pavlovian conditioned fear and thwart its renewal in rats: implications for treating human phobias.

In experiments using a total of 144 albino rat subjects, the authors assessed the ability of fear-weakening treatments to prevent fear renewal (relapse). Conditioned suppression of operant behavior served as the measure of fear in an A-B-A (acquisition-treatment-test) renewal paradigm. In Experiment 1, 100 nonreinforced exposures to a feared cue during treatment (extinction) did not reduce fear renewal relative to 20 exposures. In Experiment 2, explicitly unpaired (EU) treatments thwarted both renewal and reacquisition. In Experiment 3, conditioned inhibition (CI) and differential conditioning (DC) treatments weakened renewal and resisted both reacquisition and a form of reinstatement. In Experiment 4, EU, DC, and CI treatments all thwarted renewal. Evidence suggested that the ability of the treatments to do so reflected the combined effects of transfer of extinction across treatment and test contexts and habituation to the unconditioned stimulus.

Animals↗
PubMed2005

Trace fear conditioning is enhanced in mice lacking the delta subunit of the GABAA receptor.

The delta subunit of the GABA(A) receptor (GABA(A)R) is highly expressed in the dentate gyrus of the hippocampus. Genetic deletion of this subunit reduces synaptic and extrasynaptic inhibition and decreases sensitivity to neurosteroids. This paper examines the effect of these changes on hippocampus-dependent trace fear conditioning. Compared to controls, delta knockout mice exhibited enhanced acquisition of tone and context fear. Hippocampus-independent delay conditioning was normal in these animals. These results suggest that reduced inhibition in the dentate gyrus facilitates the acquisition of trace fear conditioning. However, the enhancement in trace conditioning was only observed in female knockout mice. The sex-specificity of this effect may be a result of neuroactive steroids. These compounds vary during the estrus cycle, can increase GABAergic inhibition, and have been shown to impair hippocampus-dependent learning. We propose that activation of GABA(A)Rs by neuroactive steroids inhibits learning processes in the hippocampus. Knockouts are immune to this effect because of the reduced neurosteroid sensitivity that accompanies deletion of the delta subunit. Relationships between neurosteroids, hippocampal excitability, and memory are discussed.

Acoustic Stimulation↗
PubMed2004

Central NPY receptor-mediated alteration of heart rate dynamics in mice during expression of fear conditioned to an auditory cue.

Neuropeptide Y (NPY) is involved in the regulation of emotionality including fear and anxiety, which modulate autonomic control of cardiovascular function. We therefore investigated the central effects of porcine NPY, selective Y1, Y2 and Y5 receptor agonists and a Y1 receptor antagonist on heart rate (HR) and HR variability in freely moving mice using auditory fear conditioning. Intracerebroventricular (i.c.v.) injections were applied 15 min before the tone-dependent memory test. NPY dose-dependently induced bradycardia associated with decreased HR variability, and blunted the stress-induced tachycardic response. The selective Y1 receptor antagonist BIBO 3304 blocked the NPY- and Y1-receptor agonist-induced suppression of conditioned tachycardia without affecting basal HR. The tachycardia elicited by both conditioned and unconditioned stressor was effectively attenuated by the Y1 receptor agonist. These results suggest a specific contribution of Y1, but not Y2 and Y5 receptors, to modulation of emotional responses most likely unrelated to impairment or modulation of memory. The NPY-induced bradycardia is attributed to not yet characterized NPY receptor subtypes other than Y1, Y2 and Y5, or a complex receptor interaction. In conclusion, NPY mediates central inhibition of sympathetic outflow, potentially coupled with attenuation of parasympathetic tone, i.e., mechanisms that may be associated with the reported anxiolytic action.

Animals↗
PubMed2006

Substantia nigra role in fear conditioning consolidation.

The substantia nigra (SN) is known to be involved in the memorization of several conditioned responses. To investigate the role of the SN in fear conditioning consolidation this neural site was subjected to fully reversible tetrodotoxin (TTX) inactivation during consolidation in adult male Wistar rats which had undergone fear training to acoustic CS and context. TTX was stereotaxically administered to different groups of rats at increasing intervals after the acquisition session. Memory was assessed as conditioned freezing duration measured during retention testing, always performed 72 and 96 h after TTX administration. In this way there was no interference with normal SN function during either acquisition or retrieval phases, so that any amnesic effect could be due only to consolidation disruption. The results show that SN functional integrity is necessary for contextual fear response consolidation up to the 24-h after-acquisition delay. On the contrary SN functional integrity was shown not to be necessary for the consolidation of acoustic CS fear responses. The present findings help to elucidate the role of the SN in memory consolidation and better define the neural circuits involved in fear memories.

Analysis of Variance↗
PubMed2001

Acute withdrawal from repeated cocaine treatment enhances latent inhibition of a conditioned fear response.

Psychostimulant-induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non-preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine-sensitized animals exhibited markedly enhanced LI compared to saline-treated animals, due to the fact that NPE-cocaine animals spent more time freezing during the tone CS than NPE-saline animals, whereas PE-cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine-withdrawn NPE animals, the absence of this effect in cocaine-withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.

Acoustic Stimulation↗