PMID- 17522015
OWN - NLM
STAT- MEDLINE
DCOM- 20070703
LR  - 20191210
IS  - 1549-5485 (Electronic)
IS  - 1072-0502 (Print)
IS  - 1072-0502 (Linking)
VI  - 14
IP  - 4
DP  - 2007 Apr
TI  - Histone modifications around individual BDNF gene promoters in prefrontal cortex 
      are associated with extinction of conditioned fear.
PG  - 268-76
AB  - Extinction of conditioned fear is an important model both of inhibitory learning 
      and of behavior therapy for human anxiety disorders. Like other forms of 
      learning, extinction learning is long-lasting and depends on regulated gene 
      expression. Epigenetic mechanisms make an important contribution to persistent 
      changes in gene expression; therefore, in these studies, we have investigated 
      whether epigenetic regulation of gene expression contributes to fear extinction. 
      Since brain-derived neurotrophic factor (BDNF) is crucial for synaptic plasticity 
      and for the maintenance of long-term memory, we examined histone modifications 
      around two BDNF gene promoters after extinction of cued fear, as potential 
      targets of learning-induced epigenetic regulation of gene expression. Valproic 
      acid (VPA), used for some time as an anticonvulsant and a mood stabilizer, 
      modulates the expression of BDNF, and is a histone deacetylase (HDAC) inhibitor. 
      Here, we report that extinction of conditioned fear is accompanied by a 
      significant increase in histone H4 acetylation around the BDNF P4 gene promoter 
      and increases in BDNF exon I and IV mRNA expression in prefrontal cortex, that 
      VPA enhances long-term memory for extinction because of its HDAC inhibitor 
      effects, and that VPA potentiates the effect of weak extinction training on 
      histone H4 acetylation around both the BDNF P1 and P4 gene promoters and on BDNF 
      exon IV mRNA expression. These results suggest a relationship between histone H4 
      modification, epigenetic regulation of BDNF gene expression, and long-term memory 
      for extinction of conditioned fear. In addition, they suggest that HDAC 
      inhibitors may become a useful pharmacological adjunct to psychotherapy for human 
      anxiety disorders.
FAU - Bredy, Timothy W
AU  - Bredy TW
AD  - Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, 
      Semel Institute for Neuroscience and Human Behavior, Los Angeles, California 
      90095, USA.
FAU - Wu, Hao
AU  - Wu H
FAU - Crego, Cortney
AU  - Crego C
FAU - Zellhoefer, Jessica
AU  - Zellhoefer J
FAU - Sun, Yi E
AU  - Sun YE
FAU - Barad, Mark
AU  - Barad M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070406
PL  - United States
TA  - Learn Mem
JT  - Learning & memory (Cold Spring Harbor, N.Y.)
JID - 9435678
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Histones)
RN  - 0 (RNA, Messenger)
RN  - 614OI1Z5WI (Valproic Acid)
SB  - IM
MH  - Acetylation
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*genetics
MH  - *Conditioning, Psychological
MH  - Enzyme Inhibitors/pharmacology
MH  - Extinction, Psychological/*physiology
MH  - *Fear
MH  - Histone Deacetylase Inhibitors
MH  - Histones/metabolism
MH  - Male
MH  - Memory/drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Prefrontal Cortex/metabolism/*physiology
MH  - *Promoter Regions, Genetic
MH  - RNA, Messenger/metabolism
MH  - Time Factors
MH  - Valproic Acid/pharmacology
PMC - PMC2216532
EDAT- 2007/05/25 09:00
MHDA- 2007/07/04 09:00
PMCR- 2008/04/01
CRDT- 2007/05/25 09:00
PHST- 2007/05/25 09:00 [pubmed]
PHST- 2007/07/04 09:00 [medline]
PHST- 2007/05/25 09:00 [entrez]
PHST- 2008/04/01 00:00 [pmc-release]
AID - 14/4/268 [pii]
AID - 10.1101/lm.500907 [doi]
PST - epublish
SO  - Learn Mem. 2007 Apr 6;14(4):268-76. doi: 10.1101/lm.500907. Print 2007 Apr.