Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction

Jinzhao Ji1 and Stephen Maren1,2,3

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Abstract

There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of the DH blunted the expression of conditional freezing to an auditory conditional stimulus (CS), but did not affect the acquisition of extinction to that CS. In contrast, DH lesions impaired the context-specific expression of extinction, eliminating the renewal of fear normally observed to a CS presented outside of the extinction context. Post-extinction DH lesions also eliminated the context dependence of fear extinction. These results are consistent with those using pharmacological inactivation of the DH and suggest that the DH is required for using contextual stimuli to regulate the expression of fear to a Pavlovian CS after extinction.

It has been recognized for decades that the expression of memory depends on the context in which memory is retrieved (Spear 1973; Tulving and Thomson 1973). Contextual retrieval operates on both declarative memory in humans (Maguire et al. 1997) and Pavlovian conditioning in animals (Bouton 1993; Maren and Holt 2000). And despite the importance of contextual retrieval in normal memory function, little is known concerning its brain mechanisms.

The hippocampus has a critical role in several memory processes, including episodic memory (for reviews, see Squire and Zola 1996; Eichenbaum 2000). Years ago it was suggested that the hippocampus has an important role in contextual memory retrieval (Hirsh 1974). Consistent with this view, an abundance of studies implicate the hippocampus not only in encoding contextual representations (Kim and Fanselow 1992; Phillips and LeDoux 1992; Maren et al. 1997; Frankland et al. 1998; Good et al. 1998; Rudy and O'Reilly 2001), but also in using these representations in the service of memory retrieval (Good and Honey 1991; Honey and Good 1993; Kennedy and Shapiro 2004). We have recently shown in a series of experiments using intrahippocampal muscimol infusions that the dorsal hippocampus (DH) plays an important role in the context-dependent retrieval of fear memory in two different Pavlovian interference paradigms: latent inhibition (Holt and Maren 1999) and extinction (Corcoran and Maren 2001, 2004). Both procedures yield context-dependent memory, insofar as conditional responding is low in the pre-exposure or extinction contexts and high outside of those contexts. Reversible inactivation of the DH prior to retrieval testing eliminates the renewal of fear to a CS outside of the pre-exposure or extinction context, without affecting fear expression per se or context discrimination.

Reversible lesions reveal an important role for the DH in the context specificity of latent inhibition and extinction. Earlier studies, however, using permanent hippocampal lesions found that electrolytic lesions of the fimbria/fornix (Wilson et al. 1995) or neurotoxic lesions of the entire hippocampus (Frohardt et al. 2000) had no effect on the context-dependent expression of extinction. It may be the case that the nature (reversible vs. permanent) and timing (pre-training vs. pre-testing) of the lesions is an important determinant of their effects on the context dependence of extinction. Indeed, lesions and reversible inactivation may yield different behavioral outcomes, as other neural systems may compensate for irreversible damage, and the timing of hippocampal manipulation is critical in determining hippocampal deficits in contextual fear conditioning (Maren et al. 1997). Thus, in the present study, we used Pavlovian fear conditioning in rats to examine the effects of electrolytic lesions made either before conditioning or after extinction on the context specificity of extinction. Because recent data suggest that the method for testing context-specific fear memory may affect hippocampal involvement in extinction (Corcoran and Maren 2004), we also examined the renewal of extinction either in a neutral context (Experiment 1) or in the conditioning context (Experiment 2). Our results reveal that electrolytic lesions of the DH disrupt the context dependence of extinction independent of when they are made relative to extinction, and independent of the context in which the renewal of extinguished fear is tested.

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Results

Experiment 1: Pre- or post-extinction dorsal hippocampal lesions and renewal testing in a neutral context