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PubMed2005

Cholinergic effects on fear conditioning I: the degraded contingency effect is disrupted by atropine but reinstated by physostigmine.

RATIONALE: The cholinergic system has been shown to modulate contextual fear conditioning. However, with the exception of trace conditioning studies, most of the available data have focussed on independent context, i.e., context that do not compete with the conditioned stimulus to control for the conditioned response (interactive context). OBJECTIVE: In the present series of experiments, the effects of the muscarinic antagonist, atropine, were assessed when contextual fear memory interacts with cued fear memory to regulate conditioned response, using a Pavlovian degraded contingency preparation in rats. This preparation not only afforded an insight into simple Pavlovian associations but also enabled us to test for the processes of competition that made use of these associations to make an appropriate response to a stimulus [degraded contingency effect (DCE)]. METHODS: In experiment 1, three doses of atropine [2.5, 5.0, and 10.0 mg/kg, intraperitoneally (i.p.)] were evaluated on male Sprague-Dawley rats. In experiment 2, physostigmine (0.037-0.3 mg/kg, i.p.) was injected after the administration of 5 mg/kg of atropine. RESULTS: Experiment 1A and its partial replication (experiment 1B) showed that at asymptotic level of training, atropine did not alter contextual and cued fear memories when the subjects were directly tested for them, whereas it suppressed the DCE for a 5 mg/kg dose. Indeed, atropine-induced suppression of the DCE was found to be an inverted U-shaped dose-response curve. Experiment 2 showed that physostigmine caused a dose-dependent reversal of the atropine-induced alleviation of the DCE, without altering the expression of simple cued and contextual fear memories. CONCLUSION: These results evidence at asymptotic level of training a cholinergic modulation of the processing of interactive context, but not of independent ones. They are discussed in the framework of the mechanisms that are involved in both types of contextual processing.

Animals↗
PubMed2005

Modulation of an activity response with associative and nonassociative fear in the rat: a lighting differential influences the form of defensive behavior evoked after fear conditioning.

Rats confronted with the onset of a light gradient display a transient increase in locomotion called the activity response (AR) and a dark preference (Godsil & Fanselow, 2004). These experiments demonstrate that the magnitude of the AR can be blunted with Pavlovian fear-conditioning procedures via associative and nonassociative fear. Although manifested in decreased locomotion, the blunted AR effect was not due to increased freezing or immobility behaviors. Instead, rats displayed reduced rearing and an increase in a class of behaviors called stationary activity. These results suggest that the lighting differential supplied by the cue influences the topography of defensive behavior and reduces the expression of freezing. This procedure provides a means by which to examine learned and unlearned defensive responses to the same stimulus.

Animals↗
PubMed1999

Involvement of dopamine D(1) and D(2) receptors in the ethanol-associated place preference in rats exposed to conditioned fear stress.

The present study was designed to investigate: (1) the involvement of dopamine D(1) and D(2) receptors, and (2) the roles of these receptors and endogenous opioid systems (endorphinergic and enkephalinergic systems) in the ethanol-induced place preference in rats exposed to conditioned fear stress using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) induced a significant place preference. The selective D(1) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H3-benzazepine)hydrochloride (SCH23390; 0.01 and 0.03 mg/kg, s.c.) and the selective D(2) receptor antagonist S(-)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2- methoxybenzamide (sulpiride; 20 and 40 mg/kg, s.c.) significantly attenuated the ethanol-induced place preference. The administration of ethanol (75 mg/kg, i.p.) tended to produce a place preference, but this effect was not significant. SCH23390 (0.03 mg/kg, s.c.) and sulpiride (40 mg/kg, s.c.) significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.). In addition, SCH23390 (0.03 mg/kg, s.c.) also significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12aalpha-octahydroquinolino[2,3,3,-g]isoquinoline (TAN-67; 20 mg/kg, s.c.). On the other hand, sulpiride (40 mg/kg) had no significant effect on the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by TAN-67. These results suggest that D(1) and D(2) receptors may be involved in the rewarding mechanism of ethanol under psychological stress. In addition, D(1) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu- and delta-opioid receptors, whereas D(2) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu-opioid receptors, but not in that modulated by the activation of delta-opioid receptors.

