Molecular epigenetics of auditory memory and cortical plasticity

听觉记忆和皮质可塑性的分子表观遗传学

• 批准号: 8955447
• 负责人: Kasia Bieszczad
• 金额: $ 14.87万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8955447
• 关键词: Acoustics; Address; Adult; Animal Behavior; Auditory; Auditory area; Auditory system; Bees; Behavior; Behavioral; Caliber; Candidate Disease Gene; Cells; Chad; Cochlear implant procedure; Communication; Comprehension; Cues; Data; Deacetylase; Epigenetic Process; Event; Extinction (Psychology); Frequencies; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Health; Hearing; Histone Acetylation; Histone Deacetylation; Histones; Human; Information Storage; Investigation; Laboratory Research; Lead; Learning; Life; Link; Maps; Mediating; Memory; Molecular; Molecular Genetics; Mutate; Neuronal Plasticity; Neurons; Neurosciences; Operant Conditioning; Phase; Physiological; Process; Rattus; Regulation; Rehabilitation therapy; Repression; Research; Research Personnel; Resistance; Rewards; Rodent Model; Role; Seeds; Sensory; Signal Transduction; Specificity; Staging; Stimulus; Structure; System; Techniques; Tinnitus; Tissues; Training; Universities; Viral; Work; auditory comprehension; base; classical conditioning; experience; gene function; genome-wide; hearing impairment; histone deacetylase 3; histone modification; inhibitor/antagonist; insight; long term memory; memory process; mind control; neural circuit; neuromechanism; neurophysiology; novel; novel therapeutic intervention; programs; public health relevance; receptive field; relating to nervous system; small molecule; sound; sound frequency

 DESCRIPTION (provided by applicant): This application will seed the research program of an Early Stage Investigator recently hired at Rutgers University (Asst. Prof., January 2015), Dr. Kasia M. Bieszczad (bee-YESH-chad). The ultