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PubMed2004

Opioid receptors in the midbrain periaqueductal gray regulate extinction of pavlovian fear conditioning.

Four experiments studied the role of opioid receptors in the midbrain periaqueductal gray matter (PAG), an important structure eliciting conditioned fear responses, in the extinction of Pavlovian fear. Rats received pairings of an auditory conditioned stimulus (CS) with a foot shock unconditioned stimulus (US). The freezing conditioned response (CR) elicited by the CS was then extinguished via nonreinforced presentations of the CS. Microinjection of the opioid receptor antagonist naloxone into the ventrolateral PAG (vlPAG) before nonrein-forced CS presentations impaired development of extinction, but such microinjections at the end of extinction did not reinstate an already extinguished freezing CR. This role for opioid receptors in fear extinction was specific to the vlPAG because infusions of naloxone into the dorsal PAG did not impair fear extinction. Finally, the impairment of fear extinction produced by vlPAG infusions of naloxone was dose-dependent. These results show for the first time that the midbrain PAG contributes to fear extinction and specifically identify a role for vlPAG opioid receptors in the acquisition but not the expression of such extinction. Taken together with our previous findings, we suggest that, during fear conditioning, activation of vlPAG opioid receptors contributes to detection of the discrepancy between the actual and expected outcome of the conditioning trial. vlPAG opioid receptors regulate the learning that accrues to the CS and other stimuli present on a trial because they instantiate an associative error correction process influencing US information reaching the site of CS-US convergence in the amygdala. During nonreinforcement, this vlPAG opioid receptor contribution signals extinction.

Animals↗

PubMed2002

Distinct contributions of median raphe nucleus to contextual fear conditioning and fear-potentiated startle.

Ascending 5-HT projections from the median raphe nucleus (MRN), probably to the hippocampus, are implicated in the acquisition of contextual fear (background stimuli), as assessed by freezing behavior. Foreground cues like light, used as a conditioned stimulus (CS) in classical fear conditioning, also cause freezing through thalamic transmission to the amygdala. As the MRN projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to explicit cues remains to be explained. Here we analyzed the behavior of rats with MRN electrolytic lesions in a contextual conditioning situation and in a fear-potentiated startle procedure. The animals received MRN electrolytic lesions either before or on the day after two consecutive training sessions in which they were submitted to 10 conditioning trials, each in an experimental chamber (same context) where they received foot-shocks (0.6 mA, 1 sec) paired to a 4-sec light CS. Seven to ten days later, the animals were submitted to testing sessions for assessing conditioned fear when they were placed for five shocks, and the duration of contextual freezing was recorded. The animals were then submitted to a fear-potentiated startle in response to a 4-sec light-CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same context showed more freezing than did rats with pre- or post-training MRN lesions. Startle was clearly potentiated in the presence of light-CS in the sham-lesioned animals. Whereas pre-training lesions reduced both freezing and fear-potentiated startle, the post-training lesions reduced only freezing to context, without changing the fear-potentiated startle. In a second experiment, neurotoxic lesions of the MRN with local injections of N-methyl-D-aspartate or the activation of 5-HT1A somatodendritic auto-receptors of the MRN by microinjections of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) before the training sessions also reduced the amount of freezing and the fear-potentiated startle. Freezing is a prominent response of contextual fear conditioning, but does not seem to be crucial for the enhancement of the startle reflex by explicit aversive cues. As fear-potentiated startle may be produced in post-training lesioned rats that are unable to freeze to fear contextual stimuli, dissociable systems seem to be recruited in each condition. Thus, contextual fear and fear-potentiated startle are conveyed by distinct 5-HT-mediated circuits of the MRN.

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

PubMed2005

Single neurons in the medial prefrontal cortex of the rat exhibit tonic and phasic coding during trace fear conditioning.

Trace fear conditioning is a learning task that requires the association of an auditory conditioned stimulus (CS) and a shock unconditioned stimulus (US) that are separated by a 20-s trace interval. Single neuron activity was recorded from the prelimbic and infralimbic areas of the medial prefrontal cortex in rats during trace fear conditioning or nonassociative unpaired training. Prelimbic neurons showed learning-related increases in activity to the CS and US, whereas infralimbic neurons showed learning-related decreases in activity to these stimuli. A subset of prelimbic neurons exhibited sustained increases in activity during the trace interval. These sustained prelimbic responses may provide a bridging code that allows for overlapping representations of CS and US information within the trace fear conditioning circuit.

