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At least 397 records · Page 22Linked to original sources
PubMed2000

Human immunodeficiency virus-1 coat protein gp120 impairs contextual fear conditioning: a potential role in AIDS related learning and memory impairments.

Many AIDS patients suffer from cognitive impairments including deficits in learning and memory. The Human Immunodeficiency Virus-1 (HIV-1) envelope glycoprotein gp120 is one possible mediator of these impairments. This is because gp120 activates brain microglial cells and astrocytes, and in vivo activation of glia leads to the release of the proinflammatory cytokine interleukin-1 beta (IL-1beta). gp120 induced IL-1beta release could be involved in producing memory impairments associated with AIDS because central IL-1beta activity adversely affects cognitive function. The reported experiments evaluated the effects of i.c.v. gp120 administration and subsequent IL-1beta activity on learning and memory processes in the rat. Intracerebroventricular gp120 produced memory impairments on hippocampally dependent contextual fear conditioning, but not hippocampally independent auditory-cue fear conditioning following post-conditioning gp120 administration. Central gp120 administration also caused increases in IL-1beta protein levels in the hippocampus and frontal cortex but not in the hypothalamus. gp120 induced memory impairments were blocked by 2 different IL-1 antagonists, alpha melanocyte stimulating hormone (alphaMSH) and interleukin-1 receptor antagonist (IL-1ra). Finally, heat denaturation of the tertiary structure of gp120 abolished its effects on fear conditioning, suggesting that gp120 impairs contextual fear conditioning by binding to its receptors on glia.

AIDS Dementia Complex↗
PubMed2002

Regulation of synaptic plasticity genes during consolidation of fear conditioning.

In mammals, long-term memory induced by Pavlovian fear conditioning has been shown to be dependent on the amygdala during a protein and mRNA synthesis-dependent phase of memory consolidation. We have used genes identified in a kainic acid model of synaptic plasticity as in situ hybridization probes during the consolidation period after fear conditioning. We found that these genes were transcriptionally regulated in several brain areas only when stimuli were presented in a manner that supported behavioral learning and not after unpaired presentations or footshocks alone. Immediate early genes and neurofilament mRNA peaked approximately 30 min after conditioning, as expected. Interestingly, nurr-1, alpha-actinin, and 16c8 increased approximately 2-4 hr later, whereas neurogranin and gephyrin decreased during that time. Our results suggest that fear memory consolidation occurs within a broad neural circuit that includes, but is not limited to, the amygdala. Together, a broad array of transcriptionally regulated genes, encoding transcription factors, cytoskeletal proteins, adhesion molecules, and receptor stabilization molecules, appear to mediate the neural plasticity underlying specific forms of long-term memory in mammals.

Animals↗
PubMed1994

Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning.

Three experiments investigated sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats. Experiment 1 revealed a robust sex difference in the magnitude of LTP induced at perforant path synapses in the dentate gyrus of pentobarbital-anesthetized rats. This sex difference in LTP was evident in rats of 35 and 60 days of age and was not the result of pre-LTP sex differences in perforant path synaptic transmission; 20-day-old rats did not show LTP. An analysis of field potentials evoked during LTP induction revealed a sex difference in the magnitude of N-methyl-D-aspartate (NMDA) receptor activation that was highly correlated with the magnitude of LTP. Experiment 2 showed that males condition more fear, measured as freezing, to the contextual conditional stimuli (CSs) of a conditioning chamber compared to their female counterparts. This sex difference in conditional freezing was apparent with both low and high unconditional stimulus (US, footshock) intensities. Experiment 3 revealed that the enhanced fear conditioning in males was specific to contextual CSs, and consisted of a more rapid rate of conditioning. Together, these experiments reveal a positive correlation between the magnitude of hippocampal LTP and a form of learning that depends on the hippocampus. Furthermore, they suggest a neural basis for sex differences in hippocampus-dependent learning tasks.

Acoustic Stimulation↗
PubMed2002

Force transducer-based movement detection in fear conditioning in mice: a comparative analysis.

