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PubMedDate not supplied

Generalization of extinguished skin conductance responding in human fear conditioning.

In a human fear conditioning paradigm using the skin conductance response (SCR), participants were assigned to two groups. Following identical acquisition, group ABA (n = 16) was extinguished to a generalization stimulus (GS), whereas group AAB (n = 20) was extinguished to the conditioned stimulus (CS). At test, presenting the CS in group ABA yielded a strongly recovered SCR. Presenting the GS in group AAB, on the other hand, did not disrupt the effects of extinction. We conclude that extinguishing the CS (group AAB) is an efficient strategy to overcome the stimulus specificity of extinction observed otherwise (group ABA). Clinical implications are discussed.

Association Learning↗
PubMedDate not supplied

Adrenergic transmission facilitates extinction of conditional fear in mice.

Extinction of classically conditioned fear, like its acquisition, is active learning, but little is known about its molecular mechanisms. We recently reported that temporal massing of conditional stimulus (CS) presentations improves extinction memory acquisition, and suggested that temporal spacing was less effective because individual CS exposures trigger two opposing processes: (1) fear extinction, which is favored by CS massing, and (2) fear incubation (increase), which is favored by spacing. We here report the effects of manipulating the adrenergic system during massed or spaced CS presentations in fear-conditioned mice. We administered yohimbine (5 mg/kg), an alpha(2)-receptor antagonist, or propranolol (10 mg/kg), a beta-receptor antagonist, systemically prior to CS presentation sessions and recorded both short- and long-term changes in conditional freezing. Yohimbine treatment facilitated extinction of both cue and context fear with massed protocols. When given before spaced CS presentations, propranolol led to a persistent incubation of cue fear, whereas yohimbine led to persistent extinction, compared with vehicle-treated animals, which showed no change in fear. These results suggest that norepinephrine positively modulates the formation of fear extinction memories in mice. They also provide clear evidence that spaced CS presentations trigger both fear-reducing (extinction) and fear-increasing (incubation) mechanisms.

Adrenergic Agonists↗
PubMed2006

The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice.

We studied the effects of cannabinoids on contextual conditioned fear responses. CB1 knockout and wild-type (CD1) mice were exposed to a brief session of electric shocks, and their behavior was studied in the same context 24 h later. In wild-type mice, shock exposure increased freezing and resting, and decreased locomotion and exploration. The genetic disruption of the CB1 receptor abolished the conditioned fear response. The CB1 antagonist AM-251 reduced the peak of the conditioned fear response when applied 30 min before behavioral testing (i.e. 24 h after shocks) in CD1 (wild-type) mice. The cannabinoid agonist WIN-55,212-2 markedly increased the conditioned fear response in CD1 mice, the effect of which was potently antagonized by AM-251. Thus, cannabinoid receptor activation appears to strongly promote the expression of contextual conditioned fear. In earlier experiments, cannabinoids did not interfere with the expression of cue-induced conditioned fear but strongly promoted its extinction. Considering the primordial role of the amygdala in simple associative learning (e.g. in cue-induced fear) and the role of the hippocampus in learning more complex stimulus relationships (e.g. in contextual fear), the present and earlier findings are not necessarily contradictory, but suggest that cannabinoid signaling plays different roles in the two structures. Data are interpreted in terms of the potential involvement of cannabinoids in trauma-induced behavioral changes.

Amygdala↗
PubMed1996

Hippocampal lesions impair contextual fear conditioning in two strains of mice.

Two different strains of mice, C57BL/6J and BALB/c, with hippocampal, cortical, or sham lesions, underwent contextual fear conditioning. In both strains, contextual fear, as measured by the freezing response, was significantly impaired in hippocampus-lesioned animals compared with sham control animals. Fear conditioning was not affected in the cortical-lesioned group. Moreover, there was a strain difference in fear conditioning: The C57BL/6J mice exhibited freezing more frequently than the BALB/c mice. Consistent with previous hippocampal lesion studies in rats, these results indicate that contextual fear conditioning in mice also requires the intact hippocampus. This study provides a basis for evaluating hippocampal synaptic mechanisms in relation to contextual fear conditioning in widely available gene knockout or transgenic mice.