Acoustic Stimulation↗

PubMed2001

Postnatal anoxia from CO2 for one minute produces sex-specific changes in contextual fear conditioning in adult rats.

In a split-litter design, equal numbers of male and female rats were exposed either to carbon dioxide for 1 min, or to the control condition on either postnatal Days 9-10 or 17-18. At 120 days of age half the numbers of rats in each condition were given subclinical dosages of lithium (1.5 mEq/kg) and pilocarpine (15 mg/kg) or saline. 40 days later all rats were tested in a conditioned fear paradigm. A four-way analysis of variance as a function of the variables anoxia, age at the time of anoxia sex, and subclinical seizure induction indicated a significant interaction between sex and anoxic history. Post hoc analysis showed that performance of male rats exposed to the anoxic condition did not differ from normal or anoxic female rats. The results suggest that only 1 min. of preweaning anoxia may produce permanent changes in contextual fear conditioning for male but not female rats.

Animals↗

PubMed1999

Memorization of contextual and CS conditioned fear response (freezing) in a one-trial acquisition paradigm.

In fear-conditioned Wistar rats freezing was induced by the delivery of a series of footshocks paired to tones (CS) in a specific conditioning chamber (context). CS and contextual fear were acquired in the same single conditioning session without preexposition to the conditioning chamber (day 1). Different groups of animals were conditioned employing three increasing US (footshock) intensities (0.25, 0.5, 0.75 mA). During the retention sessions context and CS conditioned freezing (fear response) were measured using a paradigm that fulfilled the following conditions: i) CS freezing retention was measured in a context different from the conditioning one; ii) CS and context freezing were measured at increased delays after the training session (days 3 and 4, 14 and 15, 28 and 29). The results show that there are significant differences between CS and context freezing retention, which are clearly related to delay after the initial session and to US intensity. In particular: 1) conditioned freezing to a discrete tone is better retained than conditioned freezing to context (irrespective of US intensity); 2) context freezing is directly related to US intensity much more than to tone freezing; 3) context freezing is easier to extinguish than tone freezing. The results are discussed in relation to previous ones and to their relevance to freezing genesis neural correlates.

Acoustic Stimulation↗

PubMed2006

Auditory fear conditioning and conditioned stress raise NO(3) level in the Amygdala.

BACKGROUND: The conditioned fear response is considered to be acquired by experimental animals when tone information is combined with that of an electrical foot shock (unconditioned stimulus) in the amygdala. Nitric oxide biosynthesized in the brain is reportedly involved in several kinds of learning. METHODS: In this study, we continuously monitored the NO(3)(-) level, as a marker of nitric oxide production, in the amygdala starting before the application of tone and electrical foot shock stimuli together (conditioned group) or the tone stimulus alone (control group) on day 1, until after the tone information was given (both groups) on day 2, using the in vivo microdialysis method. RESULTS: The NO(3)(-) level of the conditioned group was increased on both day 1 and day 2, while that of the control group was not elevated on either day. Freezing behavior was observed in the conditioned but not the control rats. CONCLUSIONS: Although the sources of NO(3)(-) remain uncertain, these results suggest that nitric oxide is associated with auditory fear conditioning and the response to a conditioned stimulus.

Acoustic Stimulation↗

PubMed2005

Dissociation of temporal dynamics of heart rate and blood pressure responses elicited by conditioned fear but not acoustic startle.

Fear-inducing stimuli were hypothesized to elicit fast heart rate (HR) responses but slow mean arterial blood pressure (MAP) responses and thus were studied in auditory fear conditioning and acoustic startle at high temporal resolution in freely moving mice and rats. Fear-induced instantaneous acceleration of HR reaching maximum physiological values and subsequent recovery to baseline were observed. The MAP response consisted of an immediate, mild, and transient increase followed by a sluggish, profound elevation and slow recovery. HR and MAP responses served as reliable indicators of conditioned fear in mice with dissociated temporal dynamics. Unconditioned auditory stimuli, including acoustic startle stimuli, elicited only fast, mild, and transient MAP and HR elevations in mice and rats, reflecting arousal and attention under these experimental conditions.

