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PubMed2001

Is there savings for pavlovian fear conditioning after neurotoxic basolateral amygdala lesions in rats?

Considerable evidence indicates an important role for amygdaloid nuclei in both the acquisition and expression of Pavlovian fear conditioning. Recent reports from my laboratory have focused on the impact of neurotoxic lesions of the basolateral complex of the amygdala (BLA) on conditional freezing behavior in rats. In these studies, I have observed severe effects of posttraining BLA lesions on the expression of conditional freezing even after extensive presurgical overtraining (25-75 trials). Moreover, I have found no evidence for sparing of fear memory (i.e., savings) in these rats when I assess their rate of reacquisition relative to BLA rats receiving minimal training (1 trial). In these experiments, freezing behavior was assessed using a conventional time-sampling procedure and expressed as a response probability. Although this measure is well established in the literature, it is conceivable that it is not sensitive to spared memory in rats with BLA lesions. To address this issue, I present a more detailed analysis of freezing behavior that quantifies latency to freeze, the number of freezing bouts, the duration of freezing bouts, and the probability distribution of bout lengths. I also include control data from untrained (no-shock) rats. Consistent with my earlier reports, I find no evidence of savings of fear memory in rats with neurotoxic BLA lesions using several measures of freezing behavior. These results reiterate the conclusion that fear memory, as it is expressed in freezing behavior, requires neurons in the BLA.

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PubMedDate not supplied

[The role of protein synthesis in memory reconsolidation in different time periods after fear conditioning in mice].

We have studied the role of protein synthesis in reconsolidation of memory, activated by reminder at different time period after initial acquisition. Mice were trained in a single-trial fear conditioning task and then subjected to reminder, preceded by injection of protein synthesis inhibitor cycloheximide. It was found that this procedure impaired later memory retrieval if applied at 3, 6 and 24 h as well as 14 and 30 days after initial training. This data suggests that reactivated memory is followed by protein synthesis-dependent reconsolidation both at short (3-6 h) and long (14-30 days) intervals after initial acquisition.

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PubMed2003

Pre-training prevents context fear conditioning deficits produced by hippocampal NMDA receptor blockade.

These experiments explore parallels between the neurobiological substrates of spatial and context learning. Male Long-Evans rats were employed in a context fear conditioning protocol that involved sequential acquisition and testing in two distinct contexts. Rats received three unsignaled footshocks in one context and were tested for context fear, measured as freezing, the next day. Four days later, the procedure was repeated in a different, distinct context. Rats received a hippocampal infusion of either the NMDA receptor antagonist 5-amino-phosphonovaleric acid (APV, 10 microg) or vehicle prior to training in each context. NMDA receptor blockade was effective in impairing context learning only in the first context. Context fear acquisition was not impaired by APV in the second context, indicating that pre-training (in the first context) mitigated the effects of APV. These data agree with those seen previously in the water maze, where pre-training prevented learning deficits produced by NMDA receptor blockade. The data thus suggest that the neurobiological substrates of context learning and place learning overlap.

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PubMed2005

The role of the human amygdala in the production of conditioned fear responses.

The amygdala plays a central role in the acquisition and expression of fear memories. Laboratory animal studies indicate that the amygdala both receives sensory information and produces learned behavioral and autonomic fear responses. However, prior functional imaging research in humans has largely focused on amygdala activity elicited by fearful stimuli, giving less attention to this region's role in the production of fear responses. In contrast, the present study used functional magnetic resonance imaging to investigate the amygdala's influence on the generation of conditional fear responses. Significant increases in amygdala activity were observed during the production of conditioned (learning-related), but not orienting, nonspecific, and unconditioned (nonlearning-related) skin conductance responses. Further, greater amygdala activity was demonstrated during conditioned response production than during conditioned stimulus presentation. These results suggest the amygdala not only responds to fearful stimuli, but also generates learning-related changes in human autonomic fear expression.

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PubMed1992

[From a standpoint of psychiatry: effects of conditioned fear stress on monoaminergic systems in the rat brain].

