Fear of the unexpected: Hippocampus mediates novelty-induced return of extinguished fear in rats
Introduction
A major challenge to behavioral therapies for anxiety disorders, including post-traumatic stress disorder, is the relapse of fear that occurs outside of the clinical context. One account of relapse builds on the observation that the extinction of Pavlovian conditioned responses (CRs), including fear responses, is context-specific (Bouton and Bolles, 1979, Bouton et al., 2001, Craske et al., 2008). For example, if a conditional stimulus (CS) that once predicted an aversive footshock unconditional stimulus (US) is presented alone several times in a distinct context, fear to the CS will be lost—but only in the extinction context (Bouton & Bolles, 1979). That is, the fear CR will return or ‘renew’ if the CS is encountered outside of the extinction context, including the conditioning context (‘ABA’ renewal, where the letters denote the contexts used for conditioning, extinction, and testing) or an equally familiar context in which the CS has never been experienced (‘AAB’ or ‘ABC renewal’, which is often found to be weaker than ABA renewal). This reveals that extinction does not erase the CS–US association but encourages the formation of a new inhibitory CS–‘no US’ memory (Konorski, 1967, Pavlov, 1927). It has been posited that these inhibitory memories are particularly context-bound, and that animals use contexts as retrieval cues to determine how to respond to a CS (Bouton, 1993, Bouton et al., 2006). By this view, inhibition acquired during extinction (e.g., the formation of a CS–‘no US’ association) is linked to the extinction context, and is not retrieved outside of that context. In other contexts, fear is supported by the context-independent expression of the CS–US association—as a result, conditioned fear is broadly generalized, whereas extinction is not.
Another possibility is that the inhibition acquired during extinction fails to generalize to other contexts because the circumstances of the test situation produce “inhibition of an inhibition” (Pavlov, 1927). Pavlov observed that novel or unexpected events (including his own presence during a colleague’s experiment) caused a spontaneous return of an extinguished salivary response, a phenomenon he termed ‘external disinhibition’ (Pavlov, 1927). The loss of inhibition that occurs when novel stimuli accompany an extinguished CS might account for other forms of CR recovery that are accompanied by unexpected events, including renewal. In this case, extinguished CSs are unexpectedly encountered in contexts in which they had never been presented (AAB, ABC), or had not been encountered recently (ABA). Hence, renewal may be a form of disinhibition produced by associative novelty when testing occurs in a familiar context. This account has found recent support in a computational model of extinction that includes attentional mechanisms and novelty in determining conditioned responding (Larrauri & Schmajuk, 2008).
Interestingly, there is considerable evidence in both rats and humans that the hippocampus plays an important role in novelty detection, particularly in the detection of associative novelty (Honey and Good, 2000, Knight, 1996, Kumaran and Maguire, 2006, Vinogradova, 2001). For example, hippocampal lesions in rats reduce the orienting response to the novel pairing of habituated stimuli, a phenomenon that requires the detection of an associative mismatch among familiar cues (Honey, Watt, & Good, 1998). In addition, human neuroimaging experiments have revealed that hippocampal activity is elevated under conditions in which unexpected sequences of familiar stimuli are encountered (Kumaran and Maguire, 2006, Wessel et al., 2012). Moreover, it is now apparent that the hippocampus and its afferents are critical for the renewal of extinguished fear that occurs when an extinguished is unexpectedly encountered outside the extinction context (Corcoran, 2004, Corcoran and Maren, 2001; Corcoran, Desmond, Frey, & Maren, 2005; Hobin et al., 2006, Ji and Maren, 2005; Ji and Maren, 2008a, Ji and Maren, 2008b; Maren and Hobin, 2007, Zelikowsky et al., 2011). While most authors have interpreted these hippocampal lesion effects in terms of contextual retrieval processes and occasion setting (Maren, 2005, Maren and Holt, 2000), a more parsimonious account appeals to the role of the hippocampus in novelty detection. That is, the hippocampus may mediate the renewal effect, because it is detects associative novelty during the retrieval test that leads to the disinhibition of extinguished fear. If true, hippocampal inactivation should limit the return of extinguished fear that accompanies exposure to a novel stimulus (external disinhibition) or presentation of the extinguished CS in a novel context (renewal). To examine this question, we examined the effect of hippocampal inactivation with the GABAA agonist muscimol on the expression of fear to an extinguished CS presented in either a novel context (Experiment 1) or after delivery of a novel stimulus (white noise) in the extinction context (Experiment 2). Insofar as the hippocampus is required for detecting novel or unexpected events, we hypothesized that hippocampal inactivation would impair the return of fear driven by the presence of novel contexts or cues.
Section snippets
Subjects
The subjects were 64 (Experiment 1) and 32 (Experiment 2) adult male Long-Evans rats (200–224 g) obtained from a commercial supplier (Harlan Sprague Dawley, Indianapolis, IN). After arrival, the rats were housed individually in Plexiglas hanging cages on a 14:10 h light/dark cycle (lights on at 7:00 a.m.) and were allowed unlimited access to food and water. After being housed, the rats were handled (10–20 s per rat per day) for 5 days to habituate them to the experimenter. All experiments were
Histology
A representative cannula placement in the dorsal hippocampus is illustrated in Fig. 1. Placements in both Experiments 1 and 2 were similar to those reported in our previously published work using this methodology. None of the rats in Experiment 1 were excluded from analysis based on their cannula placements, and two rats were excluded in Experiment 2 because their cannula were placed ventral to the target.
Experiment 1
Conditioned freezing during the conditioning, extinction, and test sessions is shown in
Discussion
The present results reveal that inactivation of the dorsal hippocampus attenuates the return of fear to an extinguished CS in a novel context (Experiment 1) and when the CS is accompanied by a novel stimulus in the extinction context (Experiment 2). Interestingly, the hippocampal impairment differed in severity in the two experiments, and was relatively transient when a novel stimulus renewed fear. Together, these results add to the growing list of studies pointing to an important role of the
Acknowledgments
This research was supported by a Grant from the NIMH (R01065961) to SM. The authors would like to thank Jinzhao Ji and April Qian for assisting with data collection.
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