The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear

Abstract

Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its function as a histone deacetylase inhibitor (HDAC). Here we report that VPA enhances long-term memory for both acquisition and extinction of cued-fear. Interestingly, VPA enhances extinction, but also enhances renewal of the original conditioned fear when tested in a within-subjects design. This effect appears to be related to a reconsolidation-like process since a single CS reminder in the presence of VPA can enhance long-term memory for the original fear in the context in which fear conditioning takes place. We also show that by modifying the intertrial interval during extinction training, VPA can strengthen reconsolidation of the original fear memory or enhance long-term memory for extinction such that it becomes independent of context. These findings have important implications for the use of HDAC inhibitors as adjuncts to behavior therapy in the treatment of phobia and related anxiety disorders.

Figure 1.

Effect of VPA on long-term memory for conditioned fear after partial acquisition when tested 7 d after training (A) in context B and (B) in context A, and after partial extinction when tested 7 d after training (C) in context B and (D) in context A. VPA (100 mg/kg, i.p.), given prior to fear conditioning, enhances long-term memory for fear in both contexts. VPA (100 mg/kg, i.p.), given prior to extinction training, enhances long-term memory for extinction in context B but enhances memory for fear in the original training context A (n = 15–16/group; [RC] retention control; *P < 0.05; **P < 0.001). The context B data presented in panel C are from Bredy et al. (2007).

Figure 2.

Effect of VPA on reconsolidation of cued-fear after a single CS reactivation trial (LTM) when tested 24 h (PR-LTM) and 7 d (PR-LTM2) later in context B and context A. VPA (100 mg/kg, i.p.), given 90 min prior to a single CS reactivation, enhances long-term memory for fear in the original acquisition context A (n = 8/group; *P < 0.05).

Figure 3.

Effect of VPA on reconsolidation and extinction of conditioned fear using (A) a massed CS exposure protocol or (B) a spaced CS exposure protocol, when tested 24 h (PR-LTM) and 7 d (PR-LTM2) after training in context B and context A. VPA (100 mg/kg, i.p.), administered prior to training, enhances fear reconsolidation in a massed CS presentation protocol but enhances fear extinction in a spaced CS presentation protocol. On day 2, VPA had (C) no effect on within-session extinction with massed CS presentations, but (D) significantly increased freezing during spaced CS presentations (n = 8/group; *P < 0.05; **P < 0.001).