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PubMed2004

Amygdalar lateralization in fear conditioning: evidence for greater involvement of the right amygdala.

The relative contribution of left and right amygdalae in the acquisition and retention of fear conditioning was investigated in rats. Pretraining bilateral electrolytic lesions blocked the acquisition of conditioned fear to tone and context, whereas unilateral lesions induced partial impairments with no left-right amygdala differences. In contrast, posttraining bilateral and unilateral lesions produced significant deficits in the retention of conditioned fear to tone and context. Although no left-right difference was observed to tone, the right amygdala lesions generated greater deficits in contextual fear than the left amygdala lesions. These results indicate that fear conditioning is partially disrupted with unilateral amygdalar lesions, but that the right amygdala has greater involvement than the left amygdala when conditioning occurs under a normal brain state.

Amygdala↗
PubMed1996

Scopolamine administered before and after training impairs both contextual and auditory-cue fear conditioning.

When administered before training to 23-day-old Long-Evans rats, scopolamine hydrobromide significantly impaired both contextual and auditory-cue fear conditioning in a dose-dependent manner. Methylscopolamine which does not cross the blood-brain barrier, however, had no effect on either form of conditioned fear. Scopolamine administered up to 3 h after training also impaired both forms of fear conditioning when administered following a single pairing of the auditory cue and shock. When rats received three pairings, however, a posttraining treatment with scopolamine only impaired contextual fear conditioning. These results suggest that central cholinergic systems are involved in the posttrial processes that establish the memory trace for the conditioning experience.

Animals↗
PubMed1998

Differential effects of amygdala lesions on early and late plastic components of auditory cortex spike trains during fear conditioning.

In auditory fear conditioning, pairing of a neutral acoustic conditioned stimulus (CS) with an aversive unconditioned stimulus (US) results in an enhancement of neural responses to the CS in the amygdala and auditory cortex. It is not clear, however, whether cortical plasticity governs neural changes in the amygdala or vice versa, or whether learning in these two structures is determined by independent processes. We examined this issue by recording single-cell activity in the auditory cortex (areas Te1, Te1v, and Te3) of freely behaving, amygdalectomized rats using a movable bundle of microwires. Amygdala damage did not affect short-latency (0-50 msec) tone responses, nor did it interfere with conditioning-induced increases of these onset responses. In contrast, lesions of the amygdala interfered with the development of late (500-1500 msec) conditioned tone responses that were not present before conditioning. Furthermore, whereas onset conditioned responses in the control group remained elevated after 30 extinction trials (presentation of CS alone), onset responses in lesioned animals returned to their preconditioning firing level after approximately 10 extinction trials. These results suggest that the amygdala enables the development of long-latency (US anticipatory) responses and prevents the extinction of short-latency onset responses to threatening stimuli. The findings further suggest that auditory cortex cells may participate differently in explicit and implicit memory networks.

Acoustic Stimulation↗
PubMedDate not supplied

Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning.

It is well established that the amygdala plays an essential role in Pavlovian fear conditioning, with the lateral nucleus serving as the interface with sensory systems that transmit the conditioned stimulus and the central nucleus as the link with motor regions that control conditioned fear responses. The lateral nucleus connects with the central nucleus directly and by way of several other amygdala regions, including the basal, accessory basal, and medial nuclei. To determine which of these regions is necessary, and thus whether conditioning requires the direct or one of the indirect intra-amygdala pathways, we made lesions in rats of the lateral, central, basal, accessory basal, and medial nuclei, as well as combined lesions of the basal and accessory basal nuclei and of the entire amygdala. Animals subsequently underwent fear conditioning trials in which an auditory conditioned stimulus was paired with a footshock unconditioned stimulus. Animals that received lesions of the lateral or central nucleus, or of the entire amygdala, were dramatically impaired, whereas the other lesions had little effect. These findings show that only the lateral and central nuclei are necessary for the acquisition of conditioned fear response to an auditory conditioned stimulus.

Acoustic Stimulation↗
PubMed2003

Expression of conditional fear with and without awareness.

