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PubMed2001

The amygdala is essential for the development of neuronal plasticity in the medial geniculate nucleus during auditory fear conditioning in rats.

The medial geniculate nucleus of the thalamus (MGN) and the basolateral complex of the amygdala (BLA) are critical components of the neural circuit that mediates auditory fear conditioning. Several studies indicate that neurons in both the MGN and BLA exhibit associative plasticity of spike firing during auditory fear conditioning. In the present study, we examined whether the development of plasticity in the MGN requires the BLA. Single units were recorded from chronic multichannel electrodes implanted in the medial division of the MGN of conscious and freely moving rats. Rats received auditory fear conditioning trials, which consisted of a white-noise conditional stimulus (CS) and a co-terminating footshock unconditional stimulus (US). Unpaired (sensitization) controls received the same number of trials as paired animals, but the CS and US were explicitly unpaired. Before fear conditioning, rats received either an intra-amygdala infusion of muscimol, a GABA(A) receptor agonist, to inactivate BLA neurons or an infusion of the saline vehicle. Auditory fear conditioning produced a substantial increase in both CS-elicited spike firing in the MGN and conditional freezing behavior in vehicle-treated rats receiving paired training. Muscimol inactivation of the BLA severely attenuated the development of both conditioning-related increases in CS-elicited spike firing in the MGN and conditional freezing to the auditory CS. Unpaired training did not yield increases in either CS-elicited spike firing or freezing to the tone CS. These results reveal that the BLA is essential to the development of plasticity in the auditory thalamus during fear conditioning.

Acoustic Stimulation↗
PubMed2004

Intra-amygdala administration of polyamines modulates fear conditioning in rats.

Amygdalar NMDA receptor activation has been implicated in the acquisition of fear memories in rats. However, little is known about the role of endogenous modulators of the NMDA receptor, such as polyamines, in pavlovian fear-conditioning learning. Therefore, in the present study we investigated whether the immediate pretraining or post-training bilateral infusion of arcaine, an antagonist of the NMDA receptor polyamine-binding site, or spermidine, an agonist of the NMDA receptor polyamine-binding site, into the amygdala affected classical fear conditioning in rats. Bilateral microinjections of arcaine (0.0002-0.2 nmol) decreased, whereas spermidine (0.002-20 nmol) increased, contextual and auditory fear conditioning. Arcaine coadministration, at a dose that had no effect per se, reversed the facilitatory effect of spermidine. These results provide evidence that endogenous and exogenous polyamines modulate the acquisition or early consolidation (or both) of the fear-conditioning task in the amygdala.

Amygdala↗
PubMed2001

Human fear conditioning is related to dopaminergic and serotonergic biological markers.

Biological markers for acquisition and extinction of fear conditioning were studied in 40 individuals selected for displaying either good or poor acquisition of fear conditioning. as estimated by the skin conductance response. Participants with a short serotonin transporter (5-HTT) promoter allele or low monoamine oxidase activity in platelets (trbc-MAO) displayed better acquisition than those with only long alleles or high trbc-MAO, whereas participants with a long dopamine D4 receptor (D4DR) exon III allele showed delayed extinction compared with those with only short alleles. The findings, that D4DR exon III and 5-HTT promoter genotypes and trbc-MAO activity are related to human fear conditioning, a basic form of associative learning, are consistent with animal studies suggesting a genetic contribution to fear conditioning. The authors suggest that in humans these genetic mechanisms are partly dopaminergic and serotonergic in origin.

Alleles↗
PubMed2006

Metabotropic glutamate subtype 5 receptors modulate fear-conditioning induced enhancement of prepulse inhibition in rats.

Non-startling acoustic events presented shortly before an intense startling sound can inhibit the acoustic startle reflex. This phenomenon is called prepulse inhibition (PPI), and is widely used as a model of sensorimotor gating. The present study investigated whether PPI can be modulated by fear conditioning, whose acquisition can be blocked by the specific antagonist of metabotropic glutamate receptors subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The results show that a gap embedded in otherwise continuous noise sounds, which were delivered by two spatially separated loudspeakers, could inhibit the startle reflex induced by an intense sound that was presented 50 ms after the gap. The inhibitory effect depended on the duration of the gap, and was enhanced by fear conditioning that was introduced by temporally pairing the gap with footshock. Intraperitoneal injection of MPEP (0.5 or 5mg/kg) 30 min before fear conditioning blocked the enhancing effect of fear conditioning on PPI, but did not affect either the baseline startle magnitude or PPI if no fear conditioning was introduced. These results indicate that PPI is enhanced when the prepulse signifies an aversive event after fear conditioning. Also, mGlu5Rs play a role in preserving the fear-conditioning-induced enhancement of PPI.

