TY - JOUR
T1 - P300/CBP-associated factor selectively regulates the extinction of conditioned fear
AU - Wei, Wei
AU - Coelho, Carlos M.
AU - Li, Xiang
AU - Marek, Roger
AU - Yan, Shanzhi
AU - Anderson, Shawn
AU - Meyers, David
AU - Mukherjee, Chandrani
AU - Sbardella, Gianluca
AU - Castellano, Sabrina
AU - Milite, Ciro
AU - Rotili, Dante
AU - Mai, Antonello
AU - Cole, Philip A.
AU - Sah, Pankaj
AU - Kobor, Michael S.
AU - Bredy, Timothy W.
PY - 2012/8/29
Y1 - 2012/8/29
N2 - It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically dependent memory, particularly when there is competition between opposing memory traces, such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57BL/6mice, that the activityofp300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4tothe promoter of the immediate early genezif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional coactivator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace.
AB - It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically dependent memory, particularly when there is competition between opposing memory traces, such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57BL/6mice, that the activityofp300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4tothe promoter of the immediate early genezif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional coactivator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace.
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U2 - 10.1523/JNEUROSCI.0178-12.2012
DO - 10.1523/JNEUROSCI.0178-12.2012
M3 - Article
C2 - 22933779
AN - SCOPUS:84865472870
SN - 0270-6474
VL - 32
SP - 11930
EP - 11941
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 35
ER -