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PubMed2001

Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning.

The lateral nucleus of the amygdala (LA) is an essential component of the neural circuitry underlying Pavlovian fear conditioning. Although blockade of NMDA receptors in LA and adjacent areas before training disrupts the acquisition of fear conditioning, blockade before testing also often disrupts the expression of fear responses. With this pattern of results, it is not possible to distinguish a contribution of NMDA receptors to plasticity from a role in synaptic transmission. In past studies, NMDA blockade has been achieved using the antagonist d,l-2-amino-5-phosphovalerate, which blocks the entire heteromeric receptor complex. The present experiments examined the effects of selective blockade of the NR2B subunit of the NMDA receptor in LA using the selective antagonist ifenprodil. Systemic injections of ifenprodil before training led to a dose-dependent impairment in the acquisition of auditory and contextual fear conditioning, whereas injections before testing had no effect. Intra-amygdala infusions of ifenprodil mirrored these results and, in addition, showed that the effects are attributable to a disruption of fear learning rather than a disruption of memory consolidation. NMDA receptors in LA are thus involved in fear conditioning, and the NR2B subunit appears to make unique contributions to the underlying plasticity.

Acoustic Stimulation↗
PubMed2005

Effect of a dopamine D1/5 receptor antagonist on haloperidol-induced inhibition of the acquisition of conditioned fear.

This study examined the effects of combined treatment with the typical antipsychotic drug haloperidol and dopamine D1/5 receptor antagonist SCH 23390 on the acquisition of contextual conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks), compared with those of various antipsychotic adjuvants, which may increase the effects of antipsychotic drugs. Rats were treated subcutaneously with haloperidol (3 mg/kg) combined with SCH 23390 (0.03 mg/kg) and were given fear conditioning by 5 min footshocks in shock chambers 30 min after the injection. One week after the footshocks, the rats were tested in the same shock chamber without shocks and freezing behavior was observed as an index of fear and anxiety. Haloperidol significantly inhibited the acquisition of conditioned freezing. SCH 23390 combined with haloperidol inhibited the acquisition of conditioned freezing more than either drug alone did. These results suggest that combined dopamine D2-like receptor antagonism and dopamine D1-like receptor antagonism is a promising and effective strategy to increase antipsychotic effects.

Analysis of Variance↗
PubMed1999

Pretraining tetanic fimbrial stimulation impairs the expression but not the acquisition of contextual fear conditioning in mice.

We recently reported that the pretraining induction of long-term potentiation in the lateral septum by fimbrial tetanic stimulation altered contextual fear conditioning in mice. The aim of the present study was to examine at which stage of fear conditioning (i.e. either acquisition or expression) this impairment takes place. Mice implanted with stimulating electrodes in the fimbria and recording electrodes in the lateral septal were conditioned to acquire fear towards a novel context using a footshock procedure. Twenty-four hours after conditioning, animals were re-exposed to the conditioning environment and the level of freezing behavior served as the measure of conditioned fear. The level of fimbrial-lateral septal synaptic neurotransmission was manipulated using either fimbrial tetanic stimulation (which induced septal long-term potentiation) alone, or followed by fimbrial low-frequency stimulation producing depotentiation of the previously established long-term potentiation. The results showed that (i) septal long-term potentiation induced either prior to acquisition or only prior to retention testing impaired conditioned freezing; and (ii) the impairing effect of pretraining induction of long-term potentiation on conditioned freezing was not only abolished by fimbrial low-frequency stimulation administered prior to retention testing but actually produced enhanced conditioned freezing with respect to controls. These data suggest that the level of fimbrial-lateral septal synaptic neurotransmission may influence the expression, but not the acquisition, of contextual fear conditioning.

Animals↗
PubMed2004

C57BL/6J and DBA/2J mice differ in extinction and renewal of extinguished conditioned fear.