Animals↗
PubMed2001

Effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in rats: dissociation of biochemical and behavioral effects.

BACKGROUND: We have examined the effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in the rat. METHODS: Rats were pretreated daily with saline or nicotine for 20 days then challenged with nicotine or saline on day 21. Animals were trained in a classical conditioned fear paradigm. Dopamine utilization in the medial prefrontal cortex and nucleus accumbens shell and conditioned fear stress-induced immobility responses were assessed. RESULTS: Saline pretreated animals rapidly acquired the conditioned fear stress response as assessed by preferential activation of mesoprefrontal dopamine metabolism and tone-elicited immobility responses. Repeated, but not acute, nicotine pretreatment significantly reduced conditioned fear stress-induced dopamine metabolism in the medial prefrontal cortex and nucleus accumbens shell. Repeated nicotine pretreatment did not modify the acquisition or expression of conditioned fear stress responses, however. CONCLUSIONS: The dissimilar effects of repeated nicotine exposure on the cortical dopamine and behavioral responses to conditioned fear stress suggest that nicotine differs from other agents with anxiolytic activity that produce coordinated changes in conditioned fear stress-induced cortical dopaminergic and behavioral responses. Furthermore, compared with results of acute footshock stress, repeated nicotine pretreatment appears to have differential effects on physical versus psychological stressors. Results are discussed within the clinical context of stress-related psychopathology syndromes and comorbid nicotine dependence.

Animals↗
PubMed2000

Involvement of the 5-HT1A receptors in classical fear conditioning in C57BL/6J mice.

The present study examined the involvement of the 5-HT(1A) receptors in classical fear conditioning using the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propyloamino)tetralin hydrobromide (8-OH-DPAT) and the selective "silent" 5-HT(1A) receptor antagonist (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo- hexane carboxamide trihydrochloride (WAY 100635). The drugs were administered both subcutaneously and bilaterally into the dorsal hippocampus of male C57BL/6J mice. The training was performed in a single trial in which a tone was followed by a footshock. The retention of context- and tone-dependent fear was examined in separate tests conducted either 1 or 24 hr after training. Subcutaneous 8-OH-DPAT (0.1-1.0 mg/kg), when injected before but not after training, caused a dose-dependent impairment of contextual fear in both 1 and 24 hr tests, whereas tone-dependent fear was less affected. Pretraining intrahippocampal injections of 5.0 microg but not 1.0 microg 8-OH-DPAT caused a severe deficit in contextual fear when tested 24 hr after training. When injected both subcutaneously and intrahippocampally, 8-OH-DPAT induced the 5-HT syndrome, indicative of postsynaptic 5-HT(1A) receptor activation at the dose ranges that impaired fear conditioning. However, the behavioral changes induced by 8-OH-DPAT at the time of training could not account for inhibitory effects of 8-OH-DPAT on fear conditioning. Neither subcutaneous (0.03 mg/kg) nor intrahippocampal (0.5 microg per mouse) WAY 100635 altered context- or tone-dependent fear. However, subcutaneous WAY 100635 blocked both the 5-HT syndrome and the impairment of fear conditioning induced by subcutaneous or intrahippocampal 8-OH-DPAT. In contrast, intrahippocampal WAY 100635 blocked the impairment caused by intrahippocampal but not subcutaneous 8-OH-DPAT, indicating the involvement of extrahippocampal 5-HT(1A) receptors in fear conditioning. It is concluded that the deficits in fear conditioning induced by 8-OH-DPAT are a result of postsynaptic 5-HT(1A) receptor activation that interferes with learning processes operating at acquisition but not consolidation. Furthermore, the dorsohippocampal 5-HT(1A) receptors play an important but not exclusive role in the limbic circuitry subserving contextual fear conditioning.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2003

Alcohol-induced memory impairment in trace fear conditioning: a hippocampus-specific effect.

