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

Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California 90095, USA.
Learning & memory (Cold Spring Harbor, N.Y.) (Impact Factor: 4.38). 02/2008; 15(1):39-45. DOI: 10.1101/lm.801108
Source: PubMed

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.

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Available from: Timothy W Bredy, Aug 22, 2015
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    • "Associative fear conditioning occurred over 2 d and consisted of 10 conditioned stimulus (CS) tones (30 sec, 6 kHz, 75 dB) coterminating with unconditioned stimulus (US) footshocks (500 msec, 1 mA) with a 3-min inter-trial interval (ITI) in " Context A " (MED Associates, standard fear conditioning chambers, Product Number VFC-008). As we hypothesized that RGFP966 and RGFP963 would enhance extinction memory consolidation (as measured by lower levels of freezing behavior during extinction retention tests), we trained subjects to 2 d of associative fear conditioning to maximize freezing levels and avoid a floor effect of extinction training on freezing during extinction retention tests (Bredy and Barad 2008). Twenty-four hours prior to extinction training and 48 h after fear conditioning, subjects were tested to three CS trials ( " grouping " ) in a novel context, " Context B " . "
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    ABSTRACT: Evidence indicates that broad, nonspecific histone deacetylase (HDAC) inhibition enhances learning and memory, however, the contribution of the various HDACs to specific forms of learning is incompletely understood. Here, we show that the Class I HDAC inhibitor, RGFP963, enhances consolidation of cued fear extinction. However, RGFP966, a strong inhibitor of HDAC3, does not significantly enhance consolidation of cued fear extinction. These data extend previous evidence that demonstrate the Class I HDACs play a role in the consolidation of long-term memory, suggesting that HDAC1 and/or HDAC2, but less likely HDAC3, may function as negative regulators of extinction retention. The development of specific HDAC inhibitors, such as RGFP963, will further illuminate the role of specific HDACs in various types of learning and memory. Moreover, HDAC inhibitors that enhance cued fear extinction may show translational promise for the treatment of fear-related disorders, including post-traumatic stress disorder (PTSD). © 2015 Bowers et al.; Published by Cold Spring Harbor Laboratory Press.
    Learning & memory (Cold Spring Harbor, N.Y.) 04/2015; 22(4):225-31. DOI:10.1101/lm.036699.114 · 4.38 Impact Factor
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    • "SAHA Improves motor coordination in R6/2 Huntington's mouse model Hockly et al. (2003) Ameliorates MPP+ toxicity in Parkinson's mouse model Wu et al. (2008) Valproic acid Enhanced long-term memory and reconsolidation of fear memory Bredy and Barad (2008) Enhanced fear conditioning in mouse model of Alzheimer's disease (APPsew/PS1dE9 mice) Kilgore et al. (2010) Neuroprotective effects and enhanced learning in APP23 Alzheimer's mouse model Qing et al. (2008) "
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    ABSTRACT: Histone deacetylases (HDACs) are a family of chromatin remodeling enzymes that restrict access of transcription factors to the DNA, thereby repressing gene expression. In contrast, histone acetyltransferases (HATs) relax the chromatin structure allowing for an active chromatin state and promoting gene transcription. Accumulating data have demonstrated a crucial function for histone acetylation and histone deacetylation in regulating the cellular and behavioral mechanisms underlying synaptic plasticity and learning and memory. In trying to delineate the roles of individual HDACs, genetic tools have been used to manipulate HDAC expression in rodents, uncovering distinct contributions of individual HDACs in regulating the processes of memory formation. Moreover, recent findings have suggested an important role for HDAC inhibitors in enhancing learning and memory processes as well as ameliorating symptoms related to neurodegenerative diseases. In this review, we focus on the role of HDACs in learning and memory, as well as significant data emerging from the field in support of HDAC inhibitors as potential therapeutic targets for the treatment of cognitive disorders.
    Learning & memory (Cold Spring Harbor, N.Y.) 10/2014; 21(10):564-568. DOI:10.1101/lm.036012.114 · 4.38 Impact Factor
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    • "We have used this behavioral paradigm to evaluate the effects of phenytoin and carbamazapine in adult rats (Banks et al., 1999, 2001; McDowell et al., 2004), rats exposed to phenytoin in utero (Mowery et al., 2008), rats with lesions of the basal nucleus of Meynart (Butt et al., 2003), ovariectomized female rats with or without estradiol replacement (Goodman et al., 2004), and rats undergoing chronic restraint (McDowell et al., 2013). Although previous studies have shown VPA to enhance the extinction of fear conditioning (Bredy and Barad, 2008; Heinrichs et al., 2013) or performance on a simple avoidance task (Continella et al., 1984), they have also shown VPA to be detrimental to spatial learning in association with decreased cellular proliferation in the hippocampus (Umka et al., 2010). The complex nature of the aversive task employed in this study would suggest that the hippocampus facilitates task learning. "
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    ABSTRACT: Antiepileptic medications are the frontline treatment for seizure conditions. However, these medications are not without cognitive side effects. Previously, our laboratory reported learning deficits in phenytoin and carbamazepine-treated rats. In the experiment reported here, the effects of valproic acid (VPA) have been studied using the same instrumental training tasks. VPA-treated rats displayed a severe deficit in acquiring a tone-signaled avoidance response. This deficit was attenuated in animals that had prior training in an appetitive context. Thus, this deficit is specific to learning in an aversive context, and does not result from difficulties in transferring associations from an appetitive to aversive context. Learning transfer deficits were previously observed in rats treated with phenytoin, and to a lesser extent, carbamazepine. On the other hand, rats treated with VPA fail to suppress inappropriate responsiveness across aversive training whether they had undergone prior appetitive training or not.
    Frontiers in Behavioral Neuroscience 04/2014; 8:113. DOI:10.3389/fnbeh.2014.00113 · 4.16 Impact Factor
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