Fear conditioning (FC) allows the dissociation of hippocampal and nonhippocampal behavioral function in rodents, and has become a diagnostic tool in transgenic mouse research employed to investigate mutation-induced changes in brain function. Although the procedural details of the paradigm have been established, quantification of the behavioral output, freezing, remains problematic in mice. Observation-based techniques are time-consuming and may be subject to bias, while movement detection with photocells is imprecise. Here we describe an alternative method for movement detection, based on an electronic force transducer system that allows the quantification of acceleration forces generated by a moving subject. We compare the behavior of two inbred strains of mice (C57BL/6 and DBA/2) whose performance is known to differ in hippocampal tasks, including FC. The comparison is made using multiple techniques: the force transducer approach, and three observation-based methods, a computer-aided event-recording approach, a traditional time-sampling paper/pencil method, and a subjective impression-based scoring system. In addition, we investigate the correlation structures of behavioral elements quantified by event recording, using principal component analyses; we conclude that fear may manifest in multiple forms and in a stimulus- and genotype-dependent manner. We suggest that the force transducer system provides precise quantification of movements in an automated manner and will allow high-throughput screening for mutation and drug effects in mice. However, we also argue that fear responses can be complex, and freezing behavior may not be the only measure of fear or fear-associated memory.

Animals↗
PubMed1994

Cocaine preexposure sensitizes conditioned fear in a potentiated acoustic startle paradigm.

The consequences of chronic cocaine administration on fear-potentiated startle were evaluated in two experiments. Cocaine treatment (40 mg/kg) for 7 days prior to fear acquisition (light + shock pairings) had an attenuating influence on the ability of the conditioned stimulus (CS) to increase acoustic startle. When cocaine was administered in the context of the CS, following fear conditioning, a marked enhancement of potentiated startle was observed. In contrast, an extinction of the fear response was seen in saline and procaine animals repeatedly exposed to the nonreinforced CS. The results from control subjects injected with cocaine either in the shock chambers (contextual cues) or in their home cage environment, suggest that the systemic effects of this stimulant served to intensify the fear-eliciting properties acquired by the CS during fear conditioning. These findings demonstrate a cocaine sensitization of conditioned fear, and were related to the emotional and psychological disturbances associated with long-term cocaine use.

Acoustic Stimulation↗
PubMed1998

Generalization of fear responses in C57BL/6N mice subjected to one-trial foreground contextual fear conditioning.

C57BL/6N mice were trained in a foreground contextual fear conditioning paradigm by a single exposure to a context (context 1) paired with an electric shock. Conditioned mice exhibited a strong fear response, indicated by increased freezing and low locomotor activity after subsequent re-exposure to context 1, which had been used for conditioning as well as in a novel context (context 2). The fear responses to contexts 1 or 2 required the temporal sequence of the conditioned (CS) and unconditioned (US) stimuli and did not differ significantly. The intensity of the fear response was maximal 24 h after conditioning, when long-term memory was fully established. The response to context 2 was interpreted as conditioned generalization, which was also observed in the elevated plus-maze representing an environment which differed in its spatial design significantly from contexts 1 and 2. Contextual discrimination of C57BL/6N mice was enhanced after extinction of the generalized fear. Strain studies employing C57BL/6J and Balb/c mice in addition to the C57BL/6N strain revealed that Balb/c and C57BL/6J mice acquired significantly weaker conditioned fear and generalized significantly less than C57BL/6N mice. It was concluded that the intensities of the context-specific and generalized fear responses were interlinked in a strain-specific manner.

Animals↗
PubMed2001

Histamine H3 receptor-mediated impairment of contextual fear conditioning and in-vivo inhibition of cholinergic transmission in the rat basolateral amygdala.

We investigated the effects of agents acting at histamine receptors on both, spontaneous release of ACh from the basolateral amygdala (BLA) of freely moving rats, and fear conditioning. Extensive evidence suggests that the effects of histamine on cognition might be explained by the modulation of cholinergic systems. Using the microdialysis technique in freely moving rats, we demonstrated that perfusion of the BLA with histaminergic compounds modulates the spontaneous release of ACh. The addition of 100 mm KCl to the perfusion medium strongly stimulated ACh release, whereas, 0.5 microm tetrodotoxin (TTX) inhibited spontaneous ACh release by more than 50%. Histaminergic H3 antagonists (ciproxifan, clobenpropit and thioperamide), directly administered to the BLA, decreased ACh spontaneous release, an effect fully antagonized by the simultaneous perfusion of the BLA with cimetidine, an H2 antagonist. Local administration of cimetidine alone increased ACh spontaneous release slightly, but significantly. Conversely, the administration of H1 antagonists failed to alter ACh spontaneous release. Rats receiving intra-BLA, bilateral injections of the H3 antagonists at doses similar to those inhibiting ACh spontaneous release, immediately after contextual fear conditioning, showed memory consolidation impairment of contextual fear conditioning. Post-training, bilateral injections of 50 microg scopolamine also had an adverse effect on memory retention. These observations provide the first evidence that histamine receptors are involved in the modulation of cholinergic tone in the amygdala and in the consolidation of fear conditioning.

