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PubMed2003

Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning.

The acid-sensing ion channel, ASIC1, contributes to synaptic plasticity in the hippocampus and to hippocampus-dependent spatial memory. To explore the role of ASIC1 in brain, we examined the distribution of ASIC1 protein. Surprisingly, although ASIC1 was present in the hippocampal circuit, it was much more abundant in several areas outside the hippocampus. ASIC1 was enriched in areas with strong excitatory synaptic input such as the glomerulus of the olfactory bulb, whisker barrel cortex, cingulate cortex, striatum, nucleus accumbens, amygdala, and cerebellar cortex. Because ASIC1 levels were particularly high in the amygdala, we focused further on this area. We found that extracellular acidosis elicited a greater current density in amygdala neurons than hippocampal neurons and that disrupting the ASIC1 gene eliminated H+-evoked currents in the amygdala. We also tested the effect of ASIC1 on amygdala-dependent behavior; ASIC1-null mice displayed deficits in cue and context fear conditioning, yet baseline fear on the elevated plus maze was intact. These studies suggest that ASIC1 is distributed to regions supporting high levels of synaptic plasticity and contributes to the neural mechanisms of fear conditioning.

Acid Sensing Ion Channels↗
PubMedDate not supplied

Effects of post-training hippocampal injections of midazolam on fear conditioning.

Benzodiazepines have been useful tools for investigating mechanisms underlying learning and memory. The present set of experiments investigates the role of hippocampal GABA(A)/benzodiazepine receptors in memory consolidation using Pavlovian fear conditioning. Rats were prepared with cannulae aimed at the dorsal hippocampus and trained with a series of white noise-shock pairings. In the first experiment, animals received intrahippocampal infusion of midazolam or vehicle immediately or 3 h after training. Then, 24 h later, freezing to the training context and the white noise were measured independently. Results show infusion of midazolam immediately, but not 3 h, after training selectively attenuates contextual fear conditioning. In the second experiment, animals received intrahippocampal infusions of an antisense oligodeoxynucleotide (ODN) targeting the alpha5 subunit of the GABA(A) receptor or a missense control for several days prior to training and testing. Immediately after training, animals received an infusion of either midazolam or vehicle. Western blots conducted after testing showed a significant decrease in alpha5-containing GABA(A) receptor protein. This reduction did not alter the effectiveness of midazolam immediately after training at impairing context fear memory. Therefore, alpha5-containing GABA(A) receptors may not contribute to the effects of midazolam on context fear conditioning when given immediately post-training.

Animals↗
PubMed2004

Mnemonic effects of testosterone and its 5alpha-reduced metabolites in the conditioned fear and inhibitory avoidance tasks.

Experiments were conducted to examine whether performance in hippocampally-mediated learning tasks is influenced by testosterone (T) and/or its 5alpha-reduced metabolites, dihydrotestosterone (DHT) and 3alpha-androstanediol (3alpha-diol). Performance in the conditioned fear and inhibitory avoidance tasks were examined in intact and gonadectomized (GDX), androgen-replaced rats. In Experiment 1, the behavior of intact and GDX rats in the conditioned fear paradigm were compared. GDX rats spent more time freezing, an index of increased learning, in the context, hippocampally-mediated task, but not in the cued, amygdala-mediated task. In Experiment 2, GDX rats were administered T, DHT, 3alpha-diol, estrogen (E2), or vehicle 1 mg/kg sc after training in the conditioned fear paradigm. T-, 3alpha-diol-, or E2-, compared with vehicle-administered rats, spent significantly more time freezing in the contextual, but not the cued, condition. In Experiment 3, intact compared with GDX rats had significantly longer crossover latencies, indicating better performance, in the inhibitory avoidance task. In Experiment 4, T, DHT, 3alpha-diol, or vehicle 1 mg/kg sc was administered to GDX rats immediately following training in the inhibitory avoidance task. Rats administered T, DHT, or 3alpha-diol had significantly longer crossover latencies compared with vehicle controls. In Experiment 5, androgen levels in the hippocampus were elevated 1 h following administration, when androgen exposure is essential for consolidation. These data indicate that androgens effects to enhance learning may be mediated in part by actions of 5alpha-reduced metabolites in the hippocampus.

