newly acquired memory becomes stable for long-term storage through a process known as memory consolidation, which requires de novo gene expression. Disruption of gene transcription during this process specifically blocks long-term memory formation. The braln-derlved neurotrophic factor (BDNF) has been shown to play an essential role in the consolidation or storage of long-term memory. However, little is known about the regulation of exon-specific ibc/nf transcripts in the brain and how this level of bdnf ger e regulation functions in the process of memory formation. The major scientific goal of this proposal is to identify epigenetic-regulating mechanisms for /bofn^gerie expression changes that serve to stabilize long-term memory. The underlying hypothesis of this grant Is that aberrant epigenetic markings such as posttranslational modification of histones, DNA methylation and transcription factor activation plays a role in exon-specific bdnf gene regulation in memory formation. The mentored phase ofthis proposal will dissect epigenetic mechanisms of exon-specific Mn?gene regulation during memory consolidation using a combination of approaches including measuring DNA methylation associated with exon-specific bdnf transcripts, using chromatin immunoprecipition (ChIP) technology to analyze levels of post-translational modification of histones, methyl CpG binding protein 2, and histone deacetylases at tiofnf promoter regions, and investigating whether DNMT inhibition alters 6c/nf exon-specific mRNA expression during memory consolidation. During the first independent phase aim ofthe project, the role for NMDA receptor (NMDA-R) activation in the epigenetic regulation ofthe bdnf gene will be analyzed using a combination of novel technologies to assess cell-type specific chromatin remodeling of M/if transcripts in hippocampus. The second Independent phase aim will evaluate the functional Impact of NMDA -R-medlated recruitment ofthe transcription factor nuclear factor kappa B (NF-KB) to /bc/nf regulatory elements within DNA and to identify the role ofthe NF-KB DNA-binding complex in the regulation of chromatin remodeling ofthe bdnf gene. This proposal explores the role of epigenetic mechanisms of bdnf ger e regulation In long-term memory formation with a focus on identifying molecular mechanisms that may lead to drug discovery and development to intervene in the ciinicai features of mental disorders. Indeed, epigenetic mechanisms have been implicated in the etiology of mental illnesses, such as schizophrenia, depression, and bipolar disorder. Through the understanding of epigenetic-regulating mechanisms involved in /bofnf gene expression during memory formation and potentially in mental disorders, other genes involved in this process may fall into a common biochemical pathway where disease intervention Is possible
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