Analysis of Variance↗
PubMed2000

Locomotor activity and a conditioned fear response: correlation with cortical and subcortical binding of the dopamine D1 receptor antagonist.

Rat behavior in the open field and conditioned fear response test was correlated with specific binding of dopamine D1 receptor antagonist [3H]SCH 23390 within different brain structures assayed with autoradiography. A significant positive correlation was found between the ligand binding in the substantia nigra pars reticulata and both animal motor activity (r = 0.67, p < 0.05) and the number of entries into the central sector of the open field (r = 0.59, p < 0.05). On the other hand, rat motility and the central entries were negatively correlated with [3H]SCH 23390 binding within the caudate putamen (r = -0.64, p < 0.05 and r = -0.61 p <0.05, respectively). No correlation was revealed between the ligand binding in the examined brain areas and freezing reaction in the contextual fear conditioning test. The present data indicate for the first time a significant, structure-dependent correlation between rat motor behavior and the dopamine D1 receptor ligand binding within the nigrostriatal system.

Animals↗
PubMed2005

Auditory fear conditioning and long-term potentiation in the lateral amygdala require ERK/MAP kinase signaling in the auditory thalamus: a role for presynaptic plasticity in the fear system.

In the present study, we examined the role of the auditory thalamus [medial division of the medial geniculate nucleus and the adjacent posterior intralaminar nucleus (MGm/PIN)] in auditory pavlovian fear conditioning using pharmacological manipulation of intracellular signaling pathways. In the first experiment, rats were given intrathalamic infusions of the MEK (mitogen-activated protein kinase-kinase) inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene (U0126) before fear conditioning. Findings revealed that long-term memory (assessed at 24 h) was impaired, whereas short-term memory (assessed at 1-3 h) of fear conditioning was intact. In the second experiment, rats received immediate posttraining intrathalamic infusion of U0126, the mRNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), or infusion of the protein synthesis inhibitor anisomycin. Posttraining infusion of either U0126 or DRB significantly impaired long-term retention of fear conditioning, whereas infusion of anisomycin had no effect. In the final experiment, rats received intrathalamic infusion of U0126 before long-term potentiation (LTP)-inducing stimulation of thalamic inputs to the lateral nucleus of the amygdala (LA). Findings revealed that thalamic infusion of U0126 impaired LTP in the LA. Together, these results suggest the possibility that MGm/PIN cells that project to the LA contribute to memory formation via ERK (extracellular signal-regulated kinase)-mediated transcription, but that they do so by promoting protein synthesis-dependent plasticity locally in the LA.

Acoustic Stimulation↗
PubMed1995

The attenuation of suppression of motility by triazolam in the conditioned fear stress task is exacerbated by ethanol in mice.

We investigated whether triazolam attenuated the suppression of motility in the conditioned fear stress task in mice and whether ethanol modified the effects of triazolam. When mice were placed 24 hours later (retention test) in the same environment in which they had previously been exposed to an electric foot shock (training), they exhibited a marked suppression of motility (conditioned fear stress). Triazolam (0.01-0.1 mg/kg, s.c.), administered before training, attenuated the suppression of motility in the conditioned fear stress task in a dose-dependent manner, without affecting the sensitivity to an electric foot shock. The doses of triazolam that attenuated the suppression of motility were much lower that those of chlordiazepoxide (5-10 mg/kg, s.c.). Neither drug, administered before the retention test, attenuated the suppression of motility in the conditioned fear stress task. These results suggest that both benzodiazepines may inhibit the process of acquisition, but not the process of recall, of memory. Ethanol (1 g/kg, p.o.), which, by itself, did not affect either the suppression of motility or the sensitivity to an electric foot shock, exacerbated the attenuation of the suppression of motility in the conditioned fear stress task induced by both triazolam (0.01 mg/kg) and chlordiazepoxide (5 mg/kg). These results suggest that ethanol exacerbates the effects of benzodiazepines.