Conditional responding during simple Pavlovian conditioning is often characterized as a form of implicit memory. The extent to which this type of associative learning is independent of awareness is an issue of continuing debate. Previous studies have demonstrated conditioning in the absence of awareness. However, their results have been questioned based on methodological concerns with postexperimental questionnaires. In the present study, skin conductance response (SCR) and unconditioned stimulus (UCS) expectancy were measured concurrently as participants were exposed to a differential delay fear conditioning procedure in which one tone (CS+) predicted a loud white noise, whereas a second tone (CS-) was presented alone. UCS predictability was varied on a trial-by-trial basis by presenting conditioned stimuli (CSs) at volumes just above or below the perceptual threshold. Differential UCS expectancy (awareness) was observed only on perceived trials, whereas differential SCR developed on both perceived and unperceived trials. Although perceived stimuli elicited larger SCRs, the magnitude of conditioning, indexed by differential conditioned response expression (conditioned SCR to CS+ minus the SCR to CS-), was not influenced by stimulus perception. These data indicate that conditional fear can be expressed when individuals are unaware of fear-eliciting stimuli and suggest that the degree of conditioning is independent of awareness during differential Pavlovian fear conditioning.

Adult↗
PubMed2006

Dissociable effects of hippocampus lesions on expression of fear and trace fear conditioning memories in rats.

The role of the hippocampus in memory is commonly investigated by comparing fear conditioning paradigms that differ in their reliance on the hippocampus. For example, the dorsal (septal) portion of the hippocampus is involved in trace, but not delay fear conditioning, two Pavlovian paradigms in which only the relative timing of stimulus presentation is varied. However, a growing literature implicates the ventral (temporal) portion of the hippocampus in the expression of fear, irrespective of prior training. The current experiments evaluated the relative contributions of the dorsal and ventral portions of the hippocampus to trace fear conditioning specifically vs. the expression of conditioned fear in general. Lesions restricted to the dorsal hippocampus blocked acquisition of trace fear conditioning. Larger lesions, also including an adjacent portion of the ventral hippocampus, were required to impair retrieval of trace fear conditioning. Delay fear conditioning was not disrupted in either case. In contrast, lesions that encompassed almost the entire dorsal and ventral hippocampus disrupted expression of both trace and delay fear conditioning. The current data suggest distinct roles in fear conditioning for three regions of the hippocampus: the septal zone is required for acquisition of trace fear conditioning, a larger portion of the hippocampus is critical for memory retrieval, and a region including the temporal zone is required for expression of both trace and delay fear conditioning. These findings are consistent with evidence suggesting the neuroanatomical and functional segregation of the hippocampus into three zones along its septal-temporal axis.

Acoustic Stimulation↗
PubMed2003

Significance of dopamine transmission in the rat medial prefrontal cortex for conditioned fear.

Previous studies have demonstrated activation of dopamine transmission in the medial prefrontal cortex (mPFC) by conditioned fear stimuli. Therefore, the present study investigated the functional significance of mPFC dopamine for a conditioned fear response to a tone. We examined the effects of inhibition or stimulation of mPFC dopamine transmission by local microinfusion of the D1/D2-receptor antagonist cis-flupenthixol or the indirect dopamine receptor agonist D-amphetamine, respectively, in a classical fear-conditioning paradigm in Wistar rats. Rats received tone-shock pairings and were later exposed to the tone alone. Freezing was used as measure of conditioned fear. Presence of the drugs in the mPFC during the tone-shock pairings did not affect freezing during subsequent presentation of the tone alone. However, when cis-flupenthixol and D-amphetamine were present in the mPFC during presentation of the tone alone, freezing to the tone was reduced. We demonstrated that the decreased freezing could be explained neither by state dependency nor infusion-induced alterations in activity. Our data indicate that mPFC dopamine transmission is important for the retrieval/expression, but not the formation, of conditioned fear. The reduction of conditioned fear by prefrontal infusion of both cis-flupenthixol and D-amphetamine may reflect normal expression of conditioned fear requires an optimal level of mPFC dopamine activity.

Animals↗
PubMed1999

Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations.

Previous findings have demonstrated that systemic dopaminergic manipulations impair the retrieval of Pavlovian conditioned fear. A second-order fear-conditioning paradigm was used to test whether the dopaminergic projection from the ventral tegmental area (VTA) to the lateral and basal amygdala (LBA) can affect conditioned fear. Phase 1 entailed conditioned stimulus-unconditioned stimulus (CS1-US) pairings. In Phase 2, drugs were infused in either the LBA or VTA prior to pairings of CS2 (a second cue) with CS1. In Phase 3, freezing behavior elicited by CS2 was tested without drugs. Infusions of the D2 agonist quinpirole into the VTA or of the D1 antagonist SCH 23390 into the LBA caused a decrease in freezing to CS2. Both manipulations decrease D1 receptor activation in the LBA. Infusions of the D1 agonist SKF 38393 into the LBA had no effect. This pattern of results is consistent with the hypothesis that the VTA-LBA dopaminergic projection modulates the retrieval of an association between a CS and footshock US.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

The amygdala and individual differences in human fear conditioning.