It has been hypothesized that the amnesic effects of alcohol are through selective disruption of hippocampal function. Delay and trace fear conditioning are useful paradigms to investigate hippocampal-dependent and independent forms of memory. With delay fear conditioning, learning of explicit cues does not depend on normal hippocampal function, whereas learning explicit cues in trace fear conditioning does. In both delay and trace fear conditioning, the hippocampus is involved in learning to contextual cues, but it may not be entirely necessary. The present study investigates the effects of alcohol on the acquisition of delay and trace fear conditioning in mice, using freezing as a measure of learning. Male C57BL/6J mice were injected with 0.8 or 1.6 g/kg of 20% v/v alcohol and were immediately exposed to eight tone-footshock pairings in which the conditional stimulus (CS) either coterminated with a footshock unconditional stimulus (US) (delay conditioning) or was separated from the footshock by a 30-s trace interval (trace conditioning). During trace, but not delay fear conditioning, 0.8 g/kg alcohol impaired learning to a tone CS. This dose also impaired context-dependent learning in both procedures (although only slightly for trace fear conditioning). The 1.6 g/kg alcohol exerted a nonselective impairment on learning. The impairment by alcohol of learning to a tone CS when it is hippocampus-dependent, but not when it is hippocampus-independent provides further support for the hypothesis that alcohol exerts a selective effect on hippocampus-dependent learning.

Acoustic Stimulation↗
PubMedDate not supplied

Contextual and auditory fear conditioning are mediated by the lateral, basal, and central amygdaloid nuclei in rats.

A large body of literature implicates the amygdala in Pavlovian fear conditioning. In this study, we examined the contribution of individual amygdaloid nuclei to contextual and auditory fear conditioning in rats. Prior to fear conditioning, rats received a large electrolytic lesion of the amygdala in one hemisphere, and a nucleus-specific neurotoxic lesion in the contralateral hemisphere. Neurotoxic lesions targeted either the lateral nucleus (LA), basolateral and basomedial nuclei (basal nuclei), or central nucleus (CE) of the amygdala. LA and CE lesions attenuated freezing to both contextual and auditory conditional stimuli (CSs). Lesions of the basal nuclei produced deficits in contextual and auditory fear conditioning only when the damage extended into the anterior divisions of the basal nuclei; damage limited to the posterior divisions of the basal nuclei did not significantly impair conditioning to either auditory or contextual CS. These effects were typically not lateralized, although neurotoxic lesions of the posterior divisions of the basal nuclei had greater effects on contextual fear conditioning when the contralateral electrolytic lesion was placed in the right hemisphere. These results indicate that there is significant overlap within the amygdala in the neural pathways mediating fear conditioning to contextual and acoustic CS, and that these forms of learning are not anatomically dissociable at the level of amygdaloid nuclei.

Acoustic Stimulation↗
PubMedDate not supplied

Convergent but temporally separated inputs to lateral amygdala neurons from the auditory thalamus and auditory cortex use different postsynaptic receptors: in vivo intracellular and extracellular recordings in fear conditioning pathways.

The lateral nucleus of the amygdala (LA), a key component of the fear conditioning circuitry, receives a rapid but relatively impoverished auditory input from the auditory thalamus and a slower but richer input from the auditory cortex. We examined in urethane anesthetized rats whether individual cells in the LA receive convergent inputs from these two areas, and whether different postsynaptic receptors contribute to the temporally separated excitations over the two pathways. With both extracellular and intracellular recordings, individual cells could be activated by stimulation of each pathway. In extracellular recordings iontophoretic application of the N-methyl-D-aspartate (NMDA) receptor antagonist APV and the L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist CNQX demonstrated that synaptic transmission in both pathways depends on AMPA receptors, whereas transmission in the thalamic pathway also depends on the involvement of NMDA receptors. The involvement of NMDA receptors in synaptic activation of the LA from the thalamus but not the cortex was confirmed in intracellular recordings using systemic injections of the NMDA antagonist MK-801. The slow time course of NMDA currents could provide LA cells with a mechanism to integrate the inputs arriving rapidly from the thalamus and somewhat later from the cortex, thus allowing the LA to integrate signals in the two pathways during the acquisition and expression of conditioned fear reactions.

