Histone Acetylation in the Hippocampus and Fear Extinction Shigeto Yamamoto, Shigeru Morinobu, Yosuke Fujita, and Shigeto Yamawaki rowing evidence suggests that regulation of gene transcription in response to environmental stimuli is closely involved in the molecular mechanisms of memory consolidation in the hippocampus. The expression of various genes, such as neurotrophic factors and immediate early genes, is regulated during the consolidation of fear memory. With regard to gene expression, it is well known that modification of chromatin structure mediated by histone modification including acetylation, methylation, and phosphorylation, is crucial for the accessibility of transcription factor to its binding site located on the promoter region and subsequently plays an important role in gene transcription. In terms of histone modification and memory, histone deacetylase (HDAC) inhibitors have recently been shown to enhance not only contextual fear conditioning but also fear extinction (1– 4). However, little is known whether fear memory consolidation or extinction is preferentially enhanced under the condition of increased histone acetylation by HDAC inhibitors. In this issue of Biological Psychiatry, Stafford et al. (5) examine the enhanced effect of sodium butyrate (NaB) on fear extinction and initial conditioning of fear in mice using intrahippocampal or systemic administration. Across a variety of conditions, the effects of NaB on extinction were larger and more persistent compared with its effects on initial fear memory. Interestingly, they found a smaller NaB-induced enhancement of initial fear memory, inconsistent with other studies (2– 4). Most recently we examined the behavioral and molecular effects of systemic injection of vorinostat, a different type of HDAC inhibitor, on fear extinction in the rat hippocampus, and found that vorinostat enhanced both the original conditioned fear and extinction of the conditioned fear equally, depending on the timing of administration. Our results are consistent with those of Bredy and Barad (2) in terms of enhancement of both fear extinction and the original conditioned fear in response to administration of HDAC inhibitors. In their study, valproic acid either strengthened reconsolidation of the original fear memory or enhanced long-term memory for extinction, depending on the conditions of memory retrieval. It is suggested that the difference in these results may be due to methodologic differences. However, as Stafford et al. (5) note in this issue, the reason is that the rate of extinction may be slower than the rate of initial acquisition. Surely a slower rate of learning during extinction would theoretically leave more room for enhancements than the relatively fast rate of learning associated with initial acquisition. Thus, the learning that occurs during extinction may be more susceptible to pharmacological manipulations compared with initial conditioning. Further research is needed to clarify the underlying mechanisms by which HDAC inhibitors induce the enhancement of memory.
From the Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. Address correspondence to Shigeru Morinobu, M.D., Ph.D., Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551 Hiroshima, Japan; E-mail: [email protected]
Received and accepted Apr 26, 2012.
Although a growing body of evidence indicates that the interconnections among the amygdala, hippocampus, and medial prefrontal cortex (mPFC) play an important role in extinction of conditioned fear (6), the exact brain region in which chromatin remodeling through the enhancement of histone acetylation is undertaken remains unknown. It was revealed that the hippocampus has strong reciprocal connections with the mPFC, and pharmacologic lesions in the infralimbic cortex (IL) impair the retrieval of extinction (6). In addition, evidence indicates that prelimbic cortex (PL) activity is necessary for fear expression but not extinction memory, whereas IL activity is necessary for extinction memory but not fear expression (7). Both the PL and IL, which are involved in extinction, exert bidirectional regulation of fear expression. In this context, Stafford et al. (5) investigated the effects of intrahippocampal NaB after extinction on histone acetylation (H3) and c-Fos expression in the mPFC to understand how modulating the hippocampus affects transcriptional events in brain regions important for extinction. In addition, they infused NaB into the IL or PL to further examine the specificity. They observed that NaB infusion into the hippocampus resulted in increases in histone acetylation and c-Fos expression in the IL but not the PL. The involvement of the IL was confirmed with the finding that infusion of NaB into the IL but not the PL induced persistent extinction enhancement. Previously the authors showed that intrahippocampal infusions of HDAC inhibitors with extinction enhanced long-term contextual fear extinction (1). They have extended their research and, in this issue, they demonstrate the involvement of the interaction between increased H3 in the hippocampus and the IL, in the persistence of fear extinction. They also confirm that the network between the hippocampus and IL, but not the PL, is critical for fear extinction from the aspect of epigenetic machinery. Because the increased H3 generally leads to euchromatin status in which deoxyribonucleic acid is kept accessible for transcription, the results by Stafford et al. (5) indicate that changes in gene transcription in these regions play an important role in the enhancement of fear memory extinction. Although