While a number of studies have examined the acquisition and expression of conditioned fear in inbred mice, very few have examined extinction of conditioned fear in inbred mice and few attempts have been made to compare extinction learning between inbred strains. Because inbred strains differ in a number of physiological and biochemical variables, differences in extinction learning may provide insight into the genetic influence of extinction learning. The purpose of this study was to examine extinction and renewal of conditioned fear in two common inbred strains of mice. C57BL/6J and DBA/2J mice were conditioned with pairings of either a tone or light and foot shock in a single session. On the following 4 days, mice were given extinction training, consisting of tone or light alone trials (Experiment 1A). C57 mice exhibited robust spontaneous recovery between sessions, but did extinguish both within and between sessions. DBA mice extinguished more quickly relative to C57 mice, and this extinction was stable between sessions (i.e., DBA mice did not exhibit spontaneous recovery). The rapid loss of fear in DBA relative to C57 mice was extinction-dependent and not merely due to poor long-term memory (Experiment 1B). Renewal testing (Experiment 2) replicated the strain difference in extinction and also showed that DBA mice have a deficit in the context specificity of extinction. C57 mice, but not DBA mice showed renewal of extinguished fear when tested in a context different from the one in which extinction training took place. These data suggest that the nature of extinction learning is influenced by characteristics of the inbred mouse strain.

Analysis of Variance↗
PubMed2001

The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks fear conditioning in rats.

Glutamate receptors play an essential role in fear-related learning and memory. The present study was designed to assess the role of the group I metabotropic glutamate receptor (mGluR) subtype 5 in the acquisition and retrieval of conditioned fear in rats. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was applied systemically (0.0, 0.3, 3.0, 30.0 mg/kg per os) 60 min before the acquisition training and before the expression of conditioned fear, respectively, in the fear-potentiated startle paradigm. MPEP dose-dependently blocked the acquisition of fear. This effect was not due to state-dependent learning. MPEP also prevented the expression of fear at a dose of 30.0 mg/kg. As a positive control for these effects, we showed that the benzodiazepine anxiolytic compound diazepam (1.25 mg/kg intraperitoneally) also blocked acquisition and expression of fear potentiated startle. MPEP did not affect the baseline startle magnitude, short-term habituation of startle, sensitisation of startle by footshocks or prepulse inhibition of startle. These data indicate a crucial role for mGluR5 in the regulation of fear conditioning. In the highest dose MPEP might exert anxiolytic properties.

Acoustic Stimulation↗
PubMed1997

DHEA-S selectively impairs contextual-fear conditioning: support for the antiglucocorticoid hypothesis.

The authors had reported that glucocorticoids play a selective role in fear conditioning. The adrenal steroid dehydroepiandrosterone (DHEA) has been reported to act as a functional antiglucocorticoid. If DHEA has antiglucocorticoid properties, then its effects on fear conditioning might resemble those produced by adrenalectomy. The authors now report that chronic exposure to high levels of dehydroepiandrosterone sulfate (DHEA-S; converted in vivo to DHEA) produced the same pattern of results as adrenalectomy. Specifically, treatment with DHEA-S impaired contextual fear conditioning 24 hr after conditioning but not immediately after conditioning, and like adrenalectomy, DHEA-S had no effect on auditory-cue fear conditioning. Preexposure to the context before drug treatment eliminated the amnestic effects of DHEA-S, suggesting that, like adrenalectomy, DHEA-S exerted its effect by interfering with the construction of a contextual memory representation. Thus, DHEA appears to act as a functional antiglucocorticoid in the processes that mediate learning and memory.

Acoustic Stimulation↗
PubMed2007

Prediction of "fear" acquisition in healthy control participants in a de novo fear-conditioning paradigm.

Studies using fear-conditioning paradigms have found that anxiety patients are more conditionable than individuals without these disorders, but these effects have been demonstrated inconsistently. It is unclear whether these findings have etiological significance or whether enhanced conditionability is linked only to certain anxiety characteristics. To further examine these issues, the authors assessed the predictive significance of relevant subsyndromal characteristics in 72 healthy adults, including measures of worry, avoidance, anxious mood, depressed mood, and fears of anxiety symptoms (anxiety sensitivity), as well as the dimensions of Neuroticism and Extraversion. Of these variables, the authors found that the combination of higher levels of subsyndromal worry and lower levels of behavioral avoidance predicted heightened conditionability, raising questions about the etiological significance of these variables in the acquisition or maintenance of anxiety disorders. In contrast, the authors found that anxiety sensitivity was more linked to individual differences in orienting response than differences in conditioning per se.