Acetylcholine↗
PubMed2002

Reduction of extracellular GABA in the mouse amygdala during and following confrontation with a conditioned fear stimulus.

In this study we examined conditioned fear-induced changes of extracellular gamma-aminobutyric acid (GABA) levels in the mouse amygdala with the in vivo microdialysis technique. Confrontation of freely behaving mice with a previously conditioned fear stimulus was accompanied by a pronounced reduction of extracellular GABA levels, indicative of a reduced GABA release and/or increased GABA uptake from the extracellular space. Reduced GABA levels were still observed in the amygdala several hours after the presentation of the conditioned stimulus. Moreover, stimulus-specific and generalized aspects of this GABA response could be distinguished according to their magnitude and time course in different behavioural groups. Our observations suggest that changes of GABAergic transmission may be involved in retrieval and expression of conditioned fear and the modulation of emotional state through the amygdala.

Acoustic Stimulation↗
PubMed2003

Mild prenatal stress in rats is associated with enhanced conditioned fear.

We tested the hypothesis that prenatal stress would enhance conditioned fear in adult rats. Pregnant Sprague-Dawley rats were stressed by exposure to a novel environment and subcutaneous injection of saline (0.1 ml 0.9% NaCl) at random times daily from Days 14 to 21 of pregnancy. When compared to adult control (CON) male rats from unmanipulated pregnancies, adult prenatally stressed (PS) male rats showed increased freezing behavior in response to acute footshock as well as increased freezing behavior the next day in the same context, without shock delivery. In another experiment, the gestational stressor was examined for elevations in corticosterone and ACTH. At gestational days (G)15, G17, G19 and G21, maternal and fetal plasma was collected. Analysis showed elevations in corticosterone and ACTH in the PS dams when compared to the CON dams. Additionally, increased corticosterone was found in the PS fetuses when compared to the CON fetuses. Finally, some CON and PS litters were examined for alterations in length of gestation, number of pups born, bodyweight on postnatal day (P)1 and anogenital distance on P1 and differences were not found. In conclusion, our data demonstrate that a mild stressor during gestation, sufficient to raise plasma corticosterone and ACTH, is associated with enhanced conditioned fear during adulthood.

Adrenocorticotropic Hormone↗
PubMed1997

Fear conditioning induces associative long-term potentiation in the amygdala.

Long-term potentiation (LTP) is an experience-dependent form of neural plasticity believed to involve mechanisms that underlie memory formation. LTP has been studied most extensively in the hippocampus, but the relation between hippocampal LTP and memory has been difficult to establish. Here we explore the relation between LTP and memory in fear conditioning, an amygdala-dependent form of learning in which an innocuous conditioned stimulus (CS) elicits fear responses after being associatively paired with an aversive unconditioned stimulus (US). We have previously shown that LTP induction in pathways that transmit auditory CS information to the lateral nucleus of the amygdala (LA) increases auditory-evoked field potentials in this nucleus. Now we show that fear conditioning alters auditory CS-evoked responses in LA in the same way as LTP induction. The changes parallel the acquisition of CS-elicited fear behaviour, are enduring, and do not occur if the CS and US remain unpaired. LTP-like associative processes thus occur during fear conditioning, and these may underlie the long-term associative plasticity that constitutes memory of the conditioning experience.

Amygdala↗
PubMed2003

Modulation of contextual fear conditioning by chronic stress in rats is related to individual differences in behavioral reactivity to novelty.

We investigated whether contextual fear conditioning could be related to the behavioral trait of locomotor reactivity to novelty in undisturbed and chronically stressed rats. Fear conditioning was found to be specifically enhanced in low reactive-stressed animals, as compared to low reactive-undisturbed rats. The results suggest that individuals that display low reactivity to novelty are more susceptible to be influenced by stress exposure to subsequently exhibit potentiated contextual fear conditioning.

Animals↗
PubMed1998

Role of NMDA receptors in the emotional memory associated with neuroendocrine responses to conditioned fear stimuli in the rat.