Stafford et al. observed changes in c-Fos expression in the hippocampus or IL, c-Fos is only one of the transcription factors that regulate gene transcription through the activator protein-1 binding site. Thus, it is necessary to identify downstream target genes with increased expression that are critical for fear extinction. In our recent study, we observed that vorinostat increased the levels of NR2B messenger ribonucleic acid and protein as well as the levels of acetylated histone H3 and H4 at the promoter of the NR2B gene in the hippocampus along with the enhancement of fear extinction (3). This finding suggests that the NR2B gene in the hippocampus is a candidate gene involved in fear extinction. However, the possibility cannot be ruled out that alterations in the expression of NR2B were coincident with the enhancement of fear extinction in response to vorinostat. That is, there is a possibility that the NR2B gene is only one of the genes whose expression is affected by vorinostat, not the key target. In fact, fear extinction appears to involve not only N-methl-D-aspartate receptors but also neurotransmitter-mediated signals involving gammaaminobutyric acid, brain-derived neurotrophic factor, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and metabotropic BIOL PSYCHIATRY 2012;72:2–3 © 2012 Society of Biological Psychiatry
Commentary glutamate receptors (8). Further studies are warranted to identify the target genes involved in fear extinction in the future. Selective serotonin reuptake inhibitors or benzodiazepines are the first-line drugs in the treatment of human anxiety disorders such as posttraumatic stress disorder (PTSD) and phobias, whereas some patients show a poor therapeutic response to these drugs. It has been proposed that impairment of fear extinction plays a pivotal role in the pathophysiology of PTSD. Given this notion, drugs that facilitate fear extinction may be useful as novel treatments for PTSD. Although recent pharmacologic interventions have been successful in the enhancement of fear extinction, spontaneous recovery and related phenomena (e.g., renewal, reinstatement) that sometimes follow extinction treatments are a major challenge (9). Because epigenetic manipulations cause long-term changes in gene expression, thereby leading to persistent changes in behavior, enhancement of fear extinction by HDAC inhibitors would provide opportunities for the development of novel therapies. To date, little is known about the persistence of the effects of HDAC inhibitors on fear extinction. Stafford et al. (5) demonstrate the persistent effect of intrahippocampal NaB, which inhibits spontaneous recovery. As for spontaneous recovery, Bouton (10) noted that the passage of time represents a gradually changing context. In that model, extinction may be specific to the environmental context in which it occurs as well as the temporal context. Bouton likened spontaneous recovery to the renewal effect, with the changed context being a different time rather than a different environment. Based on this idea, it is possible that the hippocampus is associated with the underlying mechanisms of spontaneous recovery as well as fear renewal. Therefore, the result by Stafford et al. (5) suggests that epigenetic modulations in the hippocampus may be a key target for prevention of the return of fear. In summary, several preclinical studies have suggested that administration of HDAC inhibitors in conjunction with exposure therapy can be a promising tool for the treatment of anxiety disorders including PTSD. However, there have been no clinical studies showing the effects of HDAC inhibitors on fear extinction. Therefore, it is
BIOL PSYCHIATRY 2012;72:2–3 3 recommended that clinical trials of HDAC inhibitors are conducted in the future. This work was supported by a grant-in-aid for general scientific research from the Ministry of Education, Science, and Culture of Japan, a Health Science Research Grant for Research on Brain Science from the Ministry of Health and Welfare of Japan, and a grant from Core Research for Evolutional Science and Technology of Japan Science and Technology. The authors report no biomedical financial interests or potential conflicts of interest. 1. Lattal KM, Barrett RM, Wood MA (2007): Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction. Behav Neurosci 121:1125–1131. 2. Bredy TW, Barad M (2008): The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear. Learn Mem 15:39 – 45. 3. Fujita Y, Morinobu S, Takei S, Fuchikami M, Matsumoto T, Yamamoto S, et al. (2012): Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene. J Psychiatr Res 46:635– 643. 4. Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, et al. (2007): Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP dependent transcriptional activation. J Neurosci 27:6128 – 6140. 5. Stafford JM, Raybuck JD, Ryabinin AE, Lattal KM (2012): Increasing histone acetylation in the hippocampus-inflalimbic network enhances fear extinction. Biol Psychiatry 72:25–33. 6. Quirk GJ, Mueller D (2008): Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56 –72. 7. Sierra-Mercado D, Padilla-Coreano N, Quirk GJ (2011): Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdale in the expression and extinction of conditioned fear. Neuropsychopharmacology 36:529 –538. 8. Myers KM, Davis M (2007): Mechanisms of fear extinction. Mol Psychiatry 12:120 –150. 9. Stafford JM, Lattal KM (2011): Is an epigenetic switch the key to persistent extinction? Neurobiol Learn Mem 96:35– 40. 10. Bouton ME (2004): Context and behavioral processes in extinction. Learn Mem 11:485– 494.