Acoustic Stimulation↗

PubMed2005

Extract of Ginkgo biloba EGb 761 facilitates fear conditioning measured by fear-potentiated startle.

Extract of Ginkgo biloba EGb 761 has been used in the treatment of various common geriatric complaints including vertigo, short-term memory loss, hearing loss, lack of attention, vigilance and cerebral vascular disorder. Recent results suggest that it can serve as a cognitive enhancer and anti-stress buffer. It raises a possibility that EGb 761 may be involved in the fear conditioning. In this study, we used fear-potentiated startle (FPS) to evaluate the possible effects of EGb 761 on the acquisition stage of fear conditioning. Our results showed that administration of EGb 761 30 min prior to the conditioning facilitated acquisition of conditioned fear in a dose dependent manner. No significant differences had been observed in either basal startle response or shock activity. These results indicated that the facilitation effect of EGb 761 was not the result of impaired basal startle response or enhanced pain perception. Subsequent control experiment results indicated that the facilitation effect of EGb 761 on the acquisition was not due to anxiogenic effect or non-specific effect. Our data present the first evidence that EGb 761 can enhance fear memory formation rather than serve as an anti-stress buffer.

Acoustic Stimulation↗

PubMed1996

Changes in synaptic excitability in the lateral septum associated with contextual and auditory fear conditioning in mice.

Synaptic excitability in the lateral septum (LS) was assessed electrophysiologically in freely moving mice either submitted to a painful stimulus (shock) or tested on two forms of conditioned fear: contextual conditioning and auditory cue conditioning. Only the amplitude of the N3 component of the two negative waves (N2 and N3) evoked by fimbrial stimulation displayed significant changes in these tests. Experiment 1 showed that both the painful stimulus and subsequent re-exposure (24 h later) to the conditioning foreground context induced significant and context specific decrease in the N3 amplitude. In Experiment 2, a phasic tone (conditioned stimulus: CS) was paired (paired group) with the footshock (unconditioned stimulus: US) or not (unpaired group) and, 24 h later, animals were re-exposed successively to the auditory cue and to the context. During the auditory cue test, only the paired group displayed significant freezing and this occurred only during presentation of the CS. In this group, however, a significant reduction in the N3 amplitude was only observed immediately after the cessation of the CS. During the context test, the percentage and time-course of freezing across the 10 mm session were similar in each group. However, in the unpaired group the N3 amplitude reduction was significant and outlasted the duration of the freezing behaviour itself. These results show that alterations in LS synaptic excitability may be dissociated from fear-induced freezing behaviour. We suggest that LS synapses are part of a brain circuit that predict if and when the US is going to occur.

Acoustic Stimulation↗

PubMed2003

Generalisation of conditioned fear and its behavioural expression in mice.

Mice are favourite subjects in molecular and genetic memory research and frequently studied with classical fear conditioning paradigms that use an auditory cue (conditioned stimulus, CS(+)) to predict an aversive, unconditioned stimulus (US). Yet the conditions that control fear memory specificity and generalisation and their behavioural expression in such conditioned mice have not been analysed systematically. In the current study we addressed these issues in the most widely used mouse strain of behavioural genetics, C57Bl/6. In keeping with findings in other species we demonstrate the dependence of fear memory generalisation on training intensity (i.e. both US intensity and the number of CS(+) and US applied) after both excitatory (explicitly paired presentation of CS(+) and US) and inhibitory training (explicitly unpaired presentation of CS(+) and US). Furthermore, inhibitory overtraining was associated with changes of uncued anxiety-like behaviour in a light/dark exploration test, indicative of an emotional sensitisation reaction as consequence of a lack of US predictability. Together our results describe the qualitatively and quantitatively different increases of defensive behaviour in response to conditioned stimuli of different salience and identify training conditions that lead to fear memory generalisation and emotional sensitisation in C57Bl/6 inbred mice.

Acoustic Stimulation↗

PubMed1992

Potentiation or diminution of discrete motor unconditioned responses (rabbit eyeblink) to an aversive pavlovian unconditioned stimulus by two associative processes: conditioned fear and a conditioned diminution of unconditioned stimulus processing.