Amygdala↗
PubMed2005

Internuclear synapse in the amygdala is not facilitated in fear conditioning.

The amygdala is essential for fear learning and memory. Synaptic transmission is enhanced in two pathways in the amygdala in fear conditioning. In this study we examined whether lateral (LA) to basolateral (BLA) amygdala synapses are potentiated and participate in intra-amygdala plasticity during the maintenance of fear memory. Our data showed that synaptic strength from the LA (ventrolateral) to the BLA (parvicellular) pathway was not increased after fear conditioning and suggests that this pathway does not integrate information relevant to the coding of memories in auditory fear learning.

2-Amino-5-phosphonovalerate↗
PubMed2005

Activation of extracellular signal-regulated kinase- mitogen-activated protein kinase cascade in the amygdala is required for memory reconsolidation of auditory fear conditioning.

Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of amygdala (LA). Recently we have demonstrated that consolidated fear memories, when reactivated, return to a labile state which is sensitive to disruption by the protein synthesis inhibitor anisomycin. The specific molecular mechanisms that underlie this reconsolidation of fear memories are still largely unknown. The activation of extracellular signal-regulated kinase-mitogen-activated protein kinase (ERK-MAPK) pathway in the LA is required for the consolidation of auditory fear memories. In the present study, we examined the role of ERK-MAPK cascade in the LA during reconsolidation of auditory fear conditioning. We show that intra-LA infusions of the MAPK kinase (MEK) inhibitor U0126, a manipulation which inhibits activation of ERK-MAPK, impairs postreactivation long-term memory (PR-LTM) but leaves the postreactivation short-term memory (PR-STM) intact. The same treatment with U0126, in the absence of memory reactivation, has no effect. Furthermore, we verified that reconsolidation requires translation using a second protein synthesis inhibitor, cycloheximide. Post-reactivation infusions of cycloheximide blocked PR-LTM but not PR-STM and, in the absence of reactivation, had no effect. Our data show that activation of ERK-MAPK signalling pathway and protein synthesis in the LA are required for reconsolidation of auditory fear memories.

Acoustic Stimulation↗
PubMedDate not supplied

Differential effects of selective opioid peptide antagonists on the acquisition of pavlovian fear conditioning.

Pretreatment with opioid antagonists enhances acquisition of Pavlovian fear conditioning. The present experiments attempted to characterize the type of opioid receptor responsible for this effect using a procedure that assessed the fear of rats to a chamber previously associated with electric shock (1 mA, 0.75 s). Freezing, a species-typical immobility, was employed as an index of fear. Two mu opioid antagonists, CTOP (40 ng) and naloxonazine (10 micrograms), enhanced conditioning. On the other hand, the kappa antagonist nor-binaltorphimine reduced conditioning. Two delta antagonist treatments (16-methyl cyprenorphine and naltrindole) had no reliable effect on acquisition. Thus the enhancement of conditioning appears to be mediated by mu receptors. Previous research has shown that the conditional fear produced by these procedures caused an analgesia that is also mediated by mu receptors. It is argued that the enhancement effect occurs because of an antagonism of this analgesia and that the analgesia normally acts to regulate the level of fear conditioning.

Animals↗
PubMed2004

Latent inhibition of cued fear conditioning: an NMDA receptor-dependent process that can be established in the presence of anisomycin.

