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PubMed2006

Subchronic rolipram delivery activates hippocampal CREB and arc, enhances retention and slows down extinction of conditioned fear.

Rolipram, a type IV-specific phosphodiesterase inhibitor, is known to improve memory under various learning tasks. Moreover, Rolipram treatments have been shown to increase expression and phosphorylation of a key factor for hippocampal memory consolidation, the cAMP-dependent response element-binding protein, CREB. However, the exact correlation between hippocampal CREB phosphorylation and memory improvement induced by Rolipram has not yet been determined in a CREB-dependent type of hippocampal-related learning in normogenic, intact rodents. Here, we report that subchronic Rolipram delivery by using osmotic minipumps increased the basal rat hippocampal expression and phosphorylation of CREB, as well as the expression of the cAMP-dependent, memory-related protein, Arc. In parallel, the same treatment improved memory consolidation of conditioned fear. Furthermore, the increase of CREB phosphorylation and Arc expression consequent to the learning experience was enhanced in Rolipram-treated rats, compared to controls. By evaluating the time course of memory extinction over 10 days after the initial learning test, we also observed significant slowing down of the memory extinction rate in Rolipram-treated rats. This effect could be attributed to CREB phosphorylation and memory having been initially higher, as osmotic minipumps stopped to release Rolipram the first day after the initial learning test. Our data define the conditions through which the pharmacological manipulation of hippocampal CREB expression and activation result in memory amelioration in normogenic, intact animals. These results are relevant for the study of molecular correlates of memory, and may also be important in view of the efforts to design new pharmacological treatments, targeting the CREB pathway and leading to enhancement of learning and memory, even in the absence of patent neuropathology.

Animals↗
PubMed2005

Ginseng enhances contextual fear conditioning and neurogenesis in rats.

Panax Ginseng is a commonly used galenical known to have an enhancing effect on learning. Neurogenesis in the hippocampus has been shown to be necessary for hippocampus/amygdala-dependent learning tasks. To investigate the role of Ginseng in neurogenesis and learning of rats, we administered both Ginseng and BrdU for five consecutive days. As a result, Ginseng increased the number of BrdU-positive cells in the dentate gyrus in a dose-dependent manner. Further, we administered one dose of BrdU after Ginseng treatment for five consecutive days, and the number of BrdU-positive cells did not increase significantly. However, when one dose of BrdU was given 1 day before the following five consecutive days of Ginseng treatment, the number of BrdU-positive cells markedly increased in the hippocampus. Therefore, it is likely that Ginseng enhances not proliferation but survival of newly generated neurons in the hippocampus. Second, we administered both Ginseng and BrdU to rats for five consecutive days. One day after the last Ginseng and BrdU co-administration, contextual fear conditioning (CFC) was conducted. Ginseng in a dose-dependent manner increased the % freezing time and the number of BrdU-positive cells in the dentate gyrus of rats that received CFC. Thus, an increase in CFC-related neurogenesis may be one mechanism of Ginseng's properties to enhance learning ability.

Analysis of Variance↗
PubMed1986

Fear conditioning, pre-pulse inhibition and drug modulation of a short latency startle response measured electromyographically from neck muscles in the rat.

The present study evaluated if startle measured electromyographically in the neck muscles (having a 5 msec latency) would exhibit behavioral and pharmacological plasticity known to alter startle measured in a stabilimeter device. A total of 15 rats were implanted with bilateral EMG electrodes in the dorsal neck muscles and subsequently exposed to a variety of manipulations known to affect the whole-body startle response. The peak-to-peak EMG response that occurred within 10 msec of startle stimulus onset displayed pre-pulse inhibition, enhancement by prior fear conditioning, inhibition by clonidine, and enhancement by strychnine. The data are discussed in terms of modulation of neural transmission along a primary startle-mediating pathway.

Animals↗
PubMed1995

The benzodiazepine receptor antagonists flumazenil and CGS8216 block the enhancement of fear conditioning and interference with escape behavior produced by inescapable shock.

Prior work has suggested that the mediation of the behavioral effects of inescapable shock (IS) might involve release of an endogenous beta-carboline-like ligand at the dorsal raphe nucleus (DRN) that binds to the benzodiazepine (BZ) recognition site on the GABAA complex, thereby disinhibiting the DRN. This was tested by microinjection of the BZ receptor antagonists flumazenil and CGS8216 in the region of the DRN, either before IS or before later behavioral testing. Both compounds blocked subsequent enhancement of fear conditioning and interference with shuttlebox escape when administered before IS, but had no effect when given before testing. In addition, flumazenil did not alter the behavior of escapably shocked subjects.

Animals↗
PubMed1999

Effect of sex on fear conditioning is similar for context and discrete CS in Wistar, Lewis and Fischer rat strains.

Enhanced fear in males relative to females, both innate and conditioned, is a well-described characteristic of behavior in the laboratory rat. In the case of aversive conditioning to foot shock in Long-Evans rats, it has been described that conditioning to general (nondiscrete) contextual cues is greater in male rats relative to female rats, whereas conditioning to a discrete, predictive stimulis (CS) is not. These findings have been combined with evidence for greater levels of hippocampal LTP in males in Sprague-Dawley rats to derive a model of hippocampal-LTP-mediated contextual and not CS, fear conditioning. The present study reports on an analysis of the effect of sex in contextual and discrete CS conditioning to foot shock, assessed via measurement of freezing behavior in a novel automated paradigm, in three rat strains: Wistar, Fischer, and Lewis. In Wistar rats, there was a consistent but nonsignificant tendency for males to demonstrate both more contextual and more CS conditioning than females; in Fischer rats, males demonstrated both more contextual and more CS conditioning than females; in Lewis rats, a markedly enhanced acquisition of freezing in males did not translate into a sex difference in either context or CS conditioning at expression. Therefore, within each strain the effect of sex was consistent between context and CS conditioning. These findings, taken together with the hippocampal LTP evidence, suggest that the latter mediates both contextual and discrete CS aversive conditioning, and contributes to sex differences in both these forms of conditioning, in those strains where these sex differences exist.