In two experiments using the rabbit conditioned eyeblink preparation, the conditions under which a Pavlovian conditioned stimulus (CS) potentiates or diminishes the unconditioned response (UR) were examined. The results indicated that, after discrimination training (CS+ vs. CS-), the CS+ diminished UR amplitude at the training interstimulus interval (ISI). When CS+ trials were segregated into trials on which a conditioned response (CR) did or did not occur, the CS+ diminished the UR when it elicited a CR, but not when a CR failed to occur. When the CS-unconditioned stimulus (US) interval was lengthened to 10 s, the CS+ reliably potentiated the eyeblink UR on CR trials but did not potentiate responding on trials on which a CR was absent. The results are discussed in terms of the modulatory effects and temporal properties of conditioned fear and an associatively produced decrement in US processing.

Animals↗

PubMed2003

Evaluation of an improved automated analysis of freezing behaviour in rats and its use in trace fear conditioning.

Pavlovian fear conditioning in rodents often involves the assessment of freezing behaviour. Since human-based scoring is labour-intensive and subject to biases, several automated methods have been proposed, but few of them have been assessed for temporal definition. An accurate method for the automated analysis of freezing in rats is presented. It is based on a comparison of contrast from successive video images (Learn. Mem. 7 (2000) 58). A major improvement involves subtracting a previously recorded image of the empty background from each frame before processing. This simple operation greatly improves reliability, since it cancels the influence of video noise outside the region of interest in the image (the rat), and can also take advantage of the movements of a patterned animal over a textured background. The technique is compared with manual scoring and with the Anagnostaras method in a trace fear conditioning experiment. The method is appropriate to monitor the time course of freezing behaviour. The same system with a different threshold can also score locomotor activity. A quantitative evaluation of the residual errors inherent to automated methods is attempted.

Algorithms↗

PubMed1996

A developmental analysis of contextual fear conditioning.

Contextual fear conditioning by 18- and 23-day-old rats was compared in two training contexts, a transparent Plexiglas chamber or a black Plexiglas chamber. As measured by a conditioned defensive freezing response, older rats displayed more contextual fear than younger rats. At both ages conditioning was (a) stronger in the black chamber than in the clear chamber, (b) a nonmonotonic function of retention interval, with freezing being greater at the immediate and 24-hr retention interval than at the 10-min interval, and (c) preexposure to the context 24 hr before conditioning enhanced conditioned freezing observed at the 10-min retention interval. Additional experiments suggest that rats at both ages acquire independent representations of the visual and tactile features of the context. These results support Rudy and Morledge's (1994) hypothesis that contextual fear conditioning is mediated by both a short-term and a long-term memory system and that long-term memory for contextual fear requires the consolidation of a representation of the context. They challenge their view that there is a qualitative developmental difference in long-term memory processes between 18- and 23-day-old rats.

Aging↗

PubMed1986

Pharmacological and anatomical analysis of fear conditioning using the fear-potentiated startle paradigm.

Pharmacological and anatomical analysis of fear conditioning using the fear-potentiated startle paradigm are reviewed. This test measures conditioned fear by an increase in the amplitude of a simple reflex (the acoustic startle reflex) in the presence of a cue previously paired with a shock. This paradigm offers a number of advantages as an alternative to most animal tests of fear or anxiety because it involves no operant and is reflected by an enhancement rather than a suppression of ongoing behavior. Fear-potentiated startle is selectively decreased by drugs such as diazepam, morphine, and buspirone that reduce fear or anxiety clinically. Electrical stimulation techniques suggest that a visual conditioned stimulus ultimately alters acoustic startle at a specific point along the acoustic startle pathway. Relevant visual structures implicated in potentiated startle include the lateral geniculate nucleus, visual cortex, and deep and intermediate layers of the superior colliculus. The central nucleus of the amygdala and the caudal branch of the ventral amygdalofugal pathway projecting to or through the substantia nigra are also necessary for potentiated startle to occur. Electrical stimulation of the central nucleus of the amygdala markedly increases acoustic startle. By combining these behavioral, anatomical, physiological, and pharmacological approaches, it should soon be possible to determine each neural pathway that is required for a stimulus signaling fear to alter startle behavior. Once the exact structures are delineated, it should be possible to determine the neurotransmitters that are released during a state of fear and how this chemical information is relayed along these pathways so as to affect behavior.

Animals↗

PubMed2006

Stronger renewal in human fear conditioning when tested with an acquisition retrieval cue than with an extinction retrieval cue.