Animals↗
PubMed2002

Changes in protein kinase C (PKC) activity, isozyme translocation, and GAP-43 phosphorylation in the rat hippocampal formation after a single-trial contextual fear conditioning paradigm.

The hippocampus plays an important role in spatial learning and memory. However, the biochemical alterations that subserve this function remain to be fully elucidated. In this study, rats were subjected to a single-trial contextual fear conditioning (CFC) paradigm; the activation of different protein kinase C (PKC) subtypes and the levels and phosphorylation of the plasticity-associated protein GAP-43 were assayed in the hippocampus at varying times after training. We observed a rapid activation of hippocampal PKC (15 min through 24 h), with differential translocation of the PKC isotypes studied. At early times after CFC (15-90 min), PKCalpha and PKCgamma translocated to the membrane, while PKCbetaII and PKCepsilon moved more transiently (15 to 30 min) to the cytosol. These PKC isotypes returned to the membrane at later time points after CFC. Correlating with these changes in PKC translocation and activity, there was an early decrease in GAP-43 phosphorylation followed by a more sustained increase from 1.5-72 h. GAP-43 protein levels were also increased after 3 h, and these levels remained elevated for at least 72 h. These changes in PKC and GAP-43 were specific to the CFC trained animals and no changes were seen in animals exposed to the same stimuli in a non-associative fashion. Comparison of translocation of different PKC isotypes with the changes in GAP-43 phosphorylation suggested that PKCbetaII and PKCepsilon may mediate both the early changes in the phosphorylation of this protein and the increases in GAP-43 expression at later times after CFC.

Animals↗
PubMed2001

A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala.

Western blot analysis of neuronal tissues taken from fear-conditioned rats showed a selective activation of phosphatidylinositol 3-kinase (PI-3 kinase) in the amygdala. PI-3 kinase was also activated in response to long-term potentiation (LTP)-inducing tetanic stimulation. PI-3 kinase inhibitors blocked tetanus-induced LTP as well as PI-3 kinase activation. In parallel, these inhibitors interfered with long-term fear memory while leaving short-term memory intact. Tetanus and forskolin-induced activation of mitogen-activated protein kinase (MAPK) was blocked by PI-3 kinase inhibitors, which also inhibited cAMP response element binding protein (CREB) phosphorylation. These results provide novel evidence of a requirement of PI-3 kinase activation in the amygdala for synaptic plasticity and memory consolidation, and this activation may occur at a point upstream of MAPK activation.

Afferent Pathways↗
PubMed2005

Reinstatement of conditioned fear in humans is context dependent and impaired in amnesia.

A contextual reinstatement procedure was developed to assess the contributions of environmental cues and hippocampal function in the recovery of conditioned fear following extinction in humans. Experiment 1 showed context specificity in the recovery of extinguished skin conductance responses after presentations of an auditory unconditioned stimulus. Experiment 2 demonstrated that fear recovery did not generalize to an explicitly unpaired conditioned stimulus. Experiment 3 replicated the context dependency of fear recovery with a shock as an unconditioned stimulus. Two amnesic patients failed to recover fear responses following reinstatement in the same context, despite showing initial fear acquisition. These results extend the known functions of the human hippocampus and highlight the importance of environmental contexts in regulating the expression of latent fear associations.

Acoustic Stimulation↗
PubMed2002

Correlation between long latency evoked potentials from amygdala and evoked cardiac response to fear conditioned stimulus in rats.

We investigated relation between activity of central nucleus of amygdala (CE) and phasic heart rate deceleration during differential fear conditioning. We found that P2 component of long-lasting event potential (EP) to CS+ but not to CS- correlated strongly with HR deceleration in the 1st second after stimulus onset. The obtained results are discussed in the light of LeDoux's and Kapp's findings showing crucial role of amygdala in processing of emotionally relevant stimulation and it's involvement in initiating autonomic responses.