Adult↗
PubMed1998

Conditioned fear stress induces ethanol-associated place preference in rats.

The purpose of the present study was to establish ethanol-induced place preference under conditioned fear stress (exposure to an environment paired previously with electric foot shock) in rats by using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) with conditioned fear stress, but not without conditioned fear stress, induced a marked and significant place preference. Furthermore, additional exposure to conditioned fear stress immediately before the post-conditioning test further enhanced the development of ethanol-induced place preference. These results suggest that psychological stress may play an important role in the development of ethanol-induced place preference, and the present method may be useful for studying the mechanism of the rewarding effect of ethanol.

Animals↗
PubMed2002

Activation of orexin neurones after noxious but not conditioned fear stimuli in rats.

In rats, noxious stimuli increase food intake while conditioned fear stimuli decrease it. Orexin neurones play a facilitative role in food intake. Here, we examined expression of Fos protein in orexin neurones after noxious or conditioned fear stimuli in rats. Noxious stimuli significantly induced Fos protein in orexin neurones. On the other hand, conditioned fear stimuli did not significantly change expression of Fos protein in orexin neurones. The results demonstrate selective activation of orexin neurones by noxious stimuli, suggesting that effects of stressful stimuli upon orexin neurones are dependent upon the stimuli used. This finding is consistent with an idea that orexin neurones are involved in stress-induced food intake.

Animals↗
PubMed2002

Neonatal handling enhances contextual fear conditioning and alters corticosterone stress responses in young rats.

Previous studies have indicated that neonatal handling influences development of hypothalamic-pituitary-adrenal (HPA) control of corticosterone. In addition, corticosterone influences memory consolidation processes in contextual fear conditioning. Therefore, neonatal handling may affect hippocampal-dependent memory processes present in contextual fear conditioning by influencing the development of HPA control of corticosterone. To investigate the effects of neonatal handling on early learning, rat pups were either handled (15-min removal from home cage) on the first 15 days after birth or left undisturbed in their home cage. Handled rats and nonhandled rats were fear conditioned at 18, 21, or 30 days of age and then tested at two time points--24 h following conditioning and at postnatal day 45. Subsequently, at approximately postnatal day 60, rats were exposed to restraint stress and corticosterone levels were assessed during restraint and recovery. Handled and nonhandled rats did not differ significantly in their freezing response immediately following footshock on the conditioning day. However, when tested for contextual fear conditioning at 24 h following conditioning and at postnatal day 45, handled rats showed more freezing behavior than nonhandled rats. When exposed to restraint stress, handled rats had a more rapid return of corticosterone to basal levels than nonhandled rats. These results indicate that neonatal handling enhances developmentally early memory processes involved in contextual fear conditioning and confirms previously reported effects of neonatal handling on HPA control of corticosterone.

Animals↗
PubMed1992

Stimulation at a site of auditory-somatosensory convergence in the medial geniculate nucleus is an effective unconditioned stimulus for fear conditioning.

The medial division of the medial geniculate nucleus (MGm) and the posterior intralaminar nucleus (PIN) are necessary for fear conditioning to an auditory conditioned stimulus (CS), receive both auditory and somatosensory input, and project to the amygdala, which is involved in production of fear conditioned responses. If CS-unconditioned stimulus (US) convergence in the MGm-PIN is critical for fear conditioning, then microstimulation of this area should serve as an effective US during classical conditioning, in place of standard footshock. Guinea pigs underwent conditioning (40-60 trials) using a tone as the CS and medial geniculate complex microstimulation as the US. Conditioned bradycardia developed when the US electrodes were in the PIN. However, microstimulation was not an effective US for conditioning in other parts of the medial geniculate or for sensitization training in the PIN or elsewhere. Learning curves were similar to those found previously for footshock US. Thus, the PIN can be a locus of functional CS-US convergence for previously for footshock US. Thus, the PIN can be a locus of functional CS-US convergence for fear conditioning to acoustic stimuli.

Amygdala↗
PubMed2004

Behavioral and autonomic dynamics during contextual fear conditioning in mice.