It was previously demonstrated in our laboratory that conditioned fear in humans can renew after extinction, when this procedure took place in a different context (ABA-renewal [Vansteenwegen et al. (2005). Return of fear in a human differential conditioning paradigm caused by a return to the original acquisition context. Behaviour Research and Therapy, 43(3), 323-336]). Using the same experimental design, we now tested the power of retrieval cues to interact with this contextual renewal phenomenon. Two groups went through acquisition and extinction (in a different context). They were then tested in the original acquisition context and in the presence of a retrieval cue. In the acquisition-cue group, this cue previously featured during the acquisition procedure; in the extinction-cue group, the cue previously featured during the extinction procedure. As expected, renewal of conditioned electro-dermal responding and retrospective expectancy ratings was strongest in the acquisition-cue group. Theoretical and clinical implications of this finding are discussed.

Association Learning↗

PubMed1998

Selectively enhanced contextual fear conditioning in mice lacking the transcriptional regulator CCAAT/enhancer binding protein delta.

CCAAT/enhancer binding protein delta (C/EBPdelta) is a transcriptional regulator implicated in the hepatic acute phase response and in adipogenic and myeloid cell differentiation. We found that C/EBPdelta is widely expressed in the peripheral and central nervous systems, including neurons of the hippocampal formation, indicating a role in neural functions. To examine the role of C/EBPdelta in vivo, we generated mice with a targeted deletion of the C/EBPdelta gene. This mutation does not interfere with normal embryonic and postnatal development. Performance in a battery of behavioral tests indicates that basic neurological functions are normal. Furthermore, performance in a Morris water maze task suggests that C/EBPdelta mutant mice have normal spatial learning. However, in the contextual and auditory-cue-conditioned fear task, C/EBPdelta null mice displayed significantly more conditioned freezing to the test context than did wild-type controls, but equivalent conditioning to the auditory cue. These data demonstrate a selectively enhanced contextual fear response in mice carrying a targeted genomic mutation and implicate C/EBPdelta in the regulation of a specific type of learning and memory.

Animals↗

PubMed2004

Lesions of the ventral hippocampus, but not the dorsal hippocampus, impair conditioned fear expression and inhibitory avoidance on the elevated T-maze.

The hippocampus has been suggested to be involved in spatial (or configural) memory and also in the inhibition of certain response or goal alternatives. An increasing number of anatomical, physiological, and behavioral studies indicate that the hippocampus is functionally heterogeneous along the dorsal-ventral axis. Identification of distinct behavioral roles for the dorsal (DH) and ventral (VH) hippocampus may resolve differences between the various theoretical accounts of hippocampal function. The present study examined the effects of electrolytic lesions restricted to the DH or VH on fear-conditioned freezing, passive avoidance on the elevated T-maze (ETM) test of anxiety, and general activity in male Sprague-Dawley (Charles-River derived) albino rats. We found that rats with lesions of the VH, but not DH showed reduced freezing to both context and tone conditioned stimuli (CS). Rats with VH lesions also showed a reduced latency to emerge from the enclosed arm on trials 2 and 3 of the ETM (indicating reduced anxious behavior), while having no effect on the latency to escape from the open arms on trial 4. There were no differences in activity between the groups. These results indicate that the VH and DH are differentially involved in passive avoidance on the ETM and conditioned freezing to context and tone CS. We suggest that the VH may be specifically involved in modulating goal-oriented, defensive behavior expression through hypothalamic and amygdaloid connections.

Acoustic Stimulation↗

PubMed2005

Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear.

Inhaled anesthetics are believed to produce anesthesia by their actions on ion channels. Because inhaled anesthetics robustly enhance GABA A receptor (GABA(A)-R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABA(A)-Rs and individual GABA(A)-R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. We hypothesized that inhaled anesthetics produce amnesia, as assessed by loss of fear conditioning, by acting on the forebrain GABA(A)-Rs that harbor the alpha1 subunit. To test this, we used global knockout mice that completely lack the alpha1 subunit and forebrain-specific, conditional knockout mice that lack the alpha1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145% less sensitive to the amnestic effects of the inhaled anesthetic isoflurane. These results indicate that alpha1-containing GABA(A)-Rs in the hippocampus, amygdala, and/or cortex influence the amnestic effects of inhaled anesthetics and may be an important molecular target of the drug isoflurane.

Administration, Inhalation↗