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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    859—Fear and Aversive Learning and Memory: Extinction II

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    859.19: Cortical DNA hydroxymethylation is associated with fear extinction learning and memory

    Location: Halls B-H

    ">*X. LI1, W. WEI1, Q. ZHAO1, D. BAKER-ANDRESEN1, C. FLAVELL1, J. WIDAGDO1, A. D'ALESSIO2, Y. ZHANG3, T. BREDY1;
    1Bredy Lab., Queensland Brain Inst., St Lucia, Australia; 2Whitehead Inst. for Biomed. Res., Cambridge, MA; 3Harvard Stem Cell Inst., Boston, MA

    Abstract Body: Anxiety disorders are characterized by an impaired ability to inhibit the fear response, which is a hallmark signature of phobia and post-traumatic stress disorder (PTSD). How does the brain acquire strongly emotional memories and how are they maintained across the lifespan? Perhaps more importantly, why do these memories become debilitating in phobia and PTSD, and how can they be minimized through the inhibitory learning process known as extinction? Previous work from our lab and others has advanced the understanding of experience-dependent effects on brain function by demonstrating that epigenetic mechanisms, including histone modifications and DNA methylation, are necessary for neural plasticity associated with fear-related learning and long-term memory. We have now discovered that active DNA demethylation is associated with the extinction of conditioned fear. This process is dependent on the Ten-eleven translocation (Tet) family of enzymes, which mediate the conversion of 5-methylcytosine to 5-hydroxymethylcytosine; a critical component of the active DNA demethylation pathway. Genome-wide analysis of 5-hmC has revealed a dramatic learning-dependent redistribution of this epigenetic mark across the genome, emphasizing inter- and intra- genic regions of coding genes related to neural plasticity and fear extinction. Our data suggest that active DNA demethylation within the adult prefrontal cortex is more extensively involved in experience-dependent plasticity than currently realized, and that this epigenetic mechanism may be particularly important for the extinction of conditioned fear.

    Lay Language Summary: Our understanding of experience-dependent effects on brain function has advanced in recent years with the realization that a variety of epigenetic processes regulate gene expression underlying learning and memory. DNA methylation, in particular, was once considered to be a static epigenetic modification the primary function of which was restricted to directing the development of cellular phenotype. However, a surge of recent studies point to a continued role for DNA methylation across the lifespan, particularly with respect to alterations in neuronal gene expression that directly impact behavior. As such, variation in the accumulation of 5-methylcytosine (5-mC) has emerged as a key factor in experience-dependent plasticity and the formation of memory. These observations represent a major conceptual shift in the way we think about activity-dependent gene expression by firmly positioning the epigenome, and DNA modifications in particular, at the interface between genes, environment, and behavior.
    5-hydroxymethylcytosine (5-hmC) is a novel DNA modification that is highly enriched in the adult brain, and dynamically regulated by neural activity. 5-hmC accumulates across the lifespan; however, the functional relevance of this change in 5-hmC and whether it is necessary for behavioral adaptation has not been fully elucidated. Our research demonstrates that the experience-dependent modification of the neuronal genome is far more dynamic than currently realized. We have observed a dramatic redistribution of neocortical 5-hmC, which promotes gene expression associated with fear extinction, an important form of inhibitory learning and memory. By genome-wide mapping of 5-hmC on individual animals using a novel DNA “barcoding” approach, we have identified 233 hydroxymethylated genomic regions that are selectively associated with fear extinction. A bioinformatics analysis has revealed that the majority of these genomic regions are associated with neural plasticity. Moreover, we have found that the extinction learning-induced accumulation of 5-hmC predominantly occurs within intergenic and intronic loci where it serves to regulate the chromatin landscape. Importantly, this process is mediated by Tet3, a member of the Ten Eleven Translocation (Tet) family of DNA dioxygenases that are essential for converting methylated DNA to 5-hmC, the activity of which is required for the establishment of epigenetic states underlying rapid behavioral adaptation.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    859—Fear and Aversive Learning and Memory: Extinction II