The effects of electric footshock stress(EFS) and conditioned fear stress(CFS) on dopamine(DA) and serotonin(5-HT) metabolism in seven various brain regions of the rat were studied by measuring dihydroxyphenylacetic acid(DOPAC), homovanillic acid(HVA) and 5-hydroxyindoleacetic acid(5-HIAA). EFS for 30 min increased DOPAC and HVA levels in all seven brain regions and increased 5-HIAA levels in the medial prefrontal cortex(mPFC), nucleus accumbens and amygdala. CFS(exposure to an environment paired previously with footshock) increased plasma corticosterone levels and defecation, and induced freezing behavior. It also increased DOPAC levels in the mPFC, paraventricular nucleus of the hypothalamus and lateral hypothalamus, increased HVA levels in the mPFC and amygdala, and increased the 5-HIAA level in the mPFC. In contrast to EFS, which increased DA and 5-HT metabolism in several other brain regions, increased metabolism of both DA and 5-HT was especially marked in the mPFC after CFS. In this model, two classes of anxiolytics were examined for effects on freezing behavior. The benzodiazepine diazepam, a classical anxiolytic, reduced the freezing response. The new anxiolytic ipsapirone, a selective 5-HT1A agonist, also reduced the freezing response. These findings suggest the usefulness of this model for detecting the anxiolytic potential of drugs and examining the relation between 5-HT and anxiety.

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PubMed2000

The induction of c-Fos in the NTS after taste aversion learning is not correlated with measures of conditioned fear.

The induction of c-Fos-like immunoreactivity (c-FLI) in the nucleus of the solitary tract (NTS) has been shown to be correlated with behavioral expression of a conditioned taste aversion (CTA). However, because this cellular response is also dependent on an intact amygdala, it may represent the activation of a stress-related autonomic response. The present experiments addressed this possibility by evaluating the correlation between c-FLI in the intermediate division of the NTS (iNTS) and 2 measures of conditioned fear: freezing and changes in mean arterial pressure (MAP) and heart rate (HR). Exposure to the taste conditioned stimulus (CS) resulted in a marked induction of c-FLI in the iNTS, whereas exposure to a fear CS did not. Further, exposure to a taste CS did not selectively lead to increases in MAP or HR. Results suggest that induction of c-FLI in the iNTS may reflect the activation of a cell population whose function is unique to the CTA paradigm.

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PubMed2005

Effects of multiple exposures to D-cycloserine on extinction of conditioned fear in rats.

Previous research has shown that an acute, post-training injection of D-cycloserine (DCS) facilitates extinction of conditioned fear in rats; however, the effects of multiple exposures to DCS in this situation are not known. In Experiment 1, rats were conditioned (light-shock pairings) and 24 h later given six extinction (light-alone) trials followed by an injection of DCS (15 mg/kg) or saline. The next day, all rats were tested for light-elicited freezing. In Experiment 2, the effect of DCS on extinction was tested in the same manner, except that rats were pre-exposed to DCS (0, 1, or 5 injections) just prior to conditioning. In Experiment 3, rats received five pre-exposures of DCS but conditioning occurred either 2 or 28 days after the last pre-exposure. The results showed that DCS facilitated extinction of conditioned freezing to the light CS when no drug pre-exposure had occurred, but pre-exposure to DCS just prior to conditioning disrupted the facilitation of extinction effect. When 28 days were interposed between pre-exposure and conditioning, the facilitatory effects of DCS on extinction were restored. These findings suggest that DCS has significant clinical value but that behavioral desensitization may occur with multiple exposures; however, desensitization is not permanent and is reduced by the passage of time.

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PubMed2002

Differential contribution of some cortical sites to the formation of memory traces supporting fear conditioning.

