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PubMed1994

Parallel augmentation of hippocampal long-term potentiation, theta rhythm, and contextual fear conditioning in water-deprived rats.

The influence of water deprivation on hippocampal long-term potentiation (LTP), theta rhythm, and contextual fear conditioning in rats was examined. In Experiment 1, hippocampal EEG activity and perforant path LTP were assessed in pentobarbital-anesthetized rats. Water deprivation did not affect baseline cell excitability or low-frequency synaptic transmission in the dentate gyrus, but it increased the magnitude of perforant path LTP and elevated the proportion of theta rhythm in the EEG. In Experiment 2, rats were classically conditioned to fear a novel context through the use of aversive footshocks. Water deprivation facilitated the rate of contextual fear conditioning but did not alter the asymptote of learning. Experiment 3 demonstrated that the facilitation of contextual fear conditioning was not due to a change in unconditional shock sensitivity. These results suggest that water deprivation exerts an influence on contextual fear conditioning by modulating hippocampal LTP and theta rhythm and that these processes serve to encode contextual information during learning.

Animals↗
PubMed2004

Glutamate uptake determines pathway specificity of long-term potentiation in the neural circuitry of fear conditioning.

Long-term synaptic modifications in afferent inputs to the amygdala underlie fear conditioning in animals. Fear conditioning to a single sensory modality does not generalize to other cues, implying that synaptic modifications in fear conditioning pathways are input specific. The mechanisms of pathway specificity of long-term potentiation (LTP) are poorly understood. Here we show that inhibition of glutamate transporters leads to the loss of input specificity of LTP in the amygdala slices, as assessed by monitoring synaptic responses at two independent inputs converging on a single postsynaptic neuron. Diffusion of glutamate ("spillover") from stimulated synapses, paired with postsynaptic depolarization, is sufficient to induce LTP in the heterosynaptic pathway, whereas an enzymatic glutamate scavenger abolishes this effect. These results establish active glutamate uptake as a crucial mechanism maintaining the pathway specificity of LTP in the neural circuitry of fear conditioning.

Amygdala↗
PubMed2000

Specific induction of early growth response gene 1 in the lateral nucleus of the amygdala following contextual fear conditioning in rats.

Although the amygdala is known to be crucial for fear conditioning, little is known about the molecular and cellular mechanisms in the amygdala that are important for fear conditioning. One possible mechanism may be the activation of immediate-early genes, which function as regulatory factors of transcriptional processes. To investigate whether one of the major immediate-early gene families is involved in the learning and memory of fear, we examined the effects of fear conditioning on the expression of the four members of the early growth response (EGR) gene family, EGR-1, EGR-2, EGR-3, and EGR-4. Image analysis of in situ hybridization of messenger RNA of the four family members was performed in the amygdala, hippocampus, and neocortex 15, 30 and 60min following one-trial contextual fear conditioning. Rats were either handled, placed within the testing context without receiving the footshock, and received a footshock immediately upon placement within the context, or received a footshock after a 3-min delay (delayed-shock). Of the four groups, only the delayed-shock group exhibited a fear response (freezing). EGR-1 messenger RNA expression in the dorsolateral part of the lateral amygdaloid nucleus was significantly greater in the delayed-shock group compared with the other groups 15 and 30min following the conditioning. The increased expression of EGR-1 was specifically localized to the lateral nucleus of the amygdala; expression in the hippocampus and cortex was not increased by fear conditioning. In contrast, the expression of EGR-2, EGR-3, and EGR-4 messenger RNA was not increased in the amygdala, hippocampus or cortex following fear conditioning. In addition, following a retention test conducted 24h after fear conditioning, no increases were found in the expression of EGR-1 messenger RNA expression in the amygdala, hippocampus or cortex. The results demonstrate that of the four genes of the EGR family of transcription-regulatory factors, only EGR-1 messenger RNA in the dorsolateral portion of the lateral nucleus of the amygdala was specifically increased with contextual fear conditioning. It is suggested that EGR-1 plays a functional role during learning, but not retrieval, of contextual fear within the lateral nucleus of the amygdala.

Amygdala↗
PubMed2002

Involvement of medullary A2 noradrenergic neurons in the activation of oxytocin neurons after conditioned fear stimuli.