Behavioral experiments have shown that the N-methyl D-aspartate (NMDA) subclass of glutamate receptor plays an important role in acquisition of emotional memory. Exposure of a rat to conditioned fear stimuli suppresses vasopressin (VP) release and augments oxytocin (OT) or prolactin (PRL) release from the pituitary. Present experiments aimed at investigating the effect of intraperitonially administered MK-801, an antagonist of NMDA receptor on the emotional memory associated with the suppressive VP and the augmentative OT or PRL responses to conditioned fear stimuli in male rats. MK-801 injected 30 min before training impaired the VP, OT and PRL responses to the testing fear stimuli. The antagonist injected after training, however, did not block the responses. MK-801 administered before testing impaired the previously acquired VP, OT and PRL responses to conditioned fear stimuli. In the experiments with non-associatively applied fear stimuli, MK-801 did not block the VP, OT or PRL response. In the experiments with novel environmental stimuli, MK-801 did not impair VP, OT or PRL responses. The results suggest that an activation of NMDA receptors are required to acquire and recall but not to consolidate or retain the emotional memory associated with VP, OT and PRL responses to conditioned fear stimuli.

Animals↗
PubMed1993

5-HT1A agonists disrupt memory of fear conditioning in mice.

A series of experiments was carried out to analyze the effects of the 5-HT1A agonists tandospirone or buspirone on the retention of fear conditioning in mice. Fear was produced by pairing tone and shock in a conditioned emotional response (CER) paradigm and strength of conditioning was assessed by measuring suppression of drinking in presence of tone. Fear conditioning was disrupted if tandospirone and buspirone were administered before the conditioning session but not before the test trial. Diazepam disrupted conditioning at both times. Tandospirone did not disrupt performance if conditioning was tested 1 hr rather than 24 hr after training, suggesting that disrupted memory rather than impaired acquisition was responsible for the deficit. The effect of tandospirone on fear conditioning could be reversed by administration of d-amphetamine prior to the retention test, which suggests that information was stored but is inaccessible to normal retrieval cues. Tandospirone and buspirone also retarded extinction, a clear indication that the disruption caused by these drugs is unrelated to their anxiolytic action.

Analysis of Variance↗
PubMed1992

Frequency-specific receptive field plasticity in the medial geniculate body induced by pavlovian fear conditioning is expressed in the anesthetized brain.

Fear conditioning modifies the processing of frequency information; receptive fields (RF) in the auditory cortex and the medial geniculate body (MGB) are altered to favor processing the frequency of the conditioned stimulus (CS) over the pretraining best frequency (BF) and other frequencies. This experiment was designed to determine whether brief conditioning in the waking state produces RF plasticity that is expressed under general anesthesia. Guinea pigs bearing electrodes in the MGB received 20 trials of tone-shock pairing in a single training session. RFs were determined with animals under ketamine anesthesia before conditioning and 1-3 hr and 24 hr after conditioning. Frequency-specific RF plasticity was evident for both postconditioning periods: The BF shifted toward or to the CS frequency, responses to the BF decreased, and responses to the CS increased. Broadly tuned cells developed greater RF plasticity than narrowly tuned neurons. The results demonstrate that the specific neuronal results of brief learning experiences can be expressed in the anesthetized brain.

Amygdala↗
PubMed2000

Involvement of mu-opioid receptor in the salsolinol-associated place preference in rats exposed to conditioned fear stress.

BACKGROUND: Salsolinol, a condensation product of dopamine with acetaldehyde (the initial oxidation product of ethanol), has long been discussed as an endogenous opioid system-activating factor contributing to the etiology of alcoholism. Moreover, psychological stress has been considered to play an important role in the development of alcoholism. METHODS: Male Sprague Dawley rats were subjected to conditioned fear stress (at 24 hr after electric footshock exposure), and then salsolinol or saline was injected intraperitoneally. For conditioning, rats were immediately confined to the nonpreferred compartment after salsolinol injection and to the preferred compartment after saline injection on alternate days. This conditioning session was repeated twice daily (for 8 days). Test session was carried out 1 day after the last conditioning session. RESULTS: Salsolinol [10 mg/kg, but not 1, 3, or 30 mg/kg, intraperitoneally (ip)] without conditioned fear stress induced a slight, but significant, place preference. In contrast, salsolinol (1, 3, and 10 mg/kg, ip) with conditioned fear stress induced a marked and significant place preference. The nonselective opioid receptor antagonist naloxone hydrochloride (which can pass into the brain), but not the nonselective peripheral opioid receptor antagonist naloxone methiodide (which cannot pass into the brain), significantly attenuated the salsolinol (3 mg/kg, ip)-induced place preference under conditioned fear stress. Moreover, the selective mu-opioid receptor antagonist beta-funaltrexamine significantly attenuated the salsolinol-induced place preference. Furthermore, 0.3 mg/kg salsolinol (which produced no significant place preference) combined with the mu-opioid receptor agonist morphine [0.1 mg/kg, subcutaneously (sc)], at the dose which alone produced no significant place preference, produced a marked and significant place preference. Both naloxone hydrochloride and beta-funaltrexamine significantly attenuated the salsolinol plus morphine-induced place preference. CONCLUSIONS: Salsolinol may have some rewarding effect, and its rewarding effect may be potentiated by psychological stress. In addition, the rewarding effect of salsolinol especially under psychological stress may involve the endogenous central opioid system, i.e., mu-opioid receptor.