Amygdala↗
PubMed2004

Endogenous 5-HT inhibits firing activity of hippocampal CA1 pyramidal neurons during conditioned fear stress-induced freezing behavior through stimulating 5-HT1A receptors.

This study examines the activity of hippocampal CA, pyramidal neurons during conditioned fear stress (CFS)-induced freezing behavior in unanesthetized, unrestrained rats. The firing frequency of hippocampal CA1 pyramidal neurons was significantly decreased when conditioned rats exhibited freezing behavior. Firing frequency returned to the baseline after freezing behavior disappeared. The selective 5-hydroxytryptamine (5-HT)1A antagonists, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), and N-tert-butyl-3-[4-(2-methoxyphenyl)piperazine-1-yl]-2-phenylpropamide (WAY-100135) and 5-HT depletion with parachlorophenylalanine (PCPA) completely abolished the decrease in firing frequency during CFS-induced freezing behavior. These results suggested that endogenous 5-HT inhibited the firing activity of hippocampal CA1 pyramidal neurons during CFS-induced freezing behavior mainly through stimulating 5-HT1A receptors.

Animals↗
PubMed2001

Modulation of auditory neural responses by a visual context in human fear conditioning.

Responses to a stimulus signaling danger depend not only on the nature of that stimulus, but also on the context in which it is presented. A large body of work has been conducted in experimental animals investigating the neural correlates of contextual modulation of fear responses. However, much less is known about this process in humans. In this study we used functional MRI in a fear conditioning paradigm to explore this phenomenon. Responses to acoustic conditioned stimuli in auditory cortex were modulated by the presence of a visual context which signaled the likelihood of receiving an aversive unconditioned stimulus. Furthermore, the presence of the aversive visual context was associated with enhanced activity in parietal cortex, which may reflect an increase in attention to the presence of environmental threat stimuli.

Acoustic Stimulation↗
PubMed2003

High-alcohol-drinking rats exhibit persistent freezing responses to discrete cues following Pavlovian fear conditioning.

We previously reported that high-alcohol-drinking (HAD) rats exhibited selective deficits in active avoidance learning and that those deficits were partially reversed by moderate doses of ethanol under certain training conditions [Pharmacol. Biochem. Behav. 75 (2003) 89]. In that study, we hypothesized that HAD deficits resulted from exaggerated fear in the conditioning context and that the anxiolytic properties of ethanol, along with prior exposure to the conditioning apparatus, were responsible for the facilitated avoidance learning that was observed in HAD rats following moderate doses of ethanol. The current study was designed to test whether HAD rats exhibit behaviors consistent with increased fear in aversive learning contexts. We used a standard Pavlovian fear conditioning paradigm to assess behavioral freezing in HAD (HAD-1 and HAD-2) and low-alcohol-drinking (LAD; LAD-1 and LAD-2) rats. No significant differences were observed between HAD-1 and HAD-2 or between LAD-1 and LAD-2 rats, indicating that the replicate lines performed similarly in this study. Both HAD and LAD rats exhibited robust fear conditioning during training. Although no differences were observed between HAD and LAD rats during fear training, HAD rats failed to extinguish freezing behavior in response to the discrete tone conditional stimulus during subsequent fear retention tests. Thus, HAD rats demonstrated prolonged cue-elicited fear that was resistant to extinction.

Acoustic Stimulation↗
PubMed1976

Fear-dependent variations in continuous avoidance behavior of pigs. I. Lack of effect of diazepam on performance of discriminative fear conditioning.

Pigs trained to avoid shocks by crossing a barrier in a shuttle-box according to a continuous avoidance procedure were submitted to a Pavlovian discriminative fear-conditioning procedure in which a tone was always followed by unavoidable shock (CS+) and another tone never followed by shock (CS-). The presentation of the CS+ on a test session in the shuttle-box induced an increase of the response rate while the CS- decreased the performance. Diazepam (1 mg/kg) administered before the test session did not modify the changes in avoidance response to each CS.