The aim of the present work was to assess the role of some cortical sites of the rat (the prefrontal, PFC, frontal, FC, parietal, PAC, and perirhinal, PC, cortices) in the acquisition of classical fear conditioning (CS and context conditioned freezing). Using the reversible ablation technique the sites were inactivated with lidocaine (LIDO), administered before the one-trial training session. The freezing response, taken as memorization index, was measured in conditions of full functional recovery after the short reversible LIDO inactivation either 3 h ("short-term" memory) and/or 72 h ("long-term" memory) later, so as to follow the temporal dimension of mnemonic elaboration. The results of the inactivations performed during the training session show that PFC, FC, PAC and PC play contemporaneous but distinct roles in the memorization of aversive responses to CS and context. PC inactivation weakened the retention of both mnemonic traces at the 3-h delay. At the same delay FC and PAC inactivation weakened only freezing to acoustic CS while PFC inactivation improved the retention of both traces. Inactivation of all four sites was followed by significant amnesia for both traces at the 72-h after-acquisition delay. The present findings show that PFC, FC, PAC and PC reversible inactivation during the acquisition training session diversely interferes with the memorization of conditioned freezing to acoustic CS and context. Moreover, the different results obtained at the two different retention intervals support the hypothesis that "short-term" and "long-term" memories are not necessarily linked, the earlier one not always influencing the subsequent one.

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PubMed2006

Dopamine D2 receptor mechanisms in the expression of conditioned fear.

The increase in the startle reflex in the presence of a stimulus that has been previously paired to foot shock is taken as an index of anxiety and named fear potentiated startle (FPS). Freezing behavior, defined as a cessation of all observable movements except those associated with respiration, has also been used as an index of fear in rats. Recently, a growing body of evidence has suggested that dopaminergic mechanisms are significant for different aspects of affective memory, namely its formation, expression or retrieval. However, the results of studies that have directly examined the ability of the dopaminergic system to influence fear have been inconsistent. This work is aimed at examining the involvement of D1 and D2 receptors in the acquisition and expression of conditioned fear using the fear potentiated startle test and the freezing behavior. We evaluated the effects of systemic administration of the D1 antagonist SCH 23390, the D1 agonist SKF 38393, the D2 antagonist sulpiride and the D2 agonist quinpirole before and after conditioning on FPS and freezing as indices of fear memory. The motor activity of the animals was also evaluated in an open field test. Injections of SCH 23390, SKF 38393, sulpiride and quinpirole before conditioning sessions did not produce any significant effect on FPS, but SCH 23390 decreased freezing. Injections of SCH 23390, SKF 38393 and sulpiride before testing session did not produce any significant effect on FPS or freezing. Quinpirole caused significant reduction in FPS and freezing when injected before testing. Drugs' actions were not due to nonspecific impairments in the ability to respond to the CS because the identical drug treatments had no effect in an open field test. Our findings indicate that DA mechanisms mediated by D2 receptors are mainly involved in the expression rather than in the acquisition of fear.

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PubMed2006

Inhibition of prefrontal protein synthesis following recall does not disrupt memory for trace fear conditioning.

BACKGROUND: The extent of similarity between consolidation and reconsolidation is not yet fully understood. One of the differences noted is that not every brain region involved in consolidation exhibits reconsolidation. In trace fear conditioning, the hippocampus and the medial prefrontal cortex (mPFC) are required for consolidation of long-term memory. We have previously demonstrated that trace fear memory is susceptible to infusion of the protein synthesis inhibitor anisomycin into the hippocampus following recall. In the present study, we examine whether protein synthesis inhibition in the mPFC following recall similarly results in the observation of reconsolidation of trace fear memory. RESULTS: Targeted intra-mPFC infusions of anisomycin or vehicle were performed immediately following recall of trace fear memory at 24 hours, or at 30 days, following training in a one-day or a two-day protocol. The present study demonstrates three key findings: 1) trace fear memory does not undergo protein synthesis dependent reconsolidation in the PFC, regardless of the intensity of the training, and 2) regardless of whether the memory is recent or remote, and 3) intra-mPFC inhibition of protein synthesis immediately following training impaired remote (30 days) memory. CONCLUSION: These results suggest that not all structures that participate in memory storage are involved in reconsolidation. Alternatively, certain types of memory-related information may reconsolidate, while other components of memory may not.

