It has long been appreciated that gene transcription is required for long-term memory storage, but only recently has it become clear that transcriptional regulation for memory processes involves the concerted action of multiple transcription factors and coactivators that interact with chromatin, a protein complex that packages DNA. Originally thought to be static and structural in purpose, chromatin is now known to be very dynamic, exerting precise control over gene expression. The idea that chromatin remodeling may regulate gene expression for memory processes has gained considerable attention recently through the study of enzymes that are involved in chromatin remodeling, in particular, histone acetyltransferases (HATs) and histone deacetylases (HDACs). For example, our previous research demonstrated that CREB-binding protein (CBP), a potent HAT and transcriptional coactivator, is critical for long-lasting forms of synaptic plasticity (the activity- dependent change in the strength of neuronal connections) and long-term memory. In this proposed research program, we continue to examine our central hypothesis that enzymes involved in chromatin remodeling are essential for gene expression involved in memory processes. Our preliminary data demonstrate that HDAC inhibitors (small molecule antagonists that block HDAC activity and induce a histone hyper-acetylated state) enhance synaptic plasticity and memory storage. Further, we find that HDAC inhibitors enhance memory processes via a defined molecular mechanism. To examine the effect of HDAC inhibitors on memory storage and define the molecular mechanism underlying the modulation of memory storage by HDAC inhibitors we propose three specific aims.
In specific aim 1, we will examine how HDAC inhibition affects memory.
In specific aim 2, we will define the underlying molecular mechanism by which HDAC inhibition enhances memory.
In specific aim 3, we will examine how chromatin remodeling regulates gene expression during memory consolidation. Results from these experiments promise to significantly contribute to our understanding of how chromatin remodeling via histone modification regulates gene expression required for long-lasting forms of memory. Chromatin remodeling is considered a form of `epigenetic'regulation, in which gene expression is regulated without altering the DNA code, and may have long-lasting effects. Sustained epigenetic mechanisms of gene regulation in neurons have recently become central to several cognitive disorders including mental retardation, depression, and schizophrenia.
It has become clear that transcriptional regulation for memory processes involves the concerted action of multiple transcription factors and coactivators that interact with chromatin, a protein complex that packages DNA. Chromatin remodeling is considered a form of `epigenetic'regulation, in which gene expression is regulated without altering the DNA code, and may have long-lasting effects, an idea that has become central to understanding the molecular mechanisms underlying several cognitive disorders including mental retardation, depression, and schizophrenia. The experiments in this research proposal are focused on understanding how chromatin remodeling regulates gene expression required for memory processes.
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