Fear-related stimuli activate oxytocin neurons in the hypothalamus and facilitate oxytocin release from the pituitary. Oxytocin neurons in the supraoptic nucleus receive direct noradrenergic innervations from the A1 and A2 cell groups in the medulla oblongata. In the present study, we investigated the role of hypothalamic-projecting noradrenergic neurons in controlling oxytocin cell activity following fear-related stimuli in rats. An unconditioned fear stimulus (intermittently applied footshock) or conditioned fear stimulus induced expression of Fos protein, a protein product of an immediate-early gene, in magnocellular oxytocin neurons in the supraoptic or paraventricular nucleus. A neurotoxin, 5-amino-2,4-dihydroxy-alpha-methylphenylethylamine, microinjected into the vicinity of the supraoptic nucleus, selectively depleted the noradrenaline contents of the nucleus and blocked the Fos expression in the supraoptic nucleus after the unconditioned or conditioned fear stimulus. In the medulla oblongata, the unconditioned fear stimulus induced expression of Fos protein in both A2/C2 and A1/C1 catecholaminergic neurons. On the other hand, the conditioned fear stimulus induced expression of Fos protein preferentially in the A2/C2 neurons. Furthermore, the unconditioned fear stimulus induced Fos expression in the A1/C1 and A2/C2 catecholaminergic neurons labelled with retrograde tracers previously injected into the supraoptic nucleus. The conditioned fear stimulus induced Fos expression preferentially in the A2/C2 catecholaminergic neurons labelled with the retrograde tracers. These data suggest that the conditioned fear-induced oxytocin cell activity is mediated by the A2 noradrenergic neurons projecting to oxytocin neurons, while the unconditioned fear response is mediated by both A2 and A1 noradrenergic neurons.

Animals↗
PubMed2002

Enhancement of delayed release of dopamine in the amygdala induced by conditioned fear stress in methamphetamine-sensitized rats.

Behavior during conditioned fear stress, a form of psychological stress, and the release of dopamine in the amygdala were measured over time using methamphetamine-sensitized rats, which are considered to be a model of hypersensitivity and vulnerability to emotional stress associated with stimulant-induced psychosis and schizophrenia. Dopamine release in the amygdala showed a delayed increase following completion of freezing behavior induced by conditioned fear stress regardless of the presence or absence of methamphetamine-sensitization. Since methamphetamine treatment did not lower the basal level of dopamine in the amygdala, under the conditions of this study, methamphetamine was presumed not to show neurotoxicity. On the other hand, basal dopamine levels after 15 h of repeated electric foot shock were about 40% lower than those in the control group (p<0.0002). In addition, dopamine release following conditioned fear stress in animals repeatedly treated with methamphetamine increased significantly from 40 to 100 min after conditioned fear stress while the duration of freezing behavior or latency of the appearance of grooming were not different from those in the control group. The above results suggested that delayed dopamine release in the amygdala is a phenomenon strongly associated with the emotional context of conditioned fear stress, and hypersensitivity and vulnerability to stress are at least partially involved with the overreaction to stress.

Amygdala↗
PubMed2005

Low level lindane exposure alters extinction of conditioned fear in rats.

Gamma-hexachlorocyclohexane (lindane) is a pesticide with the potential to produce long-term effects on fear or anxiety due to its targeting of the GABA(A) receptor in the brain. Multiple chemical sensitivity (MCS) is a human condition that has been attributed to repeated chemical exposures, with pesticides heavily implicated in the initiation of MCS. The symptoms in MCS patients are wide ranging but prominent among these in a subset of patients is increased evoked panic responses. Drawing a parallel between these responses in MCS patients and a panic model in rats, these studies explored a potential animal model for MCS. The effects of repeated lindane exposure on conditioned fear behavior was examined in adult male Sprague-Dawley rats. Animals were administered vehicle or lindane (intraperitoneally) for either 3 days/week (1, 2 or 5mg) or 5 days/week (2mg) over 2 weeks, and 18 days later were examined for anxiety levels on an elevated plus-maze. One day later, animals were trained for fear conditioning to an odor conditioned stimulus (CS). Freezing behavior was measured 1 day later in the context where pairing occurred, and then for a total of 6 days in a different environment in which either no CS or the CS was presented. After a second 18-day period of no treatment, rats were again tested for their freezing response to the CS for 2 days. Lindane pretreatment did not alter elevated plus-maze performance, nor did it alter contextual freezing behavior. However, pretreatment with lindane decreased the extinction of fear conditioning to the CS such that freezing behavior in controls was significantly lower than in lindane-pretreated rats, and this effect persisted during testing 18 days later. The results indicate that repeated low-level lindane exposure may produce long-lasting changes in anxiety-related neural circuitry. This suggests that odor-triggered symptoms associated with an aversive event may persist in MCS patients because of the ability of some chemicals to alter fear or anxiety circuitry in the brain.

Animals↗
PubMed2000

Fear conditioning and latent inhibition in mice lacking the high affinity subclass of nicotinic acetylcholine receptors in the brain.

