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SFB-F44 - Cell signaling in chronic CNS disorders

Project 10:
Epigenetic mechanisms in aberrant memory regulation

Nicolas Singewald

Research indicates that neurodegenerative diseases including Parkinson’s disease, psychiatric disorders (depression, stress and anxiety) and neurodevelopmental disorders can involve aberrant modifications of histones and/or DNA methylation. Such epigenetic modifications can be influenced by experience and determine the transcriptional state of regulatory genes critical to synaptic plasticity, cognition and anxiety/mood. In this project we will focus on recent evidence that epigenetic mechanisms including, in particular, histone modifications and regulatory ncRNAs are important in the formation/regulation of memories. We are particularly interested in therapeutically improving the failure to build new extinction memory, which resembles features of anxiety disorders including post-traumatic stress disorder. We wish to identify epigenetic modifications and altered expression of ncRNAs that occur selectively in discrete brain areas of the fear circuitry and that are correlated with formation of a new extinction memory in clinically relevant models of extinction-learning failure. We will also test the effects of drugs targeting epigenetic mechanisms including HDAC inhibitors for their ability to improve fear extinction deficits. Furthermore, we will attempt to gain first information on causal relationships by identifying DNA sequences/genes that are regulated by the revealed epigenetic modifications.