Fear of the unexpected: Hippocampus mediates novelty-induced return of extinguished fear in rats

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Abstract

Several lines of evidence indicate an important role for the hippocampus in the recovery of fear memory after extinction. For example, hippocampal inactivation prevents the renewal of fear to an extinguished conditioned stimulus (CS) when it is presented outside the extinction context. Renewal of extinguished responding is accompanied by associative novelty (an unexpected occurrence of a familiar CS in a familiar place), the detection of which may require the hippocampus. We therefore examined whether the hippocampus also mediates the recovery of extinguished fear caused by other unexpected events, including presenting a familiar CS in a novel context or presenting a novel cue with the CS in a familiar context (e.g., external disinhibition). Rats underwent Pavlovian fear conditioning and extinction using an auditory CS and freezing behavior served as the index of conditioned fear. In Experiment 1, conditioned freezing to the extinguished CS was renewed in a novel context and this was eliminated by intra-hippocampal infusions of the GABAA agonist, muscimol, prior to the test. In Experiment 2, muscimol inactivation of the hippocampus reduced the external disinhibition of conditioned freezing that occurred when a novel white noise accompanied the extinguished tone CS. Collectively, these results suggest that the hippocampus mediates the return of fear when extinguished CSs are unexpected, or when unexpected stimuli accompany CS presentation. Ultimately, a violation of expectations about when, where, and with what other stimuli an extinguished CS will occur may form the basis of spontaneous recovery, renewal, and external disinhibition.

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.

References (71)

  • S. Maren et al.

    The hippocampus and contextual memory retrieval in Pavlovian conditioning

    Behavioural Brain Research

    (2000)
  • G.P. Mcnally et al.

    Placing prediction into the fear circuit

    Trends in Neurosciences

    (2011)
  • C.A. Orsini et al.

    Neural and cellular mechanisms of fear and extinction memory formation

    Neuroscience and Biobehavioral Reviews

    (2012)
  • T. Yoon et al.

    Hippocampal lesion effects on occasion setting by contextual and discrete stimuli

    Neurobiology of Learning and Memory

    (2011)
  • M. Bouton

    Context, time, and memory retrieval in the interference paradigms of Pavlovian learning

    Psychological Bulletin

    (1993)
  • M.E. Bouton

    Context and behavioral processes in extinction

    Learning and Memory

    (2004)
  • M. Bouton et al.

    Renewal of extinguished responding in a second context

    Animal Learning and Behavior

    (1994)
  • M. Bouton et al.

    A modern learning theory perspective on the etiology of panic disorder

    Psychological Review

    (2001)
  • R.L. Buckner

    The role of the hippocampus in prediction and imagination

    Annual Review of Psychology

    (2010)
  • C.H. Chang et al.

    Early extinction after fear conditioning yields a context-independent and short-term suppression of conditional freezing in rats

    Learning and Memory

    (2009)
  • N.J. Cohen et al.

    Memory, amnesia, and the hippocampal system

    (1995)
  • K.A. Corcoran

    Factors regulating the effects of hippocampal inactivation on renewal of conditional fear after extinction

    Learning and Memory

    (2004)
  • K.A. Corcoran et al.

    Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction

    The Journal of neuroscience: The official journal of the Society for Neuroscience

    (2001)
  • K.A. Corcoran et al.

    Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction

    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

    (2005)
  • A.R. Delamater

    Experimental extinction in Pavlovian conditioning: Behavioural and neuroscience perspectives

    Quarterly Journal of Experimental Psychology Section B

    (2004)
  • M. Gabriel et al.

    Hippocampal control of cingulate cortical and anterior thalamic information processing during learning in rabbits

    Experimental Brain Research

    (1987)
  • C.R. Gallistel et al.

    Time, rate, and conditioning

    Psychological Review

    (2000)
  • S.J. Gershman et al.

    Exploring a latent cause theory of classical conditioning

    Learning and Behavior

    (2012)
  • S.J. Gershman et al.

    Context, learning, and extinction

    Psychological Review

    (2010)
  • J. Harris et al.

    Contextual control over conditioned responding in an extinction paradigm

    Journal of Experimental Psychology: Animal Behavior Processes

    (2000)
  • C. Herry et al.

    Switching on and off fear by distinct neuronal circuits

    Nature

    (2008)
  • J.A. Hobin et al.

    Context-dependent neuronal activity in the lateral amygdala represents fear memories after extinction

    Journal of Neuroscience

    (2003)
  • J.A. Hobin et al.

    Ventral hippocampal muscimol disrupts context-specific fear memory retrieval after extinction in rats

    Hippocampus

    (2006)
  • P. Holland et al.

    Hippocampal lesions interfere with Pavlovian negative occasion setting

    Hippocampus

    (1999)
  • R.C. Honey et al.

    Hippocampal lesions disrupt an associative mismatch process

    Journal of Neuroscience

    (1998)
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