A 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 brain-derived 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 BDNF transcripts in the brain and how this level of BDNF gene regulation functions in the process of memory formation. The major scientific goal of this application is to identify epigenetic-regulating mechanisms for BDNF gene expression changes that serve to stabilize long-term memory. The underlying hypothesis of this grant is that aberrant epigenetic markings such as post- translational modification of histones, DNA methylation and transcription factor activation plays a role in exon-specific BDNF gene regulation in memory formation. The mentored phase of this application will dissect epigenetic mechanisms of exon-specific BDNF 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 BDNF promoter regions, and investigating whether DNMT inhibition alters BDNF exon-specific mRNA expression during memory consolidation. During the first independent phase aim of the project, the role for NMDA receptor (NMDA-R) activation in the epigenetic regulation of the BDNF gene will be analyzed using a combination of novel technologies to assess cell-type specific chromatin remodeling of BDNF transcripts in hippocampus. The second independent phase aim will evaluate the functional impact of NMDA -R-mediated recruitment of the transcription factor nuclear factor kappa B (NF-KB) to BDNF regulatory elements within DNA and to identify the role of the NF-KB DNA-binding complex in the regulation of chromatin remodeling of the BDNF gene. This application explores the role of epigenetic mechanisms of BDNF gene 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 clinical 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 BDNF 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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