Androstane-3,17-diol↗
PubMed2006

Glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction of conditioned fear in rats.

Recent results show that brain glucocorticoids are involved in the dysregulation of fear memory extinction in post-traumatic stress disorder patients. The present study was aimed to elucidate the possible mechanism of glucocorticoids on the conditioned fear extinction. To achieve these goals, male SD rats, fear-potentiated startle paradigm, and Western blot were used. We found that (1) systemic administration of the synthetic glucocorticoid agonist dexamethasone (DEX) facilitated extinction of conditioned fear in a dose-dependent manner (0.05, 0.1, 0.5, or 1.0 mg/kg, i.p.); (2) systemic administration of the glutamate NMDA receptor antagonist (+/-)-HA966 (6.0 mg/kg, i.p.) and intra-amygdala infusion of the NMDA receptor antagonists MK801 (0.5 ng/side, bilaterally) or D,L-2-amino-5-phosphonovaleric acid (AP5, 2.0 ng/side, bilaterally) blocked the DEX facilitation effect; (3) the corticosteroid synthesis inhibitor metyrapone (25 mg/kg. s.c.) blocked extinction and this was prevented by co-administration of NMDA receptor agonist D-cycloserine (DCS, 5.0 mg/kg, i.p.); (4) co-administration of DEX and DCS in subthreshold doses provided a synergistic facilitation effect on extinction (0.2 and 5 mg/kg, respectively). Control experiments indicated that co-administration of DEX and DCS did not alter the expression of conditioned fear and the effect was not due to lasting damage to the amygdala. These results suggest that glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction.

Amygdala↗
PubMed1999

[Effects of methamphetamine on responsiveness to conditioned fear stress].

The present study examined the effect of repeated methamphetamine (MA) pretreatment on conditioned fear stress in male Wistar-King rats. Rats received MA or the vehicle according to the repeated escalating dose schedule (1.25, 2.5, 3.75, 5 mg/kg s.c x2/every other day for a week). After a 5 day drug abstinent period, the rats were exposed to conditioned fear stress (CFS; exposure to an environment paired previously with footshock). Repeated but not single MA pretreatment significantly increased conditioned freezing behavior, suggesting that rats previously exposed to chronic MA are hypersensitive to subsequent stress than control rats. Repeated MA treatment did not decrease basal dopamine concentrations in the brain. Furthermore, repeated co-administration of MK-801 (non-competitive NMDA antagonist), amfonelic acid (dopamine reuptake inhibitor) or fluoxetine (serotonin reuptake inhibitor) with MA did not alter the enhanced freezing behavior. Taken together, it seems that MA-induced hypersensitivity to stress is not due to the neurotoxic effect of MA. While co-administration of SCH23390 (D1/5 antagonist) or raclopride (D2/3 antagonist) had no effect on the MA-induced increase in freezing, co-administration of nemonapride (D2/3/4 antagonist) prevented this increase. These results suggest that MA-induced enhancement of anxiety might be mediated by D4 receptors. The homovanilic acid (HVA) levels in the striatum were elevated by footshock in MA-treated rats but not in saline-treated rats. Furthermore, MA-treated rats showed increased metabolism of dopamine (DA) in the medial prefrontal cortex (mPFC), even when placed in the shock chamber without shocks. The HVA levels in the striatum in MA-treated rats were more elevated by CFS than these in saline-treated rats. These results suggest that the striatum DA system, as well as the mPFC DA system suggested previously, may be associated with emotional hypersensitivity to stress following repeated MA treatment.

Animals↗
PubMed1999

Strain and substrain differences in context- and tone-dependent fear conditioning of inbred mice.