Nicotine can enhance performance in several tests of cognition but the specific nicotinic receptor subtypes mediating these effects are largely unknown. Knock out mice lacking the beta2 subunit of the nicotinic receptor were evaluated in fear conditioning and latent inhibition tasks to begin to determine which receptor subtypes mediate the cognitive effects of nicotine. Young (2-4 months) knock out and wild type mice did not differ in either contextual or tone-conditioned fear, but aged (9-20 months) knock out males were impaired in freezing to both context and tone compared to aged wild type males. No differences in fear conditioning were observed between aged knock out and wild type females. Latent inhibition of fear to a pre-exposed tone, as measured by behavioral freezing, was also assessed. Both knock out and wild type mice displayed similar levels of latent inhibition, although overall levels of freezing were lower in knock out mice. These results support a previous study showing spatial learning deficits in aged beta2 subunit knock out mice [EMBO J. 18 (1999) 1235] and suggest that performance of other cognitive tasks may not be influenced by absence of beta2 subunit-containing receptors.

Aging↗
PubMed2005

Impaired Pavlovian cued fear conditioning in Tg2576 mice expressing a human mutant amyloid precursor protein gene.

The processing of emotional and/or fear-related events is abnormal in patients with Alzheimer's disease. AD is accompanied by a number of neuropathological features, one of which is the deposition of amyloid plaques. The main aim of the present study was to examine the effects of a human amyloid precursor protein mutation on both the acquisition and expression of fear conditioning in Tg2576 mice. Sixteen-month-old, but not 4-month-old, transgenic mice showed aberrations in post-shock freezing during training. In a retention test carried out 24 h after training, Tg2576 mice showed comparable levels of conditioned fear elicited by contextual cues. However, freezing elicited by a tone conditioned stimulus was impaired in 16-month-old but not 4-month-old Tg2576 mice. The results are discussed with reference to the role of cue competition (overshadowing) in revealing fear conditioning deficits in Tg2576 mice.

Age Factors↗
PubMed2000

Confirmation of contextual fear conditioning QTLs by short-term selection.

A short-term selection study for contextual fear conditioning was conducted as a confirmational strategy to analyze the chromosomal locations of five previously mapped contextual fear conditioning quantitative trait loci (QTLs). The founding population was a C57BL/6 (B6) x DBA/2 (D2) F2 intercross. High and low lines were selected for three generations based on contextual fear conditioning scores. Fear conditioning was quantified as the percentage of time spent in a "frozen" posture when placed back into the chamber, where a mild footshock and a tone had been paired with exposure to the context 24 h earlier. Allele frequencies of at least three SSLP DNA markers linked to each of the five QTLs were determined in each generation. As the selection progressed, the frequency of D2 alleles decreased in the low line and increased in the high line for chromosomes 1 and 16, while the opposite was observed in chromosomes 2, 3, and 10. The direction of divergence for alleles on these five chromosomes is consistent with the original QTL mapping study. Differences between the lines in D2 allele frequencies were found to be significant for markers on chromosomes 2, 3, and 16 but did not reach significance on chromosomes 1 or 10. In general, the results are in good agreement with our original fear conditioning QTL mapping study and provide further evidence that these QTLs regulate variation in contextual fear conditioning in crosses of B6 and D2 mice.

Animals↗
PubMed2006

Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning.

In the standard model of pavlovian fear learning, sensory input from neutral and aversive stimuli converge in the lateral nucleus of the amygdala (LA), in which alterations in synaptic transmission encode the association. During fear expression, the LA is thought to engage the central nucleus of the amygdala (CE), which serves as the principal output nucleus for the expression of conditioned fear responses. In the present study, we reexamined the roles of LA and CE. Specifically, we asked whether CE, like LA, might also be involved in fear learning and memory consolidation. Using functional inactivation methods, we first show that CE is involved not only in the expression but also the acquisition of fear conditioning. Next, we show that inhibition of protein synthesis in CE after training impairs fear memory consolidation. These findings indicate that CE is not only involved in fear expression but, like LA, is also involved in the learning and consolidation of pavlovian fear conditioning.

Amygdala↗
PubMed2000

Close linkage between calcium/calmodulin kinase II alpha/beta and NMDA-2A receptors in the lateral amygdala and significance for retrieval of auditory fear conditioning.