Much of the research examining the biological basis for long-term memories has focused on mechanisms that support the formation of conditioned associations. Less information is available on biological mechanisms which underlie processes that modify the strength of conditioned associations. Latent inhibition is a phenomenon by which pre-exposure to a to-be-conditioned stimulus (CS) weakens subsequent conditioning of that CS to an unconditioned stimulus (US). Here we report that latent inhibition of cued fear conditioning is dependent on NMDA receptor activation. MK-801 (1 mg/kg), an NMDA receptor antagonist, abolished latent inhibition of cued fear conditioning. This dose of MK-801 administered before training did not disrupt cued fear conditioning. Conversely, anisomycin (150 mg/kg), a protein synthesis inhibitor, had no effect on latent inhibition of cued fear conditioning when administered 20 min before, immediately after, or 2, 4, 6, or 8 h after CS pre-exposure. Furthermore, continuous anisomycin administration (50 mg/kg, administered every 2 h for 6 h starting 20 min prior to pre-exposure) did not disrupt latent inhibition of cued fear conditioning. In addition, anisomycin had no effect on a long-lasting version of latent inhibition of cued fear conditioning that was maintained over a 7-day interval. Anisomycin administered before training, however, disrupted learning of the CS-US association. These findings suggest that latent inhibition of cued fear conditioning is a long-lasting NMDA receptor-dependent process that can develop during the inhibition of protein synthesis.

Analysis of Variance↗
PubMed1995

Scopolamine impairs acquisition and facilitates consolidation of fear conditioning: differential effects for tone vs context conditioning.

Cholinergic antagonism impacts selected learning tasks. To understand where scopolamine exerts its action, learning tasks differentially sensitive to hippocampus and amygdala lesions were used. Hippocampal lesions prevent context fear conditioning without effect on tone conditioning. These lesions also produce a time-dependent retrograde deficit in context conditioning. The amygdala is necessary for both tone and context conditioning. To examine the possibility that cholinergic antagonism mimics hippocampal damage or amygdala damage, rats were given scopolamine (1 mg/kg) either before or after fear conditioning. In the fear conditioning procedure, rats received tone-footshock or context-footshock pairings. Evidence of conditioning to the tone and the context was provided by observation of freezing. When given prior to training, scopolamine blocked fear conditioning to the tone in a dose-dependent fashion but had no effect on context conditioning. The impairment of tone conditioning did not occur with methylscopolamine, indicating the central action of the drug. Rats given scopolamine immediately following fear conditioning, tested later in a drug-free state, froze more to the tone than rats given a control injection. The effect of scopolamine on freezing to the context was not reliable. The present results suggest that scopolamine's impact on fear conditioning is mediated by some mechanism other than impaired hippocampal or amygdala functioning.

Acoustic Stimulation↗
PubMed1998

Appetitive motivational states differ in their ability to augment aversive fear conditioning in rats (Rattus norvegicus).

The present experiments compared the effects of 2 appetitive motivational states on the acquisition of Pavlovian fear conditioning in rats (Rattus norvegicus). In Experiment 1, rats were deprived of either water or food prior to contextual fear conditioning, which consisted of the delivery of a single footshock in a novel observation chamber. Conditional fear to the contextual cues of the conditioning chamber was measured by observing freezing behavior. The results revealed that water, but not food, deprivation enhanced conditional freezing to contextual stimuli paired with footshock. Experiment 2 indicated that the different impact of food or water deprivation on the acquisition of conditional freezing was not due to differential generalization decrements during extinction testing. Together, these experiments suggest that the modulation of fear conditioning by deprivation state is specific to certain motivational systems.

Animals↗
PubMed1996

Lesions of the central gray block conditioned fear as measured with the potentiated startle paradigm.

