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PubMed2004

Nonassociative learning processes determine expression and extinction of conditioned fear in mice.

Freezing to a tone following auditory fear conditioning is commonly considered as a measure of the strength of the tone-shock association. The decrease in freezing on repeated nonreinforced tone presentation following conditioning, in turn, is attributed to the formation of an inhibitory association between tone and shock that leads to a suppression of the expression of fear. This study challenges these concepts for auditory fear conditioning in mice. We show that acquisition of conditioned fear by a few tone-shock pairings is accompanied by a nonassociative sensitization process. As a consequence, the freezing response of conditioned mice seems to be determined by both associative and nonassociative memory components. Our data suggest that the intensity of freezing as a function of footshock intensity is primarily determined by the nonassociative component, whereas the associative component is more or less categorical. We next demonstrate that the decrease in freezing on repeated nonreinforced tone presentation following conditioning shows fundamental properties of habituation. Thus, it might be regarded as a habituation-like process, which abolishes the influence of sensitization on the freezing response to the tone without affecting the expression of the associative memory component. Taken together, this study merges the dual-process theory of habituation with the concept of classical fear conditioning and demonstrates that sensitization and habituation as two nonassociative learning processes may critically determine the expression of conditioned fear in mice.

Acoustic Stimulation↗
PubMed2003

Fine scale mapping of a genetic locus for conditioned fear.

Fear conditioning is one of a number of models for investigating the genetic basis of individual variation in emotion and learning. Genetic mapping using crosses between strains of laboratory mice has identified a locus on chromosome one that appears to influence not only variation in conditioned fear, but also in other validated tests of fear-related behaviour, (including the open-field and the elevated-plus maze), suggesting that the rodent locus may act in ways consistent with how a locus influencing susceptibility to anxiety in humans is believed to operate. Here we use high-resolution mapping in genetically heterogeneous mice to show that a quantitative trait locus influencing conditioned fear can be separated from loci influencing open-field activity. Mapping in two different heterogeneous stocks, the Boulder and Northport HS, gave similar map locations for open-field activity at two positions on the current mouse physical map, one at 162 Mb on chromosome one (negative log P-value 5.4) the other at 173 Mb (negative log P-value 4.8), while mapping of contextual conditioned fear in the Boulder HS identified a locus at 170 Mb (negative log P-value 5.4). Estimates of the 95% confidence intervals show that the locations do not overlap. The region containing a gene or genes that influence variation in conditioned fear is approximately 1 megabase in size and contains only one gene of known function, a pre-B cell leukaemia factor.

Animals↗
PubMed1996

Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: absence of a temporal gradient.

The role of the basolateral amygdala (LA) in the acquisition and expression of Pavlovian fear conditioning was examined in 80 rats. Excitotoxic lesions were made in the BLA using N-methyl-D-aspartate 7 days before or 1, 14, or 28 days after Pavlovian fear conditioning. Conditioning consisted of three pairings of a tone with an aversive footshock in a novel chamber, and freezing behavior served as an index of conditional fear. BLA lesions abolished conditional freezing to both the contextual and acoustic conditional stimuli at all training-to-lesion intervals, and the magnitude of the impairment did not vary as a function of the training-to-lesion interval. Reacquisition training elevated levels of freezing in rats with BLA lesions but did not reduce the magnitude of their deficit in relation to that of controls. These results reveal that neurons in the BLA have an enduring role in the expression of conditional fear.

Amygdala↗
PubMed2000

Behavioral and neuropsychological foundations of olfactory fear conditioning.

Pavlovian fear conditioning procedures have been a fruitful means of exploring the neural substrates of associative learning. There is now substantial evidence suggesting that many aspects of conditioned fear depend critically upon the integrity of the amygdala and the perirhinal cortex. Recent studies in our laboratory examining the contributions of these areas to olfactory and contextual fear conditioning are reviewed; collectively the results of these studies suggest that the amygdala participates critically in the acquisition and expression of fear conditioned to both an olfactory conditioned stimulus (CS) and to the training context, while the perirhinal cortex contributes to olfactory, but not contextual, fear conditioning. Moreover, it appears that perirhinal cortex may play a prominent role in recognition of the CS following conditioning. These results are discussed in light of the extent to which they replicate and extend previous research examining the contributions of these areas to fear conditioned to auditory and visual CSs.

Animals↗
PubMed2004

Effect of mediodorsal thalamic nucleus lesion on contextual fear conditioning in rats.