The general mechanism underlying memory and learning is an area under intense investigation and debate, yet this mechanism still remains elusive. Auditory fear conditioning (when a tone is paired with a foot shock) is a simple associative form of learning for which many mechanistic details are known. Lesions of the lateral/basolateral nuclei of the amygdala result in the selective impairment of fear conditioning, indicating that this is a key region for this type of learning. Fear conditioning induces a lasting synaptic potentiation in the lateral nuclei of the amygdala. In addition, recent results from several laboratories suggest that N-methyl-D-aspartate (NMDA) receptor activation in the amygdala is required for the acquisition and expression of cue-conditioned fear responses using several kinds of antagonists. Little is known, however, about the signal transduction pathway and molecular substrate underlying fear conditioning. Here we use NMDA receptor-deficient mice to demonstrate that calmodulin-dependent kinase II, CaMKIIbeta, and CaMKIIalpha activation involves the NR2A subunit in the lateral/basolateral amygdala during memory retrieval following auditory fear conditioning. These results suggest that auditory fear conditioning involves a close linkage between NMDA2A receptors and the CaMKII cascade.

Acoustic Stimulation↗
PubMed2000

Ethanol, but not the anxiolytic drugs buspirone and diazepam, produces a conditioned place preference in rats exposed to conditioned fear stress.

The present study was designed to investigate the role of an anxiolytic effect in the development of a drug-associated place preference in rats exposed to conditioned fear stress, using the conditioned place-preference paradigm. The administration of a low dose of ethanol (300 mg/kg, IP) and the anxiolytic drugs, buspirone (1 and 2 mg/kg, IP) and diazepam (1.25 and 2.5 mg/kg, IP), did not produce a place preference in rats that were not exposed to conditioned fear stress. In rats that were exposed to conditioned fear stress, ethanol produced a significant place preference, while buspirone and diazepam failed to produce a place preference. In addition, ethanol, buspirone, and diazepam produced no place preference in rats treated with an anxiogenic dose of pentylenetetrazole (20 mg/kg, IP). A significant decrease in locomotor activity was observed in rats exposed to conditioned fear stress. Ethanol, but not buspirone and diazepam, significantly recovered or increased locomotor activity in rats exposed to conditioned fear stress. Further, the locomotor-stimulating effect of ethanol was markedly enhanced by repeated exposure to conditioned fear stress. These results suggest that the stimulating effect may be strongly related to the development of the rewarding effect of a low dose of ethanol under psychological stress, and that the conditioned place preference paradigm with conditioned fear stress may be useful for studying the rewarding mechanism of ethanol with regard to the interaction between ethanol and psychological stress.

Animals↗
PubMed1999

The benzodiazepine midazolam does not impair Pavlovian fear conditioning but regulates when and where fear is expressed.

Rats were injected with a benzodiazepine (midazolam) and shocked after presentation of an auditory conditioned stimulus (CS). They were then tested for fear reactions (freezing) to the CS in either the original context or a 2nd context after either a short (1-day) or long (21-day) retention interval. Rats tested in the original context froze less after 1 day than rats tested after that interval in the 2nd context or rats tested after 21 days. Moreover, rats tested after the long interval in the original context froze less than rats tested after that interval in the 2nd context. Therefore, midazolam does not impair the acquisition of conditioned fear but regulates when and where that fear is expressed. These effects of midazolam were interpreted as a contextually controlled deficit in the expression of conditioned fear that is similar to that associated with latent inhibition and extinction (M. E. Bouton, 1993).

Animals↗
PubMed2006

Posttraining handling facilitates memory for auditory-cue fear conditioning in rats.

A large number of studies have indicated that stress exposure or the administration of stress hormones and other neuroactive drugs immediately after a learning experience modulates the consolidation of long-term memory. However, there has been little investigation into how arousal induced by handling of the animals in order to administer these drugs affects memory. Therefore, the present study examined whether the posttraining injection or handling procedure per se affects memory of auditory-cue classical fear conditioning. Male Sprague-Dawley rats, which had been pre-handled on three days for 1 min each prior to conditioning, received three pairings of a single-frequency auditory stimulus and footshock, followed immediately by either a subcutaneous injection of a vehicle solution or brief handling without injection. A control group was placed back into their home cages without receiving any posttraining treatment. Retention was tested 24 h later in a novel chamber and suppression of ongoing motor behavior during a 10-s presentation of the auditory-cue served as the measure of conditioned fear. Animals that received posttraining injection or handling did not differ from each other but showed significantly less stimulus-induced movement compared to the non-handled control group. These findings thus indicate that the posttraining injection or handling procedure is sufficiently arousing or stressful to facilitate memory consolidation of auditory-cue classical fear conditioning.

Acoustic Stimulation↗
PubMed2006

Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear.