The amplitude of the acoustic startle response (ASR) in rats is increased in the presence of a cue which has previously been paired with an electric footshock. This phenomenon is termed fear-potentiated startle and is a useful model to investigate the neural systems underlying fear and anxiety. A series of studies have shown, that the amygdaloid complex is necessary for the acquisition and the expression of conditioned fear. Further experiments have delineated an efferent amygdalofugal pathway to the primary startle circuit, at the level of the caudal pontine reticular formation, which mediates the expression of conditioned fear [10]. Yet it was unclear, whether this amygdaloreticular pathway directly transfers the effects of conditioned fear from the amygdala to the primary startle circuit or whether there exist one or more relay nuclei within this pathway or even additional parallel circuits. Based on our previous finding that the midbrain central gray (CG) is involved in the mediation of the facilitatory effects on the ASR of unconditioned aversive events, the present study tested the hypothesis that the CG is important for the potentiation of the ASR by conditioned fear. Therefore, we lesioned the CG before and after fear-conditioning and examined the effects of these lesions on fear-potentiated startle. Pre- and post-training lesions of the CG totally blocked the potentiation of the ASR amplitude by conditioned fear, which was seen in sham-lesioned rats, indicating that CG lesions affected the expression of conditioned fear. The baseline ASR amplitude was not influenced by CG lesions. We discuss possible pathways and mechanisms underlying the expression of conditioned and unconditioned fear in rats.

Acoustic Stimulation↗
PubMed2006

Impaired trace and contextual fear conditioning in aged rats.

Trace and contextual fear conditioning were evaluated in adult (3-6 months), early middle-aged (8-12 months), late middle-aged (16-20 months), and aged (24-33 months) Sprague-Dawley rats. After trace conditioning, aged animals exhibited significantly less freezing to the tone conditioned stimulus and training context. Levels of trace-cue and context conditioning were negatively correlated with age (r = -0.56 and -0.59, respectively) and positively correlated with each other (r = +0.52). Aged rats showed robust conditioning in short- and long-delay fear paradigms, suggesting that the trace interval, rather than the use of a long interstimulus interval, is responsible for the aging-related deficits in trace fear conditioning. The authors suggest that these aging-related conditioning deficits furnish useful indices of functional changes within hippocampus or perirhinal cortex.

Acoustic Stimulation↗
PubMed2003

Dorsal hippocampus and classical fear conditioning to tone and context in rats: effects of local NMDA-receptor blockade and stimulation.

Consistent with the importance of the hippocampus in learning more complex stimulus relations, but not in simple associative learning, the dorsal hippocampus has commonly been implicated in classical fear conditioning to context, but not to discrete stimuli, such as a tone. In particular, a specific and central role in contextual fear conditioning has been attributed to mechanisms mediated by dorsal hippocampal N-methyl-D-aspartate (NMDA)-type glutamate receptors. The present study characterized the effects of blockade or tonic stimulation of dorsal hippocampal NMDA receptors by bilateral local infusion of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine maleate; 6.25 microg/side) or of NMDA (0.7 microg/side), respectively, on classical fear conditioning to tone and context in Wistar rats. Freezing was used to measure conditioned fear. Regardless of whether conditioning was conducted with tone-shock pairings or unsignaled footshocks (background or foreground contextual conditioning), both NMDA and MK-801 infusion before conditioning resulted in reduced freezing during subsequent exposure to the conditioning context. Freezing during subsequent tone presentation in a new context, normally resulting from conditioning with tone-shock pairings, was not impaired by MK-801 but was strongly reduced by NMDA infusion before conditioning; this freezing was also reduced by NMDA infusion before tone presentation (in an experiment involving NMDA infusions before conditioning and subsequent tone presentation to assess the role of state-dependent learning). It was assessed whether unspecific infusion effects (altered sensorimotor functions, state dependency) or infusion-induced dorsal hippocampal damage contributed to the observed reductions in conditioned freezing. Our data suggest that formation of fear conditioning to context, but not tone, requires NMDA receptor-mediated mechanisms in the dorsal hippocampus. As indicated by the effects of NMDA, some dorsal hippocampal processes may also contribute to fear conditioning to tone. The role of the dorsal hippocampus and local NMDA receptor-mediated processes in fear conditioning to tone and context is discussed in comparison with ventral hippocampal processes.

Acoustic Stimulation↗