Animals↗
PubMed1988

Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear.

The purpose of the present study was to determine whether lesions of areas projected to by the central amygdaloid nucleus (ACE) would disrupt the classical conditioning of autonomic and/or behavioral emotional responses. The areas studied included 3 projection targets of the ACE: the lateral hypothalamic area (LH), midbrain central gray (CG) region, and bed nucleus of the stria terminalis (BNST). Lesions were made either electrolytically or by microinjection of ibotenic acid, which destroys local neurons without interrupting fibers of passage. Two weeks later, the animals were classically conditioned by pairing an acoustic stimulus with footshock. The next day, conditioned changes in autonomic activity (increases in arterial pressure) and emotional behavior ("freezing," or the arrest of somatomotor activity) evoked by the acoustic conditioned stimulus (CS) were measured during extinction trials. Electrolytic and ibotenic acid lesions of the LH interfered with the conditioned arterial pressure response, but did not affect conditioned freezing. Electrolytic lesions of the rostral CG disrupted conditioned freezing but not conditioned changes in arterial pressure. Ibotenic acid injected into the rostral CG reduced neither the arterial pressure nor the freezing response. Injection of ibotenic acid in the caudal CG, like electrolytic lesions of the rostral CG, disrupted the freezing, but not the arterial pressure response. Injection of ibotenic acid into the BNST had no effect on either response. These data demonstrate that neurons in the LH are involved in the autonomic, but not the behavioral, conditioned response pathway, whereas neurons in the caudal CG are involved in the behavioral, but not the autonomic, pathway. Different efferent projections of the central amygdala thus appear to mediate the behavioral and autonomic concomitants of conditioned fear.

Amygdala↗
PubMed1990

The effects of cued UCS rehearsal on the retention of differential 'fear' conditioning: an experimental analogue of the 'worry' process.

This study describes a human electrodermal conditioning experiment in which subjects were asked to mentally rehearse the UCS in a period following initial fear conditioning and prior to a test period involving nonreinforced presentations of the CS. Subjects who were asked to rehearse the UCS retained a differential fear CR during subsequent unreinforced presentations of the CS, but control subjects who were asked to rehearse either a nonaversive event or an aversive event unrelated to the UCS failed to retain the differential CR they had acquired during conditioning. These results suggest that rehearsal of the UCS during periods when CS and UCS are absent can aid the persistence of a fear CR in the absence of further pairings of the CS and UCS. It is argued that these effects can be explained in terms of the effect of UCS rehearsal on the strength and evaluation of the UCS representation. It is also suggested that cued UCS rehearsal might provide a useful procedure for understanding clinical incubation effects and for understanding how the 'worry' process contributes to the maintenance and incubation of fear.

Adolescent↗
PubMed1993

Effect of conditioned fear stress on serotonin metabolism in the rat brain.

The effects of electric foot-shock stress (EFS) and conditioned fear stress (CFS) on serotonin [5-hydroxytryptamine (5-HT)] metabolism in seven various brain regions of the rat were studied by measuring tryptophan, 5-HT and 5-hydroxyindoleacetic acid (5-HIAA). EFS for 30 min increased tryptophan levels in almost all brain regions but did not change 5-HT levels in any regions. It increased 5-HIAA levels in the medial prefrontal cortex (mPFC), nucleus accumbens, and amygdala. CFS (exposure to an environment paired previously with foot-shock) increased defecation and induced freezing behavior. It failed to change tryptophan and 5-HT levels in any brain regions but increased 5-HIAA level only in the mPFC. In contrast to EFS, which increased 5-HT metabolism in several other brain regions, increased metabolism of 5-HT was especially marked in the mPFC after CFS, regarded as psychological stress.

Animals↗
PubMed2002

Modulation of spatial attention by fear-conditioned stimuli: an event-related fMRI study.

