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

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;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 neur...

Network model of fear extinction and renewal functional pathways

“…While in extinction these total effects were found to be very close to 0, in the renewal group they were approximately −0.3, suggesting that hippocampal influence on the amygdala through both direct and indirect routes plays a larger role in the renewal group than it does in the extinction group. This is consistent with the concept that the hippocampal formation may participate in the representation and the processing of contextual cues, thought to be important in context-dependent fear renewal (Corcoran and Maren, 2001, Corcoran and Maren, 2004, Corcoran et al, 2005, Ji and Maren, 2005, Bouton et al, 2006. Finally, total influences of higher brain regions on the vlPAG showed a change of sign between the extinction and the renewal groups as well (Fig.…”

“…For example, while the CA1-ILA pathway is weakly negative in the extinction group, it is strongly positive in the renewal group, suggesting that the information transmitted from CA1 hippocampal cells to the infralimbic cortex may guide the further interaction between the prefrontal cortical areas with other neural nodes of interest. Additionally, greater hippocampal activation was observed in the renewal as compared to extinction group, lending further support to the importance of hippocampus in fear renewal (Corcoran and Maren, 2001, Corcoran and Maren, 2004, Corcoran et al, 2005, Ji and Maren, 2005. Therefore, Maren's model is supported in part insofar as greater hippocampal activation was apparent in the renewal condition relative to the extinction condition.…”

“…In addition, PER has reciprocal connections to the hippocampus (Naber, Witter, & Lopes da Silva, 1999;Burwell et al, 2004). Hippocampal lesions impair renewal in some studies (Corcoran & Maren, 2004;Ji & Maren, 2005), but not others ( Wilson et al, 1995;Frohardt et al, 2000). Perhaps hippocampal lesions disrupt incoming PER influences, especially novelty/familiarity discriminations (Bussey, Muir, & Aggleton, 1999;Liu & Bilkey, 2001;Murray & Richmond, 2001).…”

Mechanisms of fear extinction

“…112 Hippocampal involvement in renewal is more complex. Studies involving permanent, pretraining lesions of fimbria-fornix 111 or hippocampus 112,113 have reported inconsistent effects, but studies employing temporary inactivation of hippocampus via localized infusions of the GABA A receptor agonist muscimol have reported specific deficits. When animals are tested in a novel context (AAB or ABC renewal) and muscimol is infused into hippocampus before test, renewal is not observed (i.e., freezing is equally low in all contexts).…”

“…In most experiments there is no effect of these manipulations 112,113,118 but there is one report of a decrease in freezing across an extinction training session following pretraining electrolytic lesions 113 and one report of a disruption of within-session extinction following pre-extinction training infusions of muscimol. 114 Two recent physiological studies by Garcia and co-workers indicate that long-term potentiation (LTP) is induced in the output pathways of the dorsal 119 and ventral 120 hippocampus by extinction training; that extinction is impaired by application of depotentiation-inducing low-frequency stimulation to the dorsal hippocampus following extinction training; 119 and that application of LTP-inducing high-frequency stimulation to the dorsal hippocampus shortly after depotentiation induction restores extinction behavior.…”