Animals↗
PubMed1995

Scopolamine selectively disrupts the acquisition of contextual fear conditioning in rats.

Muscarinic cholinergic antagonism produces learning and memory deficits in a variety of hippocampal-dependent tasks. Hippocampal lesions produce both acquisition deficits and retrograde amnesia for contextual fear conditioning, but do not impact fear conditioning to discrete cues. In order to examine the effects of muscarinic antagonism in this paradigm, rats were given scopolamine (1 mg/kg) either before or for 3 days after a Pavlovian fear-conditioning session in which tones were paired with aversive footshocks. Fear to the context and the tone was assessed by measuring freezing in separate tests. It ws found that pretraining, but not posttraining, scopolamine severely impaired contextual fear conditioning; tone conditioning was not affected under either condition (cf., Young, Bohenek, & Fanselow, Neurobiology of Learning and Memory, 63, 174-180, 1995).

Animals↗
PubMed2006

Effects of ventral and dorsal CA1 subregional lesions on trace fear conditioning.

Recent lines of research have focused on dissociating function between the dorsal and ventral hippocampus along space and anxiety dimensions. In the dorsal hippocampus, the CA1 subregion has been implicated in the acquisition of contextual fear as well as in the trace interval in trace fear conditioning. The present study was designed to test the relative contributions of dorsal (dCA1) and ventral CA1 (vCA1) in trace fear conditioning. Long-Evans rats received ibotenate lesions of the ventral CA1 (n=7), dorsal CA1 (n=9), or vehicle control lesions (n=8) prior to trace fear conditioning acquisition. Results suggest dCA1 and vCA1 groups show no significant deficits during acquisition when compared to control groups. dCA1 and vCA1 both show deficits in the retention of contextual fear when tested 24 h post-acquisition (P<.05 and P<.01, respectively), and vCA1 was impaired relative to dCA1 (P<.05). This is suggestive of a graded involvement in contextual retention between the dorsal and ventral aspects of CA1. dCA1 showed no deficit for retention of conditioned fear to the tone or the trace when tested 48 h post-acquisition, whereas vCA1 did show a significant deficit for the trace interval and a slight, non-significant reduction in freezing to the tone, when compared to the control group (p<.05). Overall the data are suggestive of a graded involvement in retention of fear conditioning between the dorsal and ventral aspects of CA1, but it is likely that vCA1 may be critically involved in retention of trace fear conditioning.

Animals↗
PubMed1997

Fear conditioning induces a lasting potentiation of synaptic currents in vitro.

The amygdala plays a critical role in the mediation of emotional responses, particularly fear, in both humans and animals. Fear conditioning, a conditioned learning paradigm, has served as a model for emotional learning in animals, and the neuroanatomical circuitry underlying the auditory fear-conditioning paradigm is well characterized. Synaptic transmission in the medial geniculate nucleus (MGN) to lateral nucleus of the amygdala (LA) pathway, a key segment of the auditory fear conditioning circuit, is mediated largely through N-methyl-D-aspartate (NMDA) and non-NMDA (such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)) glutamate receptors; the potential for neural plasticity in this pathway is suggested by its capacity to support long-term potentiation (LTP). Here we report a long-lasting increase in the synaptic efficacy of the MGN-LA pathway attributable to fear-conditioning itself, rather than an electrically induced model of learning. Fear-conditioned animals show a presynaptic facilitation of AMPA-receptor-mediated transmission, directly measured in vitro with whole-cell recordings in lateral amygdala neurons. These findings represent one of the first in vitro measures of synaptic plasticity resulting from emotional learning by whole animals.

Amygdala↗
PubMed1998

Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning.