Much evidence from animal and clinical studies has shown that the mediodorsal nucleus of the thalamus (MD) is related to various types of memory, such as visual recognition, object-reward association, spatial working, and reference memory; however, few studies have investigated its role in emotion-related learning and memory processes. This study compared the effect of pre- and posttraining bilateral lesions of the mediodorsal thalamic nucleus with those of the amygdala on contextual conditioned fear. Both pre- and posttraining amygdala lesions almost eliminated conditioned freezing, and significantly blocked postshock freezing when behavioral tests were performed immediately after footshocks, reconfirming previous studies that the amygdala is implicated in the learning of Pavlovian conditioning. Both pre- and posttraining lesions of the mediodorsal nucleus of the thalamus significantly attenuated conditioned freezing but had no effect on postshock freezing. In contrast to lesions of the amygdala, those of the mediodorsal thalamic nucleus failed to alter the increased defecation induced by conditioned fear stress. Our results suggest that the mediodorsal nucleus of the thalamus has an important role in acquisition, consolidation or retrieval in Pavlovian contextual fear conditioning. Possible neural circuits, incorporating the amygdala, MD, and hippocampus, and the functional similarity of the MD and hippocampus in contextual fear conditioning, are also discussed.

Amygdala↗
PubMed1997

Different types of fear-conditioned behaviour mediated by separate nuclei within amygdala.

The amygdala has long been thought to be involved in emotional behaviour, and its role in anxiety and conditioned fear has been highlighted. Individual amygdaloid nuclei have been shown to project to various cortical and subcortical regions implicated in affective processing. Here we show that some of these nuclei have separate roles in distinct mechanisms underlying conditioned fear responses. Rats with lesions of the central nucleus exhibited reduction in the suppression of behaviour elicited by a conditioned fear stimulus, but were simultaneously able to direct their actions to avoid further presentations of this aversive stimulus. In contrast, animals with lesions of the basolateral amygdala were unable to avoid the conditioned aversive stimulus by their choice behaviour, but exhibited normal conditioned suppression to this stimulus. This double dissociation demonstrates that distinct neural systems involving separate amygdaloid nuclei mediate different types of conditioned fear behaviour. We suggest that theories of amygdala function should take into account the roles of discrete amygdala subsystems in controlling different components of integrated emotional responses.

Amygdala↗
PubMed2001

Adenosine A1 receptor activation selectively impairs the acquisition of contextual fear conditioning in rats.

Three experiments were conducted to examine the importance of adenosine A1 receptors for the acquisition and expression of hippocampal-dependent and hippocampal-independent forms of conditioned fear. In Experiment 1, the selective adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA), or saline was administered intraperitoneally to male rats 30 min prior to Pavlovian fear conditioning, which consisted of 7 tone-shock pairings. Adenosine A1 receptor activation dose-dependently and selectively disrupted the acquisition of contextual fear conditioning while sparing tone-shock associations. Experiments 2 and 3 demonstrated that CPA's selective disruption of contextual learning could not be attributed to context being weaker than tone conditioning or to state-dependent learning. Adenosine A1 receptor activation also impaired the expression of both context- and tone-elicited fear. These results suggest that endogenous adenosine modulates the acquisition and expression of emotional (fear) memories by acting on A1 receptors in brain regions underlying fear conditioning.

Animals↗
PubMed1999

The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat.

The mesoprefrontal dopamine neurons are sensitive to physical, pharmacological and psychological stressors. In this report, the role of these neurons in the response to classical fear conditioning was investigated. 6-Hydroxydopamine lesions to the medial prefrontal cortex reduced dopamine levels to about 13% of controls but did not alter behavior during the acquisition of fear conditioning. As expected, conditioned fear increased dopamine metabolism (3,4-dihydroxyphenylacetic acid/dopamine ratio) in the nucleus accumbens in sham-lesion rats. The medial prefrontal 6-hydroxydopamine lesions did not alter this effect. During the expression, however, lesioned rats demonstrated a delayed extinction of the conditioned response without an overall increase in the initial conditioned response. This effect was consistent in rats receiving 6-hydroxydopamine lesions before or after the acquisition period. The calculated rates of extinction showed that the 6-hydroxydopamine lesioned rats had a reduced rate of extinction, but not acquisition, of fear conditioning. The results presented in this manuscript indicate that the mesoprefrontal dopamine neurons are involved in co-ordinating the normal extinction of a fear response but do not alter the acquisition of fearful behaviors. These data are consistent with the conclusion that the mesoprefrontal dopamine neurons are involved in maintaining the animal's response adaptability with regards to stress-related changes in the external environment.