The performance of C57BL/6J (6J), C57BL/6N (6N), DBA/2J (2J) and DBA/2N (2N) mice in context- and tone-dependent fear conditioning was determined 24 h after fear conditioning to evaluate and compare different behavioral measures as indices of emotional learning. Freezing, the change in activity and the size of the explored area were evaluated as behavioral parameters indicating fear. Additionally, the heart rate (HR) increase elicited by tone presentation was evaluated as an autonomic indicator of fear. During the context-dependent memory test, freezing was high only in 6J and 6N mice, whereas a drop of activity and a reduced exploratory area was measured in all strains. During the tone-dependent memory test, high freezing, low activity, reduced exploratory area and a strong HR increase were demonstrated only in 6N and 6J mice, whereas behavioral and HR changes of 2J and 2N mice were always low. In extinction tests, context- and tone-dependent freezing of 6J mice decayed significantly faster than the freezing of 6N mice, whereas in both substrains the conditioned tachycardia to tone extinguished similarly in the home cage. The data demonstrate that monitoring of additional behavioral measures besides freezing and autonomic measures is necessary to interpret differences in associative learning performance of mouse strains that could be related to a differential expression of fear.

Acoustic Stimulation↗
PubMed2000

Suppression of conditioned fear by administration of CRF receptor antagonist CP-154,526.

In order to examine the involvement of corticotropin-releasing hormone (CRF) receptor in the formation of anxiety, we investigated whether CRF receptor antagonist CP-154,526 suppressed conditioned fear stress. First, rats were individually subjected to 30 min of footshock. Twenty-four hours after footshock, the rats were again placed in the chamber and observed for 5 min without shock. CP-154,526 was administered 30 min before placing the rats in the chamber again. After that, CP-154,526 was once more administered 30 min before applying footshock. Administration of CP-154,526 30 min both before conditioned fear stress (placing the rats inside the cage but not applying footshock) and before actual footshock significantly reduced freezing behavior. These results show that CP-154,526 blocked both the acquisition and expression of conditioned fear, thus suggesting that the CRF receptor might be related to anxiety.

Animals↗
PubMed2002

Phosphorylation of hippocampal Erk-1/2, Elk-1, and p90-Rsk-1 during contextual fear conditioning: interactions between Erk-1/2 and Elk-1.

The phosphorylation of proteins involved in the MAP kinase signal transduction pathway was investigated during associative learning of C57BL/6J mice. Context-dependent fear conditioning, consisting of a single exposure of mice to a context followed by foot shock, was employed as a learning paradigm. Control groups consisted of mice exposed to context only or an immediate shock in the context. Coincident up-regulation of phosphorylated Erk-1/2 and Elk-1 was observed in the CA3 hippocampal subfield and dentate gyrus 30 min after fear conditioning but not after the control paradigms. Phosphorylated Erk-1/2 and Elk-1 were associated and predominantly colocalized in the mossy fibers. In vitro kinase assays showed that hippocampal Erk-1/2 phosphorylates Elk-1. Notably, Elk-1 in turn enhances the phosphorylation of Erk-1/2 and its downstream target p90Rsk-1. Increased phosphorylation and nuclear translocation of p90Rsk-1 was also demonstrated in the CA3 hippocampal area in vivo during contextual fear conditioning. The observed interactions between hippocampal Elk-1 and Erk-1/2 proteins may affect the consolidation of contextual memories through activation of the downstream nuclear targets of Erk-1/2, such as p90Rsk-1, without requiring nuclear translocation of Elk-1 and Erk-1/2.

Active Transport, Cell Nucleus↗
PubMed1993

Purkinje cell responses in the anterior cerebellar vermis during Pavlovian fear conditioning in the rabbit.

