Epigenetic Mechanisms of Gene Regulation in Long-Term Memory Formation

新获得的记忆通过一个称为记忆的过程变得稳定，可以长期储存 巩固，这需要从头基因表达。在此过程中基因转录的中断 专门阻止长期记忆的形成脑源性神经营养因子（BDNF）已被广泛应用于临床。 在巩固或储存长期记忆方面发挥着重要作用。然而， 关于外显子特异性IBC/NF转录物在大脑中的调节以及这种水平的BDNF如何调节 在记忆形成的过程中发挥作用。这项提案的主要科学目标是确定 表观遗传学调节机制/bofn^gerie表达变化，有助于稳定长期 记忆这项研究的基本假设是，异常的表观遗传标记，如翻译后 组蛋白的修饰、DNA甲基化和转录因子的激活在 记忆形成中bdnf基因外显子特异性调控本提案的指导阶段将剖析 外显遗传机制的外显子特异性锰？基因调控在记忆巩固过程中的作用 包括测量与外显子特异性BDNF相关的DNA甲基化的方法的组合 转录本，使用染色质免疫印迹（ChIP）技术分析翻译后水平， 在tiofnf启动子区修饰组蛋白、甲基CpG结合蛋白2和组蛋白脱乙酰酶， 并研究DNMT抑制是否改变记忆过程中6c/nf外显子特异性mRNA的表达 合并。在第一个独立的阶段，本项目的目的是，NMDA受体（NMDA-R）的作用， BDNF基因的表观遗传调节中的激活将使用新的 技术来评估海马中M/IF转录物的细胞类型特异性染色质重塑。的 第二个独立阶段的目标是评估NMDA-R介导的募集对功能的影响。 转录因子核因子κ B（NF-κ B）与DNA内的/bc/nf调节元件的结合，并鉴定 NF-κ B DNA结合复合物在调节bdnf基因染色质重塑中的作用该提案探讨了BDNF格尔调控的表观遗传机制在长期记忆形成中的作用，重点是鉴定可能导致药物发现和开发以干预精神障碍的临床特征的分子机制。事实上，表观遗传机制与精神疾病的病因学有关，如精神分裂症、抑郁症和双相情感障碍。通过对记忆过程中/bofnf基因表达的表观遗传调控机制的理解 形成和潜在的精神障碍，其他基因参与这一过程可能属于一个共同的 疾病干预可能的生化途径

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