While animal research on fear conditioning suggests crucial involvement of the amygdala, this has not been corroborated in humans when using subtractive neuroimaging methodology. Correlation analyses might be more able to reveal relations between individual differences in conditionability and central neural activity. Hence, we performed a directed search for amygdalar participation in human fear conditioning by correlating central and autonomic nervous activity. [15O]Butanol positron emission tomography evaluated regional cerebral blood flow (rCBF) in six subjects before and after aversive conditioning to visual snake stimuli. Non-specific electrodermal fluctuations (EDA) were recorded simultaneously. A significant positive correlation was obtained between conditioned EDA and conditioned rCBF in the right amygdala (r = 0.75, p < 0.05), supporting involvement of the amygdala in human fear conditioning.

Adult↗
PubMed2000

Effects of TRH on acoustic startle, conditioned fear and active avoidance in rats.

The effects of intracerebroventricular injection of thyrotropine-releasing hormone (TRH) on acoustic startle, conditioned fear and active avoidance were examined in rats. Acoustic startle was significantly depressed by 12.5 microg TRH, while increasing motor activity. In a fear-potentiated startle paradigm, 12.5 microg TRH reduced the overall startle response amplitude, but did not decrease the amount of fear-potentiated startle. When TRH was administered 15 min before contextual fear conditioning, neither fear-related freezing in acquisition nor in a retention test was affected. In contrast, when TRH was administered 15 min before the retention test, TRH significantly reduced mean percentage of time spent freezing. TRH had no effect on active avoidance. The results demonstrate that TRH decreased acoustic startle and freezing responses, but had little effect on fear conditioning and active avoidance. It is suggested that the results may be due to TRH's effects on motor activity and arousal, independent of its effects on fear.

Acoustic Stimulation↗
PubMed1999

Vasopressin in the lateral septum promotes elemental conditioning to the detriment of contextual fear conditioning in mice.

Previous experiments using a classical fear conditioning paradigm have provided evidence that the processing of contextual conditional stimuli (CSs) by the hippocampus would be controlled by the amygdala through a modulation of hippocampal-lateral septal (H-LS) excitability. More specifically, our suggestion was that vasopressin release into the LS would occur in an elemental conditioning case [pairing CS-US (unconditional stimulus) procedure] and would result in less hippocampal-dependent contextual stimuli processing (i.e. overshadowing of CSs by the simple CS). Conversely, when an unpairing CS-US procedure is used, this would result in more contextual stimuli processing through a decrease in vasopressin release into the LS. The aim of the present experiment was to test this hypothesis using intraseptal injection of vasopressin or its V1/V2 antagonist. In agreement with this hypothesis, results suggest that vasopressin release into the LS would constitute a device by which priority is given to the more salient simple stimulus to the detriment of contextual information.

Acoustic Stimulation↗
PubMed1997

Conditioned fear to context is associated with increased Fos expression in the caudal ventrolateral region of the midbrain periaqueductal gray.

Immunohistochemical detection of Fos was used to determine which regions of the periaqueductal gray are activated during conditioned fear to a context in the rat. More specifically, the aim of the study was to test the role of its lateral and ventrolateral columns in freezing behaviour during fear. Conditioned fear was evoked by re-exposing rats to the same footshock chamber in which they had received footshocks 4 h earlier. Conditioned Re-exposed rats were compared to Not Conditioned Re-exposed and Conditioned Not Re-exposed rats. Freezing was observed in the Conditioned-Re-exposed group only. It was associated with an overall increase in Fos expression in the entire periaqueductal gray that was significantly greater than in the two other groups. The largest and most significant increase in Fos immunoreactivity was found in the ventrolateral column (especially in its caudal part), whereas only a moderate increase was found in the lateral column. The present results argue in favour of the ventrolateral column as the region of the periaqueductal gray that is preferentially involved in expression of conditioned fear. As previous lesion studies suggested, the ventrolateral periaqueductal gray may play a role in mediating the immobility component of freezing induced by fear. Other lines of evidence suggest that it may also play a role in mediating the quiescence immobility associated with deep pain. We propose that the ventrolateral column of the periaqueductal gray acts as an integrating centre mediating behavioural inhibition.

Animals↗
PubMed2006

beta2 subunit-containing nicotinic receptors mediate the enhancing effect of nicotine on trace cued fear conditioning in C57BL/6 mice.