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    859.19: Cortical DNA hydroxymethylation is associated with fear extinction learning and memory

    Location: Halls B-H

    ">*X. LI1, W. WEI1, Q. ZHAO1, D. BAKER-ANDRESEN1, C. FLAVELL1, J. WIDAGDO1, A. D'ALESSIO2, Y. ZHANG3, T. BREDY1;
    1Bredy Lab., Queensland Brain Inst., St Lucia, Australia; 2Whitehead Inst. for Biomed. Res., Cambridge, MA; 3Harvard Stem Cell Inst., Boston, MA

    Abstract Body: Anxiety disorders are characterized by an impaired ability to inhibit the fear response, which is a hallmark signature of phobia and post-traumatic stress disorder (PTSD). How does the brain acquire strongly emotional memories and how are they maintained across the lifespan? Perhaps more importantly, why do these memories become debilitating in phobia and PTSD, and how can they be minimized through the inhibitory learning process known as extinction? Previous work from our lab and others has advanced the understanding of experience-dependent effects on brain function by demonstrating that epigenetic mechanisms, including histone modifications and DNA methylation, are necessary for neural plasticity associated with fear-related learning and long-term memory. We have now discovered that active DNA demethylation is associated with the extinction of conditioned fear. This process is dependent on the Ten-eleven translocation (Tet) family of enzymes, which mediate the conversion of 5-methylcytosine to 5-hydroxymethylcytosine; a critical component of the active DNA demethylation pathway. Genome-wide analysis of 5-hmC has revealed a dramatic learning-dependent redistribution of this epigenetic mark across the genome, emphasizing inter- and intra- genic regions of coding genes related to neural plasticity and fear extinction. Our data suggest that active DNA demethylation within the adult prefrontal cortex is more extensively involved in experience-dependent plasticity than currently realized, and that this epigenetic mechanism may be particularly important for the extinction of conditioned fear.

    Lay Language Summary: Our understanding of experience-dependent effects on brain function has advanced in recent years with the realization that a variety of epigenetic processes regulate gene expression underlying learning and memory. DNA methylation, in particular, was once considered to be a static epigenetic modification the primary function of which was restricted to directing the development of cellular phenotype. However, a surge of recent studies point to a continued role for DNA methylation across the lifespan, particularly with respect to alterations in neuronal gene expression that directly impact behavior. As such, variation in the accumulation of 5-methylcytosine (5-mC) has emerged as a key factor in experience-dependent plasticity and the formation of memory. These observations represent a major conceptual shift in the way we think about activity-dependent gene expression by firmly positioning the epigenome, and DNA modifications in particular, at the interface between genes, environment, and behavior.
    5-hydroxymethylcytosine (5-hmC) is a novel DNA modification that is highly enriched in the adult brain, and dynamically regulated by neural activity. 5-hmC accumulates across the lifespan; however, the functional relevance of this change in 5-hmC and whether it is necessary for behavioral adaptation has not been fully elucidated. Our research demonstrates that the experience-dependent modification of the neuronal genome is far more dynamic than currently realized. We have observed a dramatic redistribution of neocortical 5-hmC, which promotes gene expression associated with fear extinction, an important form of inhibitory learning and memory. By genome-wide mapping of 5-hmC on individual animals using a novel DNA “barcoding” approach, we have identified 233 hydroxymethylated genomic regions that are selectively associated with fear extinction. A bioinformatics analysis has revealed that the majority of these genomic regions are associated with neural plasticity. Moreover, we have found that the extinction learning-induced accumulation of 5-hmC predominantly occurs within intergenic and intronic loci where it serves to regulate the chromatin landscape. Importantly, this process is mediated by Tet3, a member of the Ten Eleven Translocation (Tet) family of DNA dioxygenases that are essential for converting methylated DNA to 5-hmC, the activity of which is required for the establishment of epigenetic states underlying rapid behavioral adaptation.