The reported experiments explore the effects of peripheral LPS administration on learning and memory processes. As measured by the conditioned freezing response, intraperitoneal LPS administration given after conditioning impaired contextual but not auditory-cue fear conditioning in both juvenile (hooded Long Evans) and adult rats (albino Sprague Dawley) of two different strains. This impairment in contextual fear conditioning was not dependent on the presence of the tone. Preexposure to the context eliminated the effect of LPS on contextual fear conditioning, and in addition, LPS given after context preexposure negated the beneficial effects of preexposure on contextual fear. These results suggest that LPS disrupts posttrial memory consolidation processes. In support of the hypothesis that LPS-induced proinflammatory cytokine release is involved in producing the impairment in contextual fear caused by LPS, peripheral interleukin-1 receptor antagonist (IL-1ra) administered subcutaneously at a dose of 100 mg/kg prevented the impairment in contextual fear caused by LPS. These experiments provide evidence for a role of immune activation and cytokine activity in learning and memory processes.

Acoustic Stimulation↗
PubMed1998

A role for brain glucocorticoid receptors in contextual fear conditioning: dependence upon training intensity.

We studied the possible involvement of corticosteroids in the establishment and long-term expression of contextual fear conditioning and questioned whether a corticosteroid action might be dependent upon stimulus intensity at training. Experiments included: (i) the intracerebroventricular administration of specific antagonists for the two types of intracellular corticosteroid receptors to rats trained at either 1 mA or 0.4 mA shock intensity at conditioning; and (ii) the administration of corticosterone after conditioning rats to 0.2 mA shocks. The results showed that the administration of a type II glucocorticoid, but not a type I mineralocorticoid, receptor antagonist before conditioning rats to the intermediate shock condition attenuated long-term expression of contextual fear conditioning. However, treatment with the antagonists before conditioning to the high shock intensity failed to influence the extent of fear conditioning. In addition, an intraperitoneal corticosterone injection, given immediately after training rats at the low shock intensity, enhanced long-term expression of the fear response. The results support the view that post-training levels of circulating corticosterone, through an interaction with central type II glucocorticoid receptors, modulate the strength to which memory for contextual fear conditioning is established and maintained.

Animals↗
PubMed1999

Nicotine enhancement of contextual fear conditioning.

Nicotine has been suggested to have cognitive enhancing effects. The present study examined the effects of nicotine and the nicotinic antagonist mecamylamine on contextual fear conditioning in C57BL/6 mice. The fear conditioning task was chosen because the task examines two types of learning: contextual learning, and conditioned stimulus (CS)-unconditioned stimulus (US) learning. Multiple doses of nicotine were tested and 0.5 mg/kg nicotine, given on both training and testing days, improved contextual learning but had no effect on formation of an auditory CS-US association. No effect was found at lower doses or when nicotine was given on training day only, or testing day only. The nicotinic receptor antagonist mecamylamine (1 and 2 mg/kg) did not alter contextual fear conditioning but mecamylamine did prevent the nicotine-associated increase in contextual learning. A higher dose of nicotine (1 mg/kg, training day only) interfered with contextual conditioning when the context was paired with both the CS and US, but had no effect on the auditory CS-US association. This effect of 1 mg/kg nicotine on contextual learning disappeared when mice were trained without the CS. The present results indicate that nicotine enhancement of contextual fear conditioning is dose-dependent, but the presence of nicotine is required both during training and testing.

Animals↗
PubMedDate not supplied

Automated measurement of mouse freezing behavior and its use for quantitative trait locus analysis of contextual fear conditioning in (BALB/cJ x C57BL/6J)F2 mice.

The most commonly measured mouse behavior in fear conditioning tests is freezing. A technical limitation, particularly for genetic studies, is the method of direct observation used for quantifying this response, with the potential for bias or inconsistencies. We report the use of a computerized method based on latency between photobeam interruption measures as a reliable scoring criterion in mice. The different computer measures obtained during contextual fear conditioning tests showed high correlations with hand-scored freezing; r values ranged from 0.87 to 0.94. Previously reported strain differences between C57BL/6J and DBA/2J in context-dependent fear conditioning were also detected by the computer-based system. In addition, the use of computer-scored freezing of 199 (BALB/cJ x C57BL/6J)F2 mice enabled us to detect a suggestive gender-dependent chromosomal locus for contextual fear conditioning on distal chromosome 8 by QTL analysis. Automation of freeze scoring would significantly increase efficiency and reliability of this learning and memory test.

Animals↗
PubMed2002

Cardiovascular and behavioural components of conditioned fear to context after ganglionic and alpha-adrenergic blockade.