We examined the effect of glucocorticoid agonists on the extinction of conditioned fear in rats by using fear-potentiated startle. Systemic injection of glucocorticoid receptor agonists dexamethasone (DEX) (0.1, 0.5, and 1.0 mg/kg) and intra-amygdala infusion of RU28362 (0.5, 1.0, and 3.0 ng/side) prior to extinction training facilitated extinction of conditioned fear in a dose-dependent manner. Extinction of conditioned fear and circulating corticosterone levels were attenuated by administration of corticosteroid synthesis inhibitor metyrapone (25 mg/kg s.c.) 90 min before extinction training. The facilitation effect of DEX was dependent on repeated presentation of the conditioned stimulus rather than exposure to the experimental context, indicating this effect did not result from impaired expression of conditioned fear or accelerated forgetting. Intra-amygdaloid administration of the glucocorticoid receptor antagonist mifepristone (0.1, 0.2, and 0.5 ng/side, bilaterally) blocked extinction of conditioned fear and the facilitation effect of DEX in a dose-dependent manner. Mifepristone (2 ng/side) did not affect extinction but blocked the facilitating effect of DEX. Systemic administration of DEX after extinction training also facilitated extinction, suggesting that DEX may influence the memory consodilation phase of extinction. The Dose of dexamethsone or metyrapone used here did not influence fear-potentiated startle when administered before testing. Thus, it is unlikely that these drugs influenced extinction by increasing or disrupting CS processing. All results suggested that amygdaloid glucocorticoid receptors were involved in the extinction of conditioned fear.

Amygdala↗
PubMed1999

Neurotoxic or electrolytic lesions of the ventral subiculum produce deficits in the acquisition and expression of Pavlovian fear conditioning in rats.

The effects of neurotoxic or electrolytic ventral subicular (vSUB) lesions on the acquisition and expression of Pavlovian fear conditioning in rats were examined. Conditioning consisted of the delivery of tone-footshock trials in a novel observation chamber, and freezing served as the measure of conditional fear. Pretraining vSUB lesions produced a severe tone freezing deficit and a modest context freezing deficit, whereas posttraining lesions produced severe deficits in freezing to both a tone and a context conditional stimulus (CS). Similar impairments were produced by neurotoxic and electrolytic lesions. Increases in motor activity associated with the lesions could not account for freezing deficits. These results reveal that neurons in the vSUB have an important role in both the acquisition and expression of Pavlovian fear conditioning to contextual and acoustic CSs.

Animals↗
PubMed2001

Estrogen modulates sexually dimorphic contextual fear conditioning and hippocampal long-term potentiation (LTP) in rats(1).

The present study examined the role of ovarian steroids in contextual fear conditioning and hippocampal synaptic plasticity in female rats. In experiment 1, adult female rats were ovariectomized and submitted to contextual fear conditioning, a procedure in which rats received unsignaled footshock in a novel observation chamber; freezing behavior served as the measure of conditional fear. Ovariectomized female rats froze at levels comparable to male rats, both of which froze significantly more than sham-operated female rats. In experiment 2, estrogen replacement in ovariectomized female rats reduced fear conditioning to a level comparable to that of sham-operated females in experiment 1. In experiment 3, the influence of estrogen on the induction of long-term potentiation (LTP) at perforant path-dentate granule cell synapses in ovariectomized female rats was examined. Estrogen decreased both population spike LTP and EPSP-spike potentiation at perforant path synapses. Taken together, these experiments indicate that ovarian steroids regulate both sexually dimorphic behavior and hippocampal plasticity in a fear-conditioning paradigm.

Animals↗
PubMed2005

Chronic stress impairs recall of extinction of conditioned fear.

Chronic restraint stress produces retraction of apical dendrites of pyramidal neurons in medial prefrontal cortex. To begin to examine the functional significance of this dendritic reorganization, we assessed the effects of chronic restraint stress on a prefrontally mediated behavior, extinction of conditioned fear. After bar press training to obtain a baseline of activity against which to measure freezing, rats were either unstressed or stressed via placement in a plastic restrainer (3 h/day for 1 week). After an additional day of bar press training, rats underwent fear conditioning and extinction. Rats received five habituation trials to a 30-s tone (4.5 kHz, 80 db) followed by seven pairings of tone and footshock (500 ms, 0.5 mA). One hour later, rats received tone-alone extinction trials to criterion. The next day, rats received 15 additional extinction trials. Percent freezing was assessed during all phases of training. Stress did not significantly affect unconditioned responding to tone, acquisition of conditioned fear, or initial extinction, but significantly increased freezing on extinction day 2. Thus, consistent with the regressive dendritic changes seen in medial prefrontal cortex, one week of restraint stress specifically impaired recall of extinction, a pattern of deficits typical of animals with impaired medial prefrontal function.

Animals↗