RATIONALE: Previous research indicates that acute nicotine administration enhances the acquisition of contextual fear conditioning and trace cued fear conditioning. Pharmacological inhibition of alpha4beta2 nicotinic acetylcholine receptors (nAChRs), but not alpha7 nAChRs, blocked the enhancing effect of nicotine on contextual fear conditioning. Similarly, genetic deletion of the beta2 nAChR subunit but not the alpha7 nAChR subunit blocked the enhancing effect of nicotine on contextual fear conditioning. OBJECTIVES: In the present study, nAChR subunit knockout mice were used to compare the involvement of beta2 subunit-containing nAChRs and alpha7 subunit-containing nAChRs in the effects of nicotine on hippocampus-dependent trace cued fear conditioning and contextual fear conditioning. METHODS: beta2 nAChR subunit knockout mice, alpha7 nAChR subunit knockout mice, and their wild-type littermates received either nicotine or saline 5 minutes before training and testing. Mice were trained using five conditioned stimulus (CS; 30 s, 85 dB white noise)--trace (30 s)--unconditioned stimulus (US; 2 s footshock) pairings. Freezing to the context and freezing to the CS were assessed 24 h later. RESULTS: Both contextual and trace cued fear conditioning were enhanced by nicotine administration in wild-type littermates and in alpha7 nAChR subunit knockout mice. In contrast, neither contextual fear conditioning nor trace cued fear conditioning was enhanced by nicotine administration in beta2 nAChR subunit knockout mice. CONCLUSIONS: These results suggest that beta2 subunit-containing nAChRs but not alpha7 nAChR subunit-containing nAChRs are critically involved in the enhancing effect of nicotine on contextual and trace cued fear conditioning.

Acoustic Stimulation↗
PubMed2006

Neurotoxic lesions centered on the perifornical hypothalamus abolish the cardiovascular and behavioral responses of conditioned fear to context but not of restraint.

The aim of this study was to test the role of the perifornical hypothalamus and adjacent areas in the behavioral and cardiovascular responses to two forms of stress, conditioned fear to context and restraint. Of particular interest was the role of the hypocretin (orexin) containing neurons in these responses. Rats implanted with radio-telemetric probes and fear conditioned to a context received bilateral injections of the neurotoxin hypocretin-2-saporin centered on the perifornical area. One week later, the animals were tested for conditioned fear to context and restraint while recording freezing, 22 kHz ultrasonic vocalizations, activity, mean arterial pressure and heart rate. Histological verification revealed that the lesions were not specific since virtually all the neurons within the injection area were lost. Nevertheless, these lesions, which were centered on the perifornical area, markedly reduced all recorded components of the contextual fear response (by 70%) but had no effect on the response to restraint. The lesions also caused a reduction in body weight and reduced the circadian rhythm of the recorded parameters. The results show (i) that hypocretin-2-saporin was not specific enough to produce lesions restricted to the hypocretin system, (ii) that neurons of the perifornical area are necessary for the expression of both the cardiovascular and behavioral components of conditioned fear to context, and (iii) that the same neurons are not necessary for the cardiovascular response to restraint. Thus, the perifornical hypothalamus is critical for some forms of stress but not others. We propose that it is a necessary relay for emotional responses in which the psychological component is stronger than the sensory component.

Animals↗
PubMed2006

5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala.

Evidence from preclinical and clinical studies has shown that 5-HT(1A) receptor agonists have anxiolytic actions. The anxiolytic actions of 5-HT(1A) receptor agonists have been tested by our previous studies using fear conditioning. However, little is known about the brain regions of anxiolytic actions of 5-HT(1A) receptor agonists in this paradigm. In the present study, we investigated the effects of bilateral microinjections of flesinoxan, a selective 5-HT(1A) receptor agonist, into the hippocampus, amygdala and medial prefrontal cortex on the expression of contextual conditioned freezing and the defecation induced by conditioned fear stress in rats. These results reveal that both intrahippocampal and intraamygdala injections of flesinoxan decreased the expression of conditioned freezing, while injections into the medial prefrontal cortex did not. In addition, intraamygdala injection of flesinoxan attenuated the increased defecation induced by conditioned fear, but injections into the hippocampus and medial prefrontal cortex failed. These results suggest that flesinoxan exerts its anxiolytic actions in the fear conditioning through stimulations of the postsynaptic 5-HT(1A) receptors in the hippocampus and amygdala.

Amygdala↗
PubMed1998

Basolateral amygdala is not critical for cognitive memory of contextual fear conditioning.