Extracellular single-unit recordings of Purkinje cells in the anterior cerebellar vermis (ACV) of the rabbit found evidence of short-latency (20-30 ms) differential responses to discriminatively-conditioned auditory stimuli during Pavlovian fear conditioning procedures. These differential unit responses appeared to be a function of learning as differential ACV Purkinje cell responses were not observed in naive (untrained) animals. Some of these evoked neurophysiological responses were also correlated with the behavioral conditioned autonomic response. (CAR); a conditioned bradycardiac response. These electrophysiological data, coupled with previous lesion results, suggest that the ACV is part of an important neural circuit for Pavlovian conditioned bradycardia.

Acoustic Stimulation↗
PubMed2001

Conjunctive representations, the hippocampus, and contextual fear conditioning.

The context in which events occur can be represented as both (1) a set of independent features, the feature representation view, and (2) a set of features bound into a unitary representation, the conjunction representation view. It is assumed that extrahippocampal (e.g., neocortical) areas provide a basis for feature representations, but the hippocampal formation makes an essential contribution to the automatic storage of conjunctive representations. We develop this dual-representation view and explore its implications for hippocampal contributions to contextual fear conditioning processes. To this end, we discuss how our framework can resolve some of the conflicts in the recent literature relating the hippocampus to contextual fear conditioning. We also present new data supporting the role of a key mechanism afforded by conjunctive representations--pattern completion (the ability of a subset of a memory pattern to activate the complete memory)--in contextual fear conditioning. As is implied by this mechanism, we report that fear can be conditioned to the memory representation of a context that is not actually present at the time of shock. Moreover, this result is predicted by our computational model of cortical and hippocampal function. We suggest that pattern completion demonstrated in animals and by our model provides a mechanistic bridge to human declarative memory.

Animals↗
PubMed1989

Response characteristics of neurons in the medial component of the medial geniculate nucleus during Pavlovian differential fear conditioning in rabbits.

Recent evidence suggests that the amygdaloid central nucleus (ACE) may contribute significantly to Pavlovian fear-conditioned bradycardic responses during the presentation of conditioned emotional stimuli. Because the medial component of the medial geniculate nucleus (MGm) is a major source of input to the region of the ACE, the extracellular single-unit responses of MGm neurons were examined during Pavlovian differentially conditioned bradycardic responding in rabbits. Conditioning involved pairing one tone (CS+) with paraorbital shock and presenting another tone (CS-) in the absence of shock. Two general classes of MGm neurons were identified based on their conditioned-response characteristics. Both groups responded differentially to the CSs. One group responded with greater increases in activity and at a shorter latency to the CS+ compared with the CS-, whereas the other group responded with greater increases in activity and at a shorter latency to the CS- compared with the CS+. Recordings from MGm neurons in naive rabbits prior to conditioning provided evidence that the acoustic stimuli used subsequently as the CS+ and CS- did not evoke differential responses. These results suggest that the MGm along with the ACE may be forebrain components of a neural circuit involved in the acquisition and/or expression of Pavlovian fear-conditioned bradycardic responses.

Amygdala↗
PubMed2006

The role of group I metabotropic glutamate receptors in acquisition and expression of contextual and auditory fear conditioning in rats - a comparison.

Glutamatergic neurotransmission in the CNS plays a predominant role in learning and memory. While NMDA receptors have been extensively studied, less is known about the involvement of group I metabotropic glutamate receptors in this area. The purpose of the present study was to evaluate the contribution of mGluR1 and mGluR5 to both acquisition and expression of behaviours in contextual and auditory fear conditioning models. The effects of both receptor types were tested using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGluR1, and [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGluR5. Their effects on acquisition were compared to those of the NMDA receptor antagonist (+)MK-801, and the unselective muscarinic antagonist scopolamine, while diazepam and citalopram served as reference compounds in the expression experiments. EMQMCM (1.25 to 5mg/kg) impaired acquisition of contextual fear conditioning (CFC), but not auditory fear conditioning (AFC). Similarly, administration of MTEP during the acquisition phase impaired learning in CFC at doses of 2.5 to 10mg/kg, but was ineffective in AFC. When given before the retention test, both EMQMCM (1 and 3mg/kg) and MTEP (3mg/kg) impaired expression of CFC. In contrast, MTEP (2.5 and 5mg/kg) blocked the expression of AFC, while EMQMCM was ineffective. In conclusion, group I mGlu receptors are shown to be involved in the acquisition of hippocampus-dependent CFC, but not hippocampus-independent AFC. Unlike mGluR5, mGluR1 does not seem be involved in expression of AFC.