Adrenergic Agents↗
PubMed2000

Lidocaine blockade of amygdala output in fear-conditioned rats reduces Fos expression in the ventrolateral periaqueductal gray.

We showed recently that conditioned fear to context induces Fos expression in the ventrolateral periaqueductal gray [Neuroscience (1997) 78, 165-177]. Neurons in this region are thought to play an important role in the expression of freezing during conditioned fear. To test the possibility that this activation comes directly from the amygdala, we looked at changes in Fos expression after a unilateral blockade of the ventral amygdalofugal pathway with lidocaine. The pathway contains fibres originating from the central nucleus of the amygdala that project directly and mainly ipsilaterally to the ventrolateral periaqueductal gray. Conditioned fear was evoked by re-exposing rats to the same box in which they had previously received electric footshocks. The test re-exposure was preceded by a unilateral microinjection of lidocaine (2%, 0.5-1 microl; n = 20) or saline (n = 14). Lidocaine was also tested in non-conditioned animals (n = 13). The results show that, when lidocaine was microinjected in the medial part of the central nucleus of the amygdala or along the ventral amygdalofugal pathway of conditioned rats, fear-induced Fos expression in the ventrolateral periaqueductal gray was reduced on the side ipsilateral to the injection (up to 37% reduction in comparison to the contralateral side). Ipsilateral reductions were also observed with saline, but they were weaker (maximum of 27% reduction). Fos expression remained low on both sides in the non-fear-conditioned animals injected with lidocaine. Finally, although freezing was only partly reduced in the conditioned animals unilaterally injected with lidocaine, it was significantly correlated to the ipsilateral reduction in Fos expression. This study provides direct evidence that the projection from the central nucleus of the amygdala to the ventrolateral periaqueductal gray is activated during fear and that it contributes to the Fos response of the ventrolateral periaqueductal gray.

Amygdala↗
PubMed2000

Acquisition, extinction, and reinstatement of Pavlovian fear conditioning: the roles of the NMDA receptor and nitric oxide.

The acquisition and extinction of Pavlovian conditioned fear have been shown to be mediated by the N-methyl-D-aspartate (NMDA) glutamate receptor. This study found that the NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801) blocked the reinstatement of Pavlovian conditioned fear in rats. The role of nitric oxide (NO) in the acquisition and extinction of Pavlovian fear conditioning was also examined. L-NAME, an NO synthase inhibitor, failed to block the acquisition or extinction of Pavlovian fear conditioning. The results are discussed in the context of hierarchical associations and the array of NMDA and calcium mediated mechanisms of synaptic strengthening.

Animals↗
PubMed1995

Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats.

The emotional reactivity of rats with lesions of the dorsal portion of medial prefrontal cortex (mPFC) was examined using a classical fear conditioning paradigm. Conditioned fear behavior (freezing responses) was measured during both the acquisition and extinction phases of the task. Lesions enhanced fear reactivity to both the conditioned stimulus (CS) and contextual stimuli during both phases, suggesting that dorsal mPFC lesions produce a general increase in fear reactivity in response to fear conditioning. M. A. Morgan, L. M. Romanski, and J. E. LeDoux (1993) found that lesions just ventral to the present lesions had no effect during acquisition of the same task and prolonged the fear response to the CS (but not the context) during extinction. Thus, both dorsal and ventral regions of mPFC are involved in the fear system, but each modulates different aspects of fear responsivity.

Animals↗
PubMed1995

Disruptive effects of posttraining perirhinal cortex lesions on conditioned fear: contributions of contextual cues.

Lesions placed in the rostral perirhinal cortex (rPRh) after fear conditioning interfere with the expression of conditioned fear responses elicited by auditory and visual conditioned stimuli when these stimuli are presented in a context that differs from the conditioning context. The present study examined whether lesions of the rPRh have similar effects when animals are tested in the conditioning context. Two days after male rats received classical fear conditioning, involving the pairing of an auditory conditioned stimulus (CS) with footshock, bilateral electrolytic lesions were produced in the rPRh. Five days later conditioned freezing behavior was measured during a 60-s exposure to the CS in a novel context and then 1 hr later in the conditioning context. There were 3 major findings. First, rPRh-lesioned animals froze significantly less than controls to the CS in the novel context, thus confirming previously reported findings. Second, rPRh-lesioned animals also froze less than controls to the CS in the conditioning context, but froze significantly more to the CS in the conditioning than in the novel context, suggesting that at least part of the deficit in the novel context is due to the absence of contextual cues. Third, animals with rPRh lesions froze significantly less than controls to the conditioning context itself. This latter finding suggests that rPRh lesions interfere with contextual processing and that the improvement of performance in the conditioning context might have been even greater had lesioned animals been able to fully process contextual cues.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1999

Amygdaloid D1 dopamine receptor involvement in Pavlovian fear conditioning.