Animals↗
PubMed1984

Retention deficits induced by acute p-chloroamphetamine following fear conditioning in the rat.

Rats were given four inescapable shocks (1.0 mA) when confined to the right-hand corner of a modified shuttlebox. p-Chloroamphetamine (PCA) injected just before the retention test 24 h later completely blocked the immobile posture that was observed after saline injections. This retention deficit was shown to be selectively associated with 5-hydroxytryptamine (5-HT) release, since the administration of the 5-HT uptake inhibitors zimelidine and citalopram 60 min prior to PCA antagonized this effect. The 5-HT specificity of the deficit was further established by the findings that 5-HT-depleted rats (PCA, 2 x 10 mg/kg, and fenfluramine, 2 x 25 mg/kg), but not NA-depleted rats (DSP4, 1 x 50 mg/kg), or rats treated with zimelidine (2 x 20 mg/kg) 60 min before PCA (2 x 10 mg/kg), showed an almost complete blockade of the retention failure. The data presented may provide a useful experimental model for investigating the efficacy of functional 5-HT activity in the treatment of phobic anxiety.

Amphetamines↗
PubMed1991

Characterization of a psychophysiological model of classical fear conditioning in healthy volunteers: influence of gender, instruction, personality and placebo.

Two experiments are described which evaluate the role of associative mechanisms and placebo effects on aversively conditioned skin conductance responses in groups of healthy volunteers. In both experiments, skin conductance level (SCL), variability (spontaneous fluctuations, SF) and amplitude (SCR) were recorded during a sequence of tone stimuli (80 dB, 1 s, 360 Hz). All the variables habituated during the first ten presentations of the tones. Tone 11 was immediately followed by a loud (100 dB) aversive brief (1 s) white noise UCS. The conditioning trial significantly enhanced SCRs to a further ten presentations of the tones and increased SCL and variability (SF). No enhancement of SCRs occurred when tone 11 was omitted and the UCS occurred in temporal isolation (experiment 1). Thus enhanced SCRs to tones following paired tone-noise presentation involves an associative mechanism. Increased "spontaneous" variability was shown to involve both conditioning and sensitization following the UCS. In both experiments females showed greater conditioned SCRs than males. In experiment 2 no effect of "anxiolytic" placebo could be discerned and there were no general relationships between questionnaires scores of extraversion or neuroticism with skin conductance measures in a group of 40 volunteers. The results question the role of conditionability and autonomic lability as major determinants of extraversion and neuroticism. These studies validate the use of the psychophysiological model of aversive conditioning in pharmacological studies of the mechanisms of habituation, conditioning and sensitization.

Adult↗
PubMed1991

The effects of false response feedback on human 'fear' conditioning.

This study describes a human electrodermal conditioning experiment in which subjects were given false skin conductance feedback during CS presentation. In comparison with appropriate attentional control groups, subjects who believed they were exhibiting a strong CR did actually emit a greater magnitude CR, while subjects who believed they were exhibiting only a weak CR emitted a significantly lower magnitude CR. When both self-report and behavioural measures of UCS revaluation were taken after conditioning, the evidence suggested that response feedback had not differentially affected subjects evaluation of the aversiveness of the UCS. The results suggest that the response modulating effects of response feedback observed in this and other studies are not caused by response feedback influencing evaluation of the UCS, but they are consistent with the hypothesis that beliefs about the nature of response feedback influence the strength of the UCS representation itself.

Adult↗
PubMed1988

Dissociation of associative and nonassociative concomitants of classical fear conditioning in the freely behaving rat.

An acoustic stimulus previously paired with footshock elicits stereotyped increases in arterial pressure and heart rate and induces freezing behavior in freely behaving rats. Although the arterial pressure and freezing responses differ between groups given paired and random presentations of the tone and shock, the increases in heart rate do not. These observations, if taken at face value, suggest that the arterial pressure and freezing responses reflect associative learning but that the heart rate change is a nonassociative or a pseudoconditioned response. In this article we describe three experiments aimed at determining why the CS elicits similar increases in heart rate in groups given paired and random training. The first study demonstrates that regardless of the pseudoconditioning control procedure used (random, backwards, shock-alone, or naive), the same pattern of results is obtained: the increases in arterial pressure are greater in the paired than in each control group, but the heart rate rises to the same extent in all groups. The second study determined that the context in which the responses are tested (conditioning apparatus vs. novel test chamber) does not affect the general pattern of results obtained. The third study demonstrates that the superficially similar increases in heart rate in conditioned and pseudoconditioned rats are achieved by different physiological mechanisms: coactivation of the sympathetic and parasympathetic nervous systems in conditioned rats and sympathetic excitation alone in pseudoconditioned rats. Thus, the heart is influenced by associative emotional processes, but heart rate is not, under these conditions, a particularly useful index of those influences.

Animals↗
PubMed1975

Stimulus compounding in classical fear conditioning.

The effect of stimulus compounding in classical conditioning was investigated by conditioning one group of rats to a compound CS consisting of a buzzer and light and then conditioning separate groups of rats to the individual elements of the compound CS. On hurdle-jump test trials, the group of Ss conditioned to the compound CS performed better than Ss conditioned to the elements of the compound. Strength of conditioning to each of the elements of the compound CS was about equal. There was some evidence of a summation effect resulting from conditioning to the compound CS. Strength of conditioning to the compound CS was somewhat greater than the sum of the response strengths conditioned to the elements of the compound CS.

Acoustic Stimulation↗