Acoustic Stimulation↗
PubMed1991

Induction of the c-fos proto-oncogene in rat amygdala during unconditioned and conditioned fear.

Induction of the nuclear proto-oncogene c-fos in rat amygdala was investigated 30-40 min following the presentation of mild footshocks (unconditioned fear) or of contextual cues associated with similar footshocks 24 h earlier (conditioned fear). Initially, it was found that handling rats for the first time elevated c-fos mRNA levels, but this response could be blocked completely by repeated handling. Unconditioned and conditioned fear both elevated amygdala c-fos mRNA dramatically above control levels.

Amygdala↗
PubMed1999

Basolateral amygdala is involved in modulating consolidation of memory for classical fear conditioning.

Previous findings indicate that the basolateral amygdala complex of nuclei (BLC) is involved in modulating (i.e., enhancing or impairing) memory consolidation for aversive training such as inhibitory avoidance. The present study examined whether the BLC also modulates the consolidation of memory for classical fear conditioning in which a specific context is paired with footshock. Adult male rats with bilateral cannulae targeting the BLC were allowed, first, to habituate in a Y maze that had differently shaped and textured arms. On the next day the rats were placed in one maze arm (shock arm), and they received four unsignaled footshocks. In Experiment 1, immediately after the training some rats received BLC inactivation with lidocaine (10 microgram/0.2 microliter per side), and control rats received buffered saline. In Experiment 2, rats received immediate post-training intra-BLC infusions of the muscarinic receptor agonist oxotremorine (10 ng/0.2 microliter per side) or saline. On a 24 hr retention test each rat was placed in a "safe" arm of the maze and allowed to access all maze arms. Lidocaine-treated rats had impaired memory for the classical fear conditioning when they were compared with the saline-treated controls: they spent less time freezing, entered the shock arm more readily and more often, and spent more time in it. In contrast, oxotremorine-treated rats had a stronger memory for the context-footshock association as assessed by all measures of memory. Thus, post-training treatments affecting BLC function modulate memory for Pavlovian contextual fear conditioning in a manner similar to that found with other types of training.

Amygdala↗
PubMed1995

Fear conditioning, preparedness, and the contingent negative variation.

Psychophysiological research on preparedness has previously focused on autonomic nervous system parameters. The present study used electrocortical indices of fear conditioning. Subjects (n = 10) were tested under fear-relevant and fear-irrelevant conditions (1 week apart, order of conditions counterbalanced). Each condition comprised acquisition and extinction sessions. The contingent negative variation (CNV) was elicited in anticipation of forewarned slides (fear relevant: small animals; fear irrelevant: landscapes). In acquisition, reinforced conditioned stimulus (CS+) (but not nonreinforced conditioned stimulus [CS-]) slides were followed by white noise as an unconditioned stimulus (UCS). In extinction, the UCS was omitted. In the fear-relevant condition, CNV amplitude was significantly larger for CS+ than CS- in both acquisition and extinction. In the fear-relevant condition, CNV amplitude was significantly larger for CS+ than CS- in both acquisition and extinction. In the fear-irrelevant condition, CNV differentiation between CS+ and CS- was weak in both sessions. CNV was significantly larger in the fear-relevant than in the fear-irrelevant condition, for CS+ but not CS-. The findings are consistent with a preparedness interpretation and suggest that CNV under such circumstances may represent an automatic affective response to fear-relevant stimuli. Electrocortical measures could be particularly useful in examining information processing mechanisms in phobia and cognition-affect relationships generally.

Adolescent↗
PubMed2004

Intra-medial prefrontal administration of SCH-23390 attenuates ERK phosphorylation and long-term memory for trace fear conditioning in rats.