Aversive conditioning to contextual stimulation was performed in mice implanted with ECG transmitters to investigate heart rate (HR) and behavioral responses during contextual retention. The dynamics of HR were analyzed by advanced nonlinear techniques to uncover central neuroautonomic outflow inferred from its sympathetic (SNS) and parasympathetic (PNS) projection onto the sinus node of the heart. Mice experienced a single foot shock (US, unconditioned stimulus) either immediately (USi) or late (USl) after placement in the conditioning context. Contextual memory was tested 24 h after training by reexposure to the conditioning context for 32 min. Only mice that experienced the USl exhibited a pronounced and sustained behavioral suppression (immobility) indicative of conditioned contextual fear. In contrast, HR was initially close to its maximal physiological limit (approximately 800 bpm) in all groups, and recovery towards baseline levels was sluggish, the most pronounced delay observed in the USl group. The results demonstrate that behavioral immobility was associated with maximum activation of autonomic system output in response to contextual reexposure. However, advanced complexity analysis of the variability of HR revealed uniform or stereotyped dynamical properties that were interpreted to reflect a generalized state of anticipatory emotional arousal experienced during reexposure to contextual stimuli. It is concluded that the dynamics of HR is a highly sensitive index of the autonomic nervous system response and emotional state elicited by sensory stimulation of an unfamiliar environment.

Animals↗
PubMed2002

Fear conditioned changes of heart rate in patients with medial cerebellar lesions.

Fear conditioned changes of heart rate and skin conductance responses were investigated in patients with medial cerebellar lesions. A classical conditioning paradigm with a tone as the conditioned stimulus (CS) and an electrical shock as the unconditioned stimulus (US) was tested on five patients with medial cerebellar lesions due to surgery for astrocytoma and five controls. The CS preceded the US by 5900 ms and coterminated with the US. Changes in heart rate and skin conductance responses were obtained as measures for autonomic fear responses. Effects of conditioning were quantified by comparison of the habituation and extinction phases. Controls, but not cerebellar patients, showed a significant decrease of heart rate during fear conditioning. However, there were no significant fear conditioned changes in electrodermal responses in either group. In summary, the medial cerebellum seems to be involved in fear-conditioned bradycardia in humans.

Adolescent↗
PubMed2001

Inbred strain variation in contextual and cued fear conditioning behavior.

A number of commonly used inbred strains were surveyed in a fear-conditioning paradigm conducted with an automated computer-controlled system. Control studies were used to verify the automated system. Response to shock was also monitored to determine if it was associated with contextual and/or cued conditioning behavior. After three pairings of tone with shock, fear conditioning was measured 24 h later in 129S1/SvImJ (129), A/J (A), BALB/cByJ (BALB), C3H/HeJ (C3H), C57BL/6J (B6), CBA/J (CBA), DBA/2J (D2), and FVB/NJ (FVB) male and female mice. There were both significant strain and sex differences in response. To determine the effects of vision on this behavior, C3H mice (with retinal degeneration) were compared with C3.BLiA-+Pde6b congenics (without retinal degeneration). Here, vision was found to play a minimal role in responsiveness in this paradigm. Because this fear-conditioning test is automated, it can be used for the rapid screening of a large number of mice, such as required for mutagenesis studies.

Animals↗
PubMed2000

Endogenous corticotropin-releasing hormone inhibits conditioned-fear-induced vagal activation in the rat.

The role of the endogenous corticotropin-releasing hormone (CRH) system in the regulation of heart rate, PQ interval (a measure of vagal activity), gross activity and release of adrenocorticotropic hormone (ACTH), noradrenaline and adrenaline into the blood during conditioned fear was studied in freely moving rats. Intracerebroventricular (i.c.v.) infusion of alpha-helical CRH-(9-41) (10 microgram/3 microliter), a non-selective CRH receptor antagonist, under resting conditions had no significant effect on gross activity, heart rate and PQ interval, indicating that alpha-helical CRH at this dose was devoid of agonist effects. Conditioned fear was induced by 10 min forced exposure to a cage in which the rat had experienced footshocks (5x0.5 mAx3 s) 1 day before. Conditioned-fear rats showed freezing behaviour, associated with an increase in heart rate, PQ interval, noradrenaline and adrenaline, indicating that the conditioned-fear-induced cardiac effects were the result of coactivation of the sympathetic and parasympathetic nervous system. The i.c.v. pre-treatment of rats with alpha-helical CRH significantly reduced the conditioned-fear-induced tachycardiac and ACTH response, and enhanced the increase in PQ interval, without affecting the noradrenaline and adrenaline response. These results suggest that endogenous CRH reduces the vagal response to conditioned-fear stress in rats. To test this, rats were pre-treated with atropine methyl nitrate (0.3 mg/kg, subcutaneously; s.c.), a peripherally acting cholinergic receptor antagonist. This resulted in a complete blockade of the alpha-helical CRH-induced decrease in heart rate response and increase in PQ interval. From these findings, it is concluded that endogenous CRH in the brain inhibits vagal outflow induced by emotional stress.