Stimuli that signal threat can capture subjects' attention, leading to more efficient detection of, and faster responses to, events occurring in that part of the environment. In the present study we explored the behavioural and anatomical correlates of the modulation of spatial attention by emotion using a fear conditioning paradigm, combined with a covert spatial orienting task. Reaction times for the detection of a peripheral target, which was preceded by brief (50ms) presentations of the visual conditioned stimulus (CS+) in either the same or opposite visual field, showed an interaction between stimulus emotionality and attention shifts. We used event-related functional magnetic resonance imaging (fMRI) to characterise the associated neural responses. Consistent with previous studies, conditioning-induced enhanced responses were observed in the amygdala and extrastriate visual cortex. The modulation of spatial attention by a conditioned stimulus was associated with enhanced activity in regions of frontal and parietal cortices previously implicated in spatial attention, as well as in the lateral orbitofrontal cortex (lOFC).

Amygdala↗
PubMed2004

Effects of beta-adrenoreceptor blockade during chronic exercise on contextual fear conditioning and mRNA for galanin and brain-derived neurotrophic factor.

The authors examined the effects of activity wheel running (AWR) and propranolol on contextual fear conditioning (CFC) and messenger RNA (mRNA) for galanin (GAL) in the locus coeruleus (LC) and brain-derived neurotrophic factor (BDNF) in the hippocampal formation (HF) in rats. Freezing behavior during the testing session of the CFC protocol was elevated in the AWR-placebo group compared to sedentary-placebo and AWR-propranolol groups. AWR increased GAL mRNA in the LC. CFC increased BDNF mRNA in the HF. These results suggest that exercise enhances CFC and that antagonism of the beta-adrenoreceptors attenuates this effect. The exercise-related induction of GAL gene expression in the LC may influence noradrenergic transmission to facilitate CFC.

Adrenergic beta-Antagonists↗
PubMed2003

Trace but not delay fear conditioning requires attention and the anterior cingulate cortex.

Higher cognitive functions such as attention have been difficult to model in genetically tractable organisms. In humans, attention-distracting stimuli interfere with trace but not delay conditioning, two forms of associative learning. Attention has also been correlated with activation of anterior cingulate cortex (ACC), but its functional significance is unclear. Here we show that a visual distractor interferes selectively with trace but not delay auditory fear conditioning in mice. Trace conditioning is associated with increased neuronal activity in ACC, as assayed by relative levels of c-fos expression, and is selectively impaired by lesions of this structure. The effects of the ACC lesions are unlikely to be caused by indirect impairment of the hippocampus, which is required for mnemonic aspects of trace conditioning. These data suggest that trace conditioning may be useful for studying neural substrates of attention in mice, and implicate the ACC as one such substrate.

Animals↗
PubMed1976

Simultaneous and backward fear conditioning as a function of number of CS-UCS pairings.

Four experiments examined the possibility that the outcome of simultaneous and backward fear conditioning procedures might depend upon the number of CS-UCS pairings. A punishment procedure will rats as subjects and shock as the UCS was used; the amount of suppression produced by response-contingent CS presentations indexed the strength of acquired fear. Experiments 1, 3, and 4 examined the suppressive tendencies of simultaneous-and backward-trained CSs after 0, 10, 20, 40, 80, and 160 pairings. The pattern of data suggested that initial pairings have the effect of increasing suppressive tendencies of the CS, while subsequent pairings decrease them. In addition, evidence of fear inhibition was found after 160 pairings in the case of the backward paradigm. Experiment 2 examined several nonassociative accounts based upon differential shock exposure. Groups given 10 pairings or 80 pairings were compared to ggroups given 10 pairings plus 70 shock-alone presentations. The results indicated that number of pairings, rather than number of UCS occurrences, is the important factor in decreasing the initial suppression. The evidence for eventual inhibition in the backward paradigm suggests that this occurs through the acquisition of inhibitory tendencies which are antagonistic to the previously conditioned excitation.

Animals↗