Temporal factors control hippocampal contributions to fear renewal after extinction

Department of Psychology and Brain Research Institute, University of California, Los Angeles, Los Angeles, California 90095-1563, USA.
Hippocampus (Impact Factor: 4.3). 05/2012; 22(5):1096-106. DOI: 10.1002/hipo.20954
Source: PubMed

ABSTRACT Fear can be extinguished by repeated exposure to a cue that signals threat. However, extinction does not erase fear, as an extinguished cue presented in a context distinct from that of extinction results in renewed fear of that cue. The hippocampus, which is involved in the formation of contextual representations, is a natural candidate structure for investigations into the neural circuitry underlying fear renewal. Thus far, studies examining the necessity of the hippocampus for fear renewal have produced mixed results. We isolated the conditions under which the hippocampus may be required for renewal. Rats received lesions of the dorsal hippocampus either prior to tone fear conditioning or following extinction. Fear renewal was measured using discrete tone presentations or a long, continuous tone. The topography of fear responding at test was assessed by comparing "early" and "sustained" renewal, where early fear was determined by freezing to the first discrete tone or the equivalent initial segment of a continuous tone and sustained fear was determined by freezing averaged across all discrete tones or the entire continuous tone. We found that following pretraining damage of the hippocampus, early renewal remained intact regardless of lesion condition. However, sustained renewal only persisted in discrete, but not continuous, tone-tested animals. A more extensive analysis of the topography of fear responding revealed that the disruption of renewal was generated when the tone duration at test began to violate that used during extinction, suggesting that the hippocampus is sensitive to mismatches in CS-duration. Postextinction lesions resulted in an overall reduction of fear renewal. This pattern of results is consistent with those observed for contextual fear conditioning, wherein animals display a resistance to anterograde amnesia despite the presence of a strong retrograde amnesia for the same contextual information. Furthermore, the data support a role for the hippocampus in sustaining renewal when the CS duration at test does not match that used during extinction.

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Available from: Michael Fanselow, Aug 16, 2015
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    • "We feel that researchers should carefully compare both measurements and decide on the best choice for their research question. Finally, we would like to stress that in the papers mentioned in Table 1, we see no interpretation problems, as most of these studies did not directly compare freezing between several contexts , and in case they did (Zelikowsky et al., 2012b), contexts were counterbalanced. Note however that, theoretically, even limited measurement deviations between contexts may induce heightened variability when counterbalancing contexts, thereby decreasing the chance of finding significant effects. "
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    Frontiers in Behavioral Neuroscience 02/2014; 8:28. DOI:10.3389/fnbeh.2014.00028 · 4.16 Impact Factor
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    • "Early studies suggested that the HPC was required for contextual but not discrete cue conditioning (Selden et al., 1991; Phillips & LeDoux, 1992). However, both dHPC and vHPC lesions can reduce freezing to discrete cues under some circumstances (Richmond et al., 1999; Maren & Holt, 2004; Maren, 2008; Quinn et al., 2008; Zelikowsky et al., 2012). "
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    ABSTRACT: Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely-moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS-) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS- trials during training and early extinction. In contrast, they were lower during CS+ than CS- trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS- trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging.
    European Journal of Neuroscience 11/2012; 37(3). DOI:10.1111/ejn.12057 · 3.67 Impact Factor
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    • "Thus, a renewal effect was observed with the ABA group. Zelikowsky et al. (2011) showed a context-dependent extinction using a procedure with the two contexts reversed as compared to our experiment. Their study provides further support to suggest that our results are due to context specificity. "
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    ABSTRACT: An extinguished conditioned response can sometimes be restored. Previous research has shown that this renewal effect depends on the context in which conditioning versus extinction takes place. Here we provide evidence that the dorsal hippocampus is critically involved in the representation of context that underscores the renewal effect. We performed electrolytic lesions in dorsal hippocampus, before or after extinction, in a conditioned taste aversion paradigm with rats. Rats that underwent all conditioning, extinction and testing procedures in the same experimental context showed no renewal during testing in the original context. In contrast, rats that underwent extinction procedures in a different experimental context than the one in which they had acquired the conditioned response, showed a reliable renewal effect during testing in the original context. When electrolytic lesion was performed prior to extinction, the context-dependent renewal effect was disrupted. When electrolytic lesion was undertaken after extinction, we observed a complex pattern of data including the blockage of the conventional renewal effect, and the appearance of an unconventional renewal effect. The implications of these results are discussed with respect to current views on the role of the dorsal hippocampus in processing context information.
    Cognitive Neurodynamics 10/2012; 6(5):399-407. DOI:10.1007/s11571-012-9208-y · 1.77 Impact Factor
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