Adrenocorticotropic Hormone↗
PubMed2001

Amygdalar nmda receptors are critical for the expression of multiple conditioned fear responses.

There is conflicting evidence regarding the issue of whether NMDA receptors in the basolateral amygdalar complex (BLA) are critically involved in the expression of conditioned fear. This matter was addressed by infusing the rat BLA with d,l-2-amino-5-phosphonovaleric acid (APV), a competitive NMDA receptor antagonist. APV infusion into the BLA was reported to block the expression of conditioned fear when measured by freezing but not when measured by fear-potentiated startle response to a loud noise. To examine this issue further, here we used multiple indices of conditioned fear, including analgesia, 22 kHz ultrasonic vocalization (USV), defecation, and freezing. Rats with bilateral BLA cannula implants underwent fear conditioning consisting of 10 tone-footshock pairings. Before context and tone fear-retention tests, animals received intra-BLA infusions with APV (2.5 microg/side) or artificial CSF. Both tone and context tests demonstrated that the expression of conditioned freezing, USV, defecation, and analgesia were significantly impaired by intra-amygdalar infusions of APV. In a second set of experiments, intra-BLA infusions of APV markedly impaired the normal expression of postshock fear responses during training, as measured by freezing, USV, and defecation. Immediate postshock fear expression was predictive of subsequent fear retention to the tone and context when the animals were not infused. These results are consistent with the hypothesis that amygdalar NMDA receptors participate in normal synaptic transmission and therefore the overall functioning of the amygdala.

2-Amino-5-phosphonovalerate↗
PubMed1997

Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task.

This study examined the effect of hippocampal lesions on acquisition of the Morris water maze and conditioned-fear task in inbred mice. C57BL/6J, DBA/2J, and B6D2F1 hybrid mice were given hippocampal lesions or sham surgery and then tested. The lesioned C57BL/6J and B6D2F1 mice failed to learn the Morris task relative to sham-operated controls, and no DBA group learned the task. In the contextual component of conditioned fear, lesions decreased freezing in all strains. But the lesions only affected freezing to the conditioned stimulus in the DBA/2J and B6D2F1 strains. These data demonstrate that C57BL/6J and B6D2F1 mice use the hippocampus to solve the Morris water maze and conditioned-fear task, and the DBA mice use the hippocampus, to some degree, in the conditioned-fear task.

Animals↗
PubMed2000

Paradoxical facilitatory effect of fornix lesions on acquisition of contextual fear conditioning in mice.

The present study examined the effect of fornix lesions on freezing behavior elicited by contextual and phasic conditioned stimuli. Male mice of the C57Bl/6 strain received electrolytic lesions of the fornix. Ten days following the lesion, they were submitted to acquisition of one-trial classical fear conditioning involving the pairing of an auditory conditioned stimulus (CS) with a footshock unconditioned stimuli (US). Analysis of conditioned fear responses showed that fornix lesions enhanced the freezing response elicited by exposure to the conditioning chamber 24 h after a single tone-shock pairing. In contrast, the two groups did not differ on their fear responses during the auditory cue test. Analysis of the time-course of freezing behavior during re-exposure to the conditioning chamber suggests, however, that the observed fornix lesion-induced facilitation of freezing to the conditioning chamber is more likely due to a facilitation of the processing of a simple (unimodal) rather than polymodal (contextual) CS-US association.

Acoustic Stimulation↗