The amygdala has long been implicated in conditioned fear. The mesencephalic dopaminergic system provides a rich innervation to the amygdala [J.H. Fallon, P. Ciofi, Distribution of monoamines within the amygdala, in: J.P. Aggleton (Ed.), The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction, Wiley, New York, 1992, pp. 97-114; L.J. Freedman, M.D. Cassell, Distribution of dopaminergic fibers in the central division of the extended amygdala of the rat. Brain Research 633 (1994) 243-252; E. Asan, The catecholaminergic innervation of the rat amygdala. Advances in Anatomy Embryology and Cell Biology 142 (1996) 1-107]. Specific activation of the mesoamygdaloid dopaminergic system has been reported to occur in response to conditioned fear-arousing stimuli [M.L. Coco, C.M. Kuhn, T.D. Ely, C.D. Kilts, Selective activation of mesoamygdaloid dopamine neurons by conditioned stress: attenuation by diazepam. Brain Research 590 (1992) 39-47] suggesting that dopamine release in the amygdala may contribute to the acquisition and/or expression of conditioned fear. Using a 2x2 factorial design, Experiment 1A investigated the effects of bilateral intra-amygdaloid infusions of the selective D1 receptor antagonist, SCH 23390 (2.0 microgram 0.5 microliter-1 side-1), on the acquisition and expression of Pavlovian conditioned fear measured by freezing to acoustic and background contextual stimuli. Infusions of SCH 23390 prior to acquisition training, prior to retention testing or prior to both significantly attenuated conditioned freezing during retention testing. Experiment 1B investigated the dose-dependent effects of pre-training infusions of SCH 23390 (0.5, 1.0 and 2.0 microgram) on conditioned fear. Pre-training infusions of SCH 23390 dose-dependently attenuated conditioned freezing during retention testing. Experiment 2A investigated the effects of bilateral infusions of the selective D1 receptor agonist, SKF 82958 (2.0 microgram 0.5 microliter-1 side-1) on the acquisition and expression of conditioned fear. Infusions of SKF 82958 prior to training facilitated conditioned freezing during retention testing. Experiment 2B investigated the dose-dependent effects of pre-training infusions of SKF 82958 (1.0, 2.0 and 4.0 microgram) on conditioned fear. Pre-training infusions of SKF 82958 dose-dependently facilitated conditioned freezing during retention testing. In conclusion, these results suggest that dopamine transmission within the amygdala contributes to the acquisition and expression of Pavlovian fear conditioning.

Amygdala↗
PubMed1999

Neurotoxic basolateral amygdala lesions impair learning and memory but not the performance of conditional fear in rats.

We examined the influence of extensive overtraining (75 trials) on the impact of neurotoxic basolateral amygdala (BLA) lesions on Pavlovian fear conditioning in rats. As we have shown previously, pretraining BLA lesions yielded severe deficits in the acquisition of conditional freezing in rats trained with either 1 or 25 conditioning trials. However, extensive overtraining (50 or 75 trials) mitigated deficits in conditional freezing. Under these conditions the rats with BLA lesions expressed normal and robust freezing behavior, although they required at least 10 times as much training as control rats to reach this level of performance. The ability of rats with BLA lesions to acquire and express conditional freezing after extensive overtraining was modality-specific; conditional freezing in individual rats was acquired to contextual, but not acoustic, conditional stimuli. These results suggest that neural circuitry outside of the amygdala can mediate contextual fear conditioning under some conditions. In contrast to pretraining lesions, post-training BLA lesions eradicated the memory for Pavlovian fear in rats trained with either 1 or 75 trials; this deficit was not modality-specific. Together, these results reveal that impairments in the acquisition and expression of conditional fear in rats with BLA lesions are not attributable to deficits in the performance of the freezing response but are attributable to disruptions in the learning and memory of Pavlovian fear conditioning.

Acoustic Stimulation↗
PubMed1994

Effects of muscimol applied to the basolateral amygdala on acquisition and expression of contextual fear conditioning in rats.