This study investigates the contribution of the peripheral nervous system to the cardiovascular component of long lasting (40 min) conditioned fear responses to context. The conditioned fear response evoked by reexposure to a footshock chamber was tested 10 min after intravenous injection of either the nicotinic ganglion blocker chlorisondamine (0.6 mg/kg) or the alpha-adrenoceptor antagonist phentolamine (10 mg/kg) in six rats implanted with telemetric probes. Compared to saline controls, chlorisondamine did not change the behavioural component of the response (freezing, ultrasonic vocalizations) but almost completely abolished its cardiovascular component (mean arterial pressure and heart rate). Phentolamine also abolished the pressor response but increased the cardiac response, and ultrasonic vocalizations were reduced by half. The results indicate that the long lasting pressor response of conditioned fear to context is sympathetically mediated like the much shorter pressor response of conditioned fear to a discrete stimulus.

Adrenergic alpha-Antagonists↗
PubMed2006

Fear conditioning is impaired in systemic kainic acid and amygdala-stimulation models of epilepsy.

PURPOSE: The lateral nucleus of the amygdala is critical for fear conditioning, a paradigm of emotional learning, which requires recognition of an unconditioned stimulus as aversive and association of conditioned stimuli with an unconditioned stimulus. Some patients with temporal lobe epilepsy have amygdaloid damage associated with impaired emotional learning. Fear conditioning also is impaired at least in some animal models of epilepsy. We studied whether contextual or tone-cued fear conditioning is impaired in two status epilepticus models of epilepsy and whether impairment correlates with the extent of damage in the lateral nucleus of the amygdala. METHODS: We induced epilepsy in rats by either systemic kainic acid administration or electrical amygdala stimulation. Behavioral reactions in all phases of fear conditioning were analyzed from videotapes. Damage to the lateral nucleus of the amygdala was analyzed from thionin-stained sections both histologically and by volumetry. RESULTS: Immediate reflexive responses to unconditioned and conditioned stimuli were preserved, whereas the freezing response to an unconditioned stimulus was reduced. Contextual conditioning was severely impaired, whereas tone-cued conditioning was better preserved. The lateral nucleus pathology did not correlate with impaired fear conditioning. CONCLUSIONS: These data suggest that processing of complex contextual stimuli is severely affected in experimental epilepsy, whereas conditioning to simple cues is better preserved.

Acoustic Stimulation↗
PubMed2005

Classical fear conditioning in the anxiety disorders: a meta-analysis.

Fear conditioning represents the process by which a neutral stimulus comes to evoke fear following its repeated pairing with an aversive stimulus. Although fear conditioning has long been considered a central pathogenic mechanism in anxiety disorders, studies employing lab-based conditioning paradigms provide inconsistent support for this idea. A quantitative review of 20 such studies, representing fear-learning scores for 453 anxiety patients and 455 healthy controls, was conducted to verify the aggregated result of this literature and to assess the moderating influences of study characteristics. Results point to modest increases in both acquisition of fear learning and conditioned responding during extinction among anxiety patients. Importantly, these patient-control differences are not apparent when looking at discrimination studies alone and primarily emerge from studies employing simple, single-cue paradigms where only danger cues are presented and no inhibition of fear to safety cues is required.

Anxiety Disorders↗
PubMed1999

Blocked and overshadowed stimuli are weakened in their ability to serve as blockers and second-order reinforcers in Pavlovian fear conditioning.

The ability of a blocked or overshadowed conditioned stimulus (CS) to serve as (a) blocker or (b) a 2nd-order reinforcer in Pavlovian fear conditioning was tested in 152 albino rats. CS-evoked suppression of barpressing for food was the index of conditioned fear. Experiments 1 and 2 showed that an overshadowed CS was weakened in its ability to serve as a blocker. In Experiment 2, a blocked CS was similarly weakened. Experiment 3 showed that an overshadowed and blocked CS was weakened in its ability to serve as a 2nd-order reinforcer. Experiments 4 and 5 failed to restore the blocking ability of blocked (Experiment 4) or overshadowed (Experiment 5) CSs by extinguishing the CSs that had blocked or overshadowed them. Results favor a learning-deficit view of blocking and overshadowing.

Animals↗