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PubMed2003

The effects of ibotenic hippocampal lesions on discriminative fear conditioning to context in mice: impairment or facilitation depending on the associative value of a phasic explicit cue.

To what extent the hippocampus is required for contextual conditioning remains a matter of debate. The present experiments examined the effects of ibotenate hippocampal lesions on discriminative fear conditioning to context in mice using measures of freezing in two conditioning paradigms. In both paradigms animals received foot shock as the unconditional stimulus (US) when placed in the (conditioning) context and no foot-shock when placed in the other (neutral) context. In both contexts, animals were presented with a tone as the conditioned stimulus (CS). In the conditioning context there was either no interval (delay condition) or a 30-s interval (trace condition) between tone CS end and shock US onset. These two paradigms were used because theory predicts that in the trace condition animals would learn more about contextual cues as predictors, or not, of shock US occurrence than in the delay condition. In agreement with this, we observed that sham-operated mice learned the context discrimination faster in the trace than in the delay condition. Lesions of the hippocampus significantly retarded, but did not prevent, the acquisition of the context discrimination in the trace condition. In contrast, lesions produced an opposite (facilitatory) effect in the delay condition, which was mainly observed during tone CS presentation. The data suggest that mice used two distinct competing strategies in solving this discrimination task: (i) a strategy relying on the processing of background contextual stimuli allowing direct establishment of context-US associations of different strengths, and (ii) a conditional cue (tone)-based strategy. Hence, hippocampal lesions may impair the use of the former strategy while exacerbating (unmasking) the use of the latter.

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PubMed2005

Enhancement of auditory fear conditioning after housing in a complex environment is attenuated by prior treatment with amphetamine.

Prior exposure to drugs of abuse has been shown to occlude the structural plasticity associated with living in a complex environment. Amphetamine treatment may also occlude some cognitive advantages normally associated with living in a complex environment. To test this hypothesis we examined the influence of prior exposure to amphetamine on fear conditioning in rats housed in either a standard or complex environment. Housing in a complex environment facilitated fear learning to an auditory conditioned stimulus (CS), but not to the training context, relative to animals housed singly or in a social group. Prior treatment with amphetamine eliminated this effect. These results indicate that living in a complex environment facilitates conditional freezing to an auditory CS, and that this effect is abolished by pretreatment with amphetamine.

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PubMed2003

Contextual fear conditioning regulates the expression of brain-specific small nucleolar RNAs in hippocampus.

Some small nucleolar RNAs (snoRNAs) are exclusively expressed in the brain but they have no known role in higher brain function. We analysed the expression pattern of four brain-specific snoRNAs: MBI-36, MBII-48, MBII-52 and MBII-85, in mouse brain using in situ hybridization. All of these genes were expressed in the hippocampus and, except for MBII-85, their levels in ventral parts were higher than those in dorsal parts. Using quantitative real-time polymer chain reaction we determined hippocampal expression changes after contextual fear conditioning in mice. Ninety minutes, but not 25 h, after conditioning, we observed significant downregulation of MBII-48 and upregulation of MBII-52. Our finding that the expression of MBII-48 and MBII-52 is regulated during learning suggests that these snoRNAs have an important role in higher brain function.

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PubMed2004

Dissociable amygdala and orbitofrontal responses during reversal fear conditioning.

The neural mechanisms underlying the persistence and plasticity of human emotional learning are unknown. Here we describe dissociable neural responses in amygdala and orbitofrontal cortex during acquisition and reversal of discriminatory fear conditioning. During acquisition, increased responses in bilateral amygdala were elicited by a face stimulus (A = CS+) predictive of an aversive noise compared to another nonpredictive face (B = CS-). With subsequent reversal of the conditioning contingency, face B (new CS+) elicited enhanced responses in right orbitofrontal cortex, while face A (old CS+) continued to evoke increased responses in right ventral amygdala. Thus, while orbitofrontal cortex exhibited rapid reversal of acquired fear responses, ventral amygdala showed a persistent, nonreversing "memory" for previous fear-related stimulus associations.