The amygdala is known to be important for normal aversive Pavlovian learning in the rat. The relative contribution of the amygdala to the learning vs. performance of conditional fear with the GABAa agonist muscimol was assessed. Rats were prepared with cannulas aimed at the basolateral amygdala and trained in a contextual fear conditioning paradigm in which each subject received a series of footshocks in a distinctive observation chamber. Conditional responses evoked after exposure to the observation chamber were assessed 24 hr later. Rats that were pretreated with muscimol before performance showed a significantly attenuated fear response, and injections made before acquisition resulted in a much smaller decrement in conditional fear measured 24 hr after training. These results indicate that acquisition-related processes that may be occurring within the amygdala are more difficult to disrupt than those associated with performance.

Amygdala↗
PubMed2004

Repeated low level formaldehyde exposure produces enhanced fear conditioning to odor in male, but not female, rats.

Multiple chemical sensitivity (MCS) is an ill-defined disorder in humans attributed to exposure to volatile organic compounds. This study draws on apparent parallels between individuals with posttraumatic stress disorder (PTSD) and panic disorder and a subset of those reporting MCS, using a conditioned fear task in rats. Male and female Sprague-Dawley rats were given repeated exposure to 2 ppm formaldehyde (Form) (1 h/day x 5 days/week x 4 week) or air, and after 2-3 weeks, rats were trained on the conditioned fear task. One half of Air and Form rats were given odor (orange oil, the conditioned stimulus, CS) paired with footshock (PRD) and the other half was given the same stimuli in an unpaired manner (UNP). After 24 h, rats were placed into the same context without the CS or footshock. Male and female PRD groups demonstrated contextual freezing 5-15% of the time, while the UNP groups showed freezing 30-50% of the time, with no effect of Air or Form pretreatment. For the next 5 days, rats were placed into a novel context and tested for freezing in the absence or presence of the CS. In male rats, Form pretreatment produced a significantly greater freezing response in both UNP and PRD groups in the presence of the CS, with no differences in freezing in the absence of the CS. In female rats, no significant differences between Form pretreated rats and Air controls were observed in either the PRD or UNP groups. The increase in conditioned fear responding to the CS after Form exposure in males suggests that repeated low-level Form may act as a stressor to produce sensitized responding within olfactory/limbic pathways, and may help explain the panic-like responses observed in a subset of individuals reporting MCS. Furthermore, the male/female differences suggest a gonadal hormonal contribution to this behavior.

Analysis of Variance↗
PubMed2005

REM sleep: a sensitive index of fear conditioning in rats.

To examine the influence of conditioned fear stimuli on sleep-wake states, we recorded sleep in Sprague-Dawley rats after exposure to tones previously paired with footshock. After habituation to a recording chamber and the recording procedure, a baseline sleep recording was obtained the next day. One day later, experimental animals were exposed to shock training designed to induce conditioned fear (FC), consisting of five tone-footshock pairings. The 5-s tones (conditioned stimuli; CS) co-terminated with 1-s footshocks (unconditioned stimuli; US). The next day sleep was recorded for 4 h in the recording chamber after presentation of five CSs alone. Sleep efficiency (total sleep time/recording period) and REM sleep (REM) and non-REM (NREM) measures were determined. While sleep efficiency was not significantly changed after CS presentation, the percentage of total sleep time spent in REM (REM percentage) was reduced in the FC animals. The reduction in REM percentage in the FC animals was due to a decrease in the number of REM bouts. In a separate experiment, we repeated the procedures, except the tones and shocks were presented in an explicitly unpaired (UP) fashion. The next day, presentation of the tones increased REM percentage in the UP group. Results are discussed in terms of the decreases in REM as a response to conditioned fear, and the relevance of these findings to the sleep changes seen in post-traumatic stress disorder (PTSD).

Acoustic Stimulation↗
PubMed2002

Right-sided human prefrontal brain activation during acquisition of conditioned fear.

This H2(15)O positron emission tomography (PET) study reports on relative regional cerebral blood flow (rCBF) alterations during fear conditioning in humans. In the PET scanner, subjects viewed a TV screen with either visual white noise or snake videotapes displayed alone, then with electric shocks, followed by final presentations of white noise and snakes. Autonomic nervous system responses confirmed fear conditioning only to snakes. To reveal neural activation during acquisition, while equating sensory stimulation, scans during snakes with shocks and white noise alone were contrasted against white noise with shocks and snakes alone. During acquisition, rCBF increased in the right medial frontal gyrus, supporting a role for the prefrontal cortex in fear conditioning to unmasked evolutionary fear-relevant stimuli.

Adult↗