The prefrontal cortex is known to be involved in the acquisition of trace conditioning, a higher-cognitive form of Pavlovian conditioning in which a conditioned stimulus and an unconditioned stimulus are separated by a time gap. We have recently reported that medial prefrontal (mPFC) extracellular-signal regulated kinase (Erk) phosphorylation is involved in the long-term memory storage of trace fear conditioning. Because of the important role dopamine D1 receptors play in prefrontal function, such as working memory, and due to evidence that dopamine D1 receptor activity can modulate plasticity, we investigated their role in prefrontal Erk phosphorylation following trace fear conditioning. We found that inhibition of dopamine D1 receptors through intra-mPFC infusion of SCH-23390 (1 microg/0.5 microL) 15 min prior to trace fear conditioning resulted in a decrease in training-related Erk phosphorylation. Additionally, pre-training intra-mPFC infusion of SCH-23390 also resulted in the impairment of long-term retention of CS-US association. These findings implicate mPFC dopamine D1 receptor activity in the storage of long-term memory for higher-cognitive associative tasks.

Analysis of Variance↗
PubMed2004

Brain-derived neurotrophic factor plays a critical role in contextual fear conditioning.

In this study, brain-derived neurotrophic factor (BDNF) heterozygous knock-outs were tested on fear conditioning, and their wild-type littermates were used as controls. Results showed that BDNF(+/-) mice are impaired in contextual learning, whereas tone learning remains intact. Because BDNF is involved in synaptic transmission and contextual learning is hippocampal dependent, we hypothesized that this deficit is attributable to abnormal BDNF-modulated synaptic plasticity in the hippocampus. A "gain-of-function" experiment was performed next by infusing recombinant BDNF protein into the hippocampal formation to investigate whether this deficit can be rescued. Infusion of BDNF protein into the hippocampus appeared to partially restore contextual fear learning of BDNF(+/-) mice. In conclusion, the present study suggests that BDNF plays a critical role in fear conditioning. Loss of one copy of the BDNF gene leads to impairment of contextual fear learning in BDNF(+/-). This deficit can be partially rescued by infusing BDNF protein into the hippocampus. Other brain regions interacting with the hippocampus in the context conditioned stimulus pathway, for example, the amygdala, may also require normal BDNF expression levels to fully rescue this impairment.

Amygdala↗
PubMed2006

Cholinergic modulation of Pavlovian fear conditioning in rats: differential effects of intrahippocampal infusion of mecamylamine and methyllycaconitine.

The cholinergic system has consistently been implicated in Pavlovian fear conditioning. Considerable work has been done to localize specific nicotinic receptor subtypes in the hippocampus and determine their functional importance; however, the specific function of many of these subtypes has yet to be determined. An alpha7 nicotinic antagonist methyllycaconitine (MLA) (35 microg), and a broad spectrum non-alpha7 nicotinic antagonist mecamylamine (35 microg) was injected directly into the dorsal hippocampus or overlying cortex either 15 min pre-, 1 min post-, or 6h post-fear conditioning. One week after conditioning, retention of contextual and cue (tone) conditioning were assessed. A significant impairment in retention of contextual fear was observed when mecamylamine was injected 15 min pre- and 1 min post-conditioning. No significant impairment was observed when mecamylamine was injected 6h post-conditioning. Likewise, a significant impairment in retention of contextual fear was observed when MLA was injected 1 min post-conditioning; however, in contrast, MLA did not show any significant impairments when injected 15 min pre-conditioning, but did show a significant impairment when injected 6h post-conditioning. There were no significant impairments observed when either drug was injected into overlying cortex. No significant impairments were observed in cue conditioning for either drug. In general, specific temporal dynamics involved in nicotinic receptor function were found relative to time of receptor dysfunction. The results indicate that the greatest deficits in long-term retention (1 week) of contextual fear are produced by central infusion of MLA minutes to hours post-conditioning or mecamylamine within minutes of conditioning.

Aconitine↗