The RNA modification N⁶-methyladenosine (m⁶A) influences mRNA stability and cell-type-specific developmental programming, and is highly abundant in the adult brain. However, it has not been determined whether m⁶A is dynamically regulated by experience. Based on transcriptome-wide profiling of m⁶A, we report that the level of m⁶A increases in the medial prefrontal cortex (mPFC) of mice in response to behavioral experience. The modulation was enriched near the stop codon of mRNAs, including genes related to neuronal plasticity. In primary cortical neurons, in vitro, modulation of m⁶A by the RNA demethylase FTO influenced the degradation profiles of a subset of transcripts with modulated sites. In vivo, the expression of Fto and the m⁶A methyltransferase, Mettl3 correlated with the observed increase in m⁶A levels post-training. Furthermore, targeted knockdown of FTO in the mPFC led to enhanced consolidation of cued fear memory. Thus, together with its role in early development, the dynamic regulation of m⁶A in the adult brain serves as an important epitranscriptomic mechanism associated with behavioral adaptation. SIGNIFICANCE STATEMENTN⁶-methyladenosine (m⁶A) is the most prevalent internal modification on RNA, however, its cellular dynamics in vivo remains elusive. Here we provide the first demonstration of m⁶A upregulation in the mouse medial prefrontal cortex (mPFC) following behavioral training. Knocking down the m⁶A demethylase FTO in the mPFC, which increases total m⁶A level, results in enhanced consolidation of fear memory. Our findings suggest that m⁶A is regulated in an activity-dependent manner in the adult brain, and may function to fine-tune mRNA turnover during memory-related processes.

Significance: We have discovered a critical role for ten-eleven translocation 3-mediated hydroxylation of 5-methycytosine in the adult prefrontal cortex in mediating rapid behavioral adaptation. 5-hydroxymethylcytosine (5-hmC) is highly dynamic in response to fear extinction training, and rather than simply reflecting a functional intermediary of active DNA demethylation, the learning-induced intergenic accumulation of 5-hmC creates an epigenetic state that promotes experience-dependent gene expression and behavioral adaptation.

There are inherent biological differences between males and females that contribute to sex differences in brain function and to many sex‐specific illnesses and disorders. Traditionally, it has been thought that such differences are due largely to hormonal regulation; however, there are also genetic and epigenetic effects caused by the inheritance and unequal dosage of genes located on the X and Y chromosomes. Here we discuss the evidence in favor of a genetic and epigenetic basis for sexually dimorphic behavior, as a consequence of underlying differences in the regulation of genes that drive brain function. A better understanding of sex‐specific molecular processes in the brain will provide further insight for the development of novel therapeutic approaches for the treatment of neuropsychiatric disorders characterized by sex differences.

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/6 mice, that the activity of p300/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 ATF4 to the 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.