Evidence that lesions of the basolateral amygdala complex (BLC) impair memory for fear conditioning in rats, measured by lack of "freezing" behavior in the presence of cues previously paired with footshocks, has suggested that the BLC may be a critical locus for the memory of fear conditioning. However, evidence that BLC lesions may impair unlearned as well as conditioned freezing makes it difficult to interpret the findings of studies assessing conditioned fear with freezing. The present study investigated whether such lesions prevent the expression of several measures of memory for contextual fear conditioning in addition to freezing. On day 1, rats with sham lesions or BLC lesions explored a Y maze. The BLC-lesioned rats (BLC rats) displayed a greater exploratory activity. On day 2, each of the rats was placed in the "shock" arm of the maze, and all of the sham and half of the BLC rats received footshocks. A 24-hr retention test assessed the freezing, time spent per arm, entries per arm, and initial entry into the shock arm. As previously reported, shocked BLC rats displayed little freezing. However, the other measures indicated that the shocked BLC rats remembered the fear conditioning. They entered less readily and less often and spent less time in the shock arm than did the control nonshocked BLC rats. Compared with the sham rats, the shocked BLC rats entered more quickly and more often and spent more time in the shock arm. These findings indicate that an intact BLC is not essential for the formation and expression of long-term cognitive/explicit memory of contextual fear conditioning.

Amygdala↗
PubMed2000

Contextual fear conditioning and baseline startle responses in the rat fear-potentiated startle test: a comparison of benzodiazepine/gamma-aminobutyric acid-A receptor agonists.

In the rat, fear-potentiated startle (FPS) test animals are first trained to associate brief light presentations with a mild electric footshock and then tested for startle responses to acoustic stimuli, delivered either in darkness (i.e. baseline startle) or after the conditioning stimulus. Following light presentation the magnitude of the startle response is markedly increased, and the test is commonly used to distinguish anxiolytic drug effects (i.e. a reduction in FPS) from non-specific effects such as sedation/muscle relaxation. However, recent studies suggest that the environment in which the animal is trained may also contribute towards the acquisition of a conditioned fear response (i.e. contextual fear conditioning) and that this may elevate startle responses recorded in the dark. In the present study, therefore, we have compared the benzodiazepine/gamma-aminobutyric acid-A receptor agonist chlordiazepoxide with the partial agonists FG 8205 and bretazenil, which are known to have a reduced propensity to produce sedation/myorelaxation, using two different FPS procedures: (i) conditioning and testing in stabilimeter chambers, and (ii) conditioning and testing in different environments. The results show that FPS can be demonstrated in both procedures and that treatment with chlordiazepoxide, FG 8205 or bretazenil dose-dependently attenuates the response. However, animals conditioned and tested in stabilimeter chambers also showed a significant increase in dark-startle amplitudes compared with non-shocked rats, suggesting that this response was elevated by contextual fear conditioning. Furthermore, despite clear differences in side-effect liabilities, FG 8205 and bretazenil significantly reduced dark-startle responses, suggesting that this measure is also sensitive to the anxiolytic effects of benzodiazepines. In contrast, when animals were conditioned and tested in different environments, dark-startle responses were not significantly different from those recorded in non-shocked rats and treatment with FG 8205 or bretazenil had no effect. Thus, conditioning and testing animals in different environments may provide a more effective means of distinguishing anxiolytic from non-specific drug effects in the rat FPS test.

Animals↗
PubMed2005

Stress differentially modulates fear conditioning in healthy men and women.

BACKGROUND: Stress and stress hormones modulate emotional learning in rats and might have similar effects in humans. Theoretic accounts of posttraumatic stress disorder (PTSD), for example, implicate the stress-induced modulation of fear conditioning in the development of intrusive emotional reactions. The present study examined the impact of acute stress and cortisol (CORT) on classically conditioned fear in men and women. METHODS: Ninety-four healthy undergraduates were exposed to a mild stressor (or control condition) while subjective anxiety and glucocorticoid stress responses (salivary CORT) were measured. One hour later, all participants participated in a differential fear conditioning procedure while conditioned skin conductance responses (SCR) were recorded. RESULTS: Exposure to the stressor increased subjective anxiety and elevated CORT levels. In men, stress exposure facilitated fear conditioning; whereas in women, stress appeared to inhibit fear conditioning. The impact of stress on differential conditioning in men was associated with increased CORT levels. CONCLUSIONS: Consistent with animal models, these results demonstrate that stress exposure can modulate classical conditioning in humans, possibly via hormonal mechanisms. The enhancing effects of stress on the formation of conditioned fear might provide a useful model for the formation of pathological emotional reactions, such as those found in PTSD.

Adolescent↗