Fear of the unexpected: hippocampus mediates novelty-induced return of extinguished fear in rats - PubMed (original) (raw)

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

Stephen Maren. Neurobiol Learn Mem. 2014 Feb.

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.

Keywords: Disinhibition; Extinction; Fear conditioning; Hippocampus; Muscimol.

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Figures

Figure 1

Figure 1

Photomicrograph showing a thionin-stained coronal section from the brain of a rat with representative cannula placements in the dorsal hippocampus.

Figure 2

Figure 2

Hippocampal inactivation disrupts renewal of fear in a novel context (Experiment 1). (Left panel) Mean (±SEM) percentage of freezing on the conditioning day. Data are 1-min averages for a 3-min baseline period (BL) and after each of the five tone-shock conditioning trials. (Middle panel) Freezing behavior during the extinction sessions. Freezing was averaged across the 30-trials extinction session. Extinction was conducted in the conditioning context for the ‘Novel’ groups (AAB design) and a novel context for the ‘Same’ groups (ABB design). Hence, the group labels refer to the treatment conditions that would later be imposed during retrieval testing (not during conditioning or extinction). (Right panel) Freezing behavior during the retrieval test. Data are 1-min averages for a 2-min baseline period (BL) and after each of the eight CS-alone trials. Rats were tested in either the extinction context (SAME) or in a novel context (NOVEL).

Figure 3

Figure 3

Hippocampal inactivation disrupts renewal of fear in a novel context (Experiment 1). Mean (±SEM) percentage of freezing during the retrieval test. Data are averages of eight post-CS blocks minus the average of the pre-CS baseline (as shown in the last panel of Figure 2). Rats were tested in either the extinction context (SAME; open bars) or in a novel context (NOVEL; gray bars). Dorsal hippocampal inactivation with muscimol (MUS) impaired the renewal of conditioned freezing to the CS in a novel context compared to saline-treated (SAL) rats.

Figure 4

Figure 4

Hippocampal inactivation disrupts renewal of fear by a novel white noise (Experiment 2). (Left panel) Mean (±SEM) percentage of freezing on the conditioning day. Data are 1-min averages for a 3-min baseline period (BL) and after each of the five tone-shock conditioning trials. (Middle panel) Freezing behavior during the extinction sessions. Freezing was averaged across all 30 trials of each extinction session. Extinction was conducted in a novel context for the all groups (ABB design). The group labels refer to the treatment conditions that would later be imposed during retrieval testing (not during conditioning or extinction). (Right panel) Freezing behavior during the retrieval test. Data are 1-min averages for the 2-min baseline period (BL) and after each of the eight CS-alone trials. Rats were tested in the extinction context and the CS was either preceded on each trial by a novel white noise (N+CS) or was presented alone (CS).

Figure 5

Figure 5

Hippocampal inactivation disrupts renewal of fear in a novel context (Experiment 1). (A) Mean (±SEM) percentage of freezing during the retrieval test. Data are averages of eight post-CS blocks minus the average of the pre-CS baseline (as shown in the right panel of Figure 4). Rats were tested in the extinction context and the CS was either preceded on each trial by a novel white noise (N+CS) or was presented alone (CS). Dorsal hippocampal inactivation with muscimol (MUS) did not impair the renewal of conditioned freezing by a novel stimulus. (B) Mean (±SEM) percentage of freezing during first test trial. Freezing data are 10-sec averages for the pre-trial period, the white noise stimulus, and the tone CS (an equivalent stimulus-free period is shown for CS rats that did not receive white noise presentations). Hippocampal muscimol infusions attenuated the renewal of fear elicited by the novel white noise on the first test trial.

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