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PubMed1988

Propranolol antagonizes the enhanced conditioned fear produced by corticotropin releasing factor.

A series of experiments examined the effects of systemic administration of the beta adrenergic antagonist propranolol on the enhanced conditioned fear and the locomotor hyperactivity induced by central administration of corticotropin releasing factor (CRF). In Experiment 1, CRF (0.5 microgram) was shown to reduce responding in both the conditioned stimulus (cs) and the pre-cs components of an on-the-base-line conditioned suppression schedule. The effects of CRF on cs, but not pre-cs responding were antagonized by propranolol, at doses (2.5, 5.0 and 10.0 mg/kg) that did not affect responding themselves. This reversal of the anxiogenic effects of CRF by propranolol was specific to l- and not d-propranolol, showing that it did not result from nonspecific membrane stabilization. Propranolol also failed to reverse the reduced responding induced by the benzodiazepine inverse agonist FG 7142 in this schedule. In Experiment 2, propranolol was shown to potentiate the locomotor hyperactivity induced by CRF in a familiar photocell cage. These results suggest that activation of beta adrenoceptors may be an important mechanism in the behavioral inhibition induced by CRF, and that the neurochemical mechanisms that underlie the "anxiogenic" and the "activating" behavioral effects of CRF are neuropharmacologically distinct.

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PubMed2006

Specific phobia: a disorder of fear conditioning and extinction.

Specific phobia is the most prevalent of the anxiety disorders. Although there have been relatively few studies of its psychobiology and pharmacotherapy, there is a rich laboratory of literature on fear conditioning and extinction and a clear evolutionary perspective. Advances in the cognitive-affective neuroscience of fear processing may ultimately lead to new approaches to the clinical management of phobias.

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PubMed2006

Dopamine activity in the nucleus accumbens modulates blocking in fear conditioning.

Associative learning depends on the discrepancy between actual and predicted outcomes. The neurochemical mechanisms involved in regulating this discrepancy in Pavlovian fear conditioning in rats are unknown. We employed the blocking paradigm to show that this learning discrepancy is decreased by heightened activation of dopamine following an accumbal infusion of d-amphetamine, and increased by dopaminegic blockade following an accumbal infusion of cis-(z)-flupenthixol or by combined infusions of the D1 (SCH23390) and D2 (sulpiride) antagonists but not by infusion of either alone.

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PubMed2006

Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fear-conditioning paradigm.

Polysialic acid (PSA) regulates functions of the neural cell adhesion molecule (NCAM) during development and in neuroplasticity in the adult; the underlying mechanisms at different phases of learning and memory consolidation are, however, unknown. To investigate the contributions of PSA versus the extracellular domain of the NCAM glycoprotein backbone to synaptic plasticity, we applied NCAM, PSA-NCAM, and PSA to acute slices of the hippocampal CA1 region of NCAM-deficient mice and measured their effects on long-term potentiation (LTP). Remarkably, only PSA and PSA-NCAM, but not NCAM restored normal LTP. Application of these molecules to the dorsal hippocampus of wild-type mice showed that PSA-NCAM and PSA, but not NCAM, injected before fear conditioning, impaired formation of hippocampus-dependent contextual memory. Consolidation of contextual memory was affected by PSA-NCAM only when injected during its late, but not early phases. None of the tested compounds disturbed extrahippocampal-cued memory. Mice lacking the polysialyltransferase (ST8SialV/PST) responsible for attachment of PSA to NCAM in adulthood showed a mild deficit only in hippocampal contextual learning, when compared with NCAM-deficient mice that were disturbed in both contextual and cued memories. Contextual and tone memory in NCAM-deficient mice could be partially restored by injection of PSA-NCAM, but not of NCAM, into the hippocampus, suggesting that the impact of PSA-NCAM in synaptic plasticity and learning is not mediated by modulation of NCAM-NCAM homophilic interactions. In conclusion, our data support the view that polysialylated NCAM is involved in both formation and late consolidation of contextual memory.

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