Alcoholism↗
PubMed2005

Memory consolidation of Pavlovian fear conditioning requires nitric oxide signaling in the lateral amygdala.

Nitric oxide (NO) has been widely implicated in synaptic plasticity and memory formation. In studies of long-term potentiation (LTP), NO is thought to serve as a 'retrograde messenger' that contributes to presynaptic aspects of LTP expression. In this study, we examined the role of NO signaling in Pavlovian fear conditioning. We first show that neuronal nitric oxide synthase is localized in the lateral nucleus of the amygdala (LA), a critical site of plasticity in fear conditioning. We next show that NO signaling is required for LTP at thalamic inputs to the LA and for the long-term consolidation of auditory fear conditioning. Collectively, the findings suggest that NO signaling is an important component of memory formation of auditory fear conditioning, possibly as a retrograde signal that participates in presynaptic aspects of plasticity in the LA.

Acoustic Stimulation↗
PubMed1995

Activation of both dopamine D1 and D2 receptors necessary for amelioration of conditioned fear stress.

Mice exhibited a marked suppression of motility when they were re-placed in the same environment in which they had previously received an electric footshock. This psychological stress-induced motor suppression, known as conditioned fear stress, was dose dependently attenuated by apomorphine, a non-selective dopamine receptor agonist. Combined treatment with the dopamine D1 receptor agonist, SKF 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1-H-3-benzazepine), and the dopamine D2 receptor agonist, quinpirole, also synergistically attenuated the conditioned fear stress although, alone, neither SKF 38393 nor quinpirole did so at the doses used. The effects of apomorphine and of the coadministration of SKF 38393 and quinpirole on the conditioned fear stress were completely blocked by the dopamine D1 receptor antagonist, SCH 23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H- 3-benzazepine), and by the dopamine D2 receptor antagonist, (-)-sulpiride. These results suggest that a dysfunction in the dopaminergic neuronal system is responsible for the conditioned fear stress, and that the activation of both dopamine D1 and D2 receptors is necessary to attenuate this stress-induced motor suppression.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMedDate not supplied

Exploratory activity and a conditioned fear response: correlation with cortical and subcortical binding of the alpha4beta2 nicotinic receptor agonist [3H]-epibatidine.

Rat behavior in the open field and the conditioned fear response test was correlated with specific binding of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) agonist, [3H]-pibatidine, assayed in different brain structures by autoradiography. A significant positive correlation was found between the ligand binding in the frontal cortex (r = 0.529, p < 0.011), the entorhinal cortex (r = 0.603, p < 0.003), and CA1 layer of the hippocampus (r = 0.465, p < 0.029), and the conditioned freezing reaction in the contextual fear conditioning test. In the frontal cortex, there was also a significant positive correlation between [3H]-epibatidine binding and preconditioned freezing reaction (r = 0.469, p < 0.028), and a negative correlation with rat motility (r = -0.452, p < 0.035). Rat motor activity correlated in a negative way with preconditioned freezing reaction (r = -0.436, p < 0.043), and in a positive way with the number of entries into the central sector of the open field (r = 0.690, p < 0.001). The neophobia-related parameter of the open field behavior (the number of central entries) did not correlate with the [3H]-epibatidine binding. Factor analysis confirmed these findings and showed that rat behavioral parameters measured in the tests of neophobia and conditioned freezing were loading on different factors, thus, pointing to separate central mechanisms operating in both behavioral models of anxiety. Furthermore, factor analysis showed that rat conditioned freezing behavior and [3H]-epibatidine binding in the CA1 layer of the hippocampus and enorhinal cortex, represented similar central processes. These findings suggest that rat emotional reactions evoked by different stressors (neophobia vs. conditioned fear) are differently regulated by the central cholinergic system. The presented data indicate also a significant, structure dependent correlation between rat conditioned emotional reaction and the alpha4beta2 nAChR ligand binding, in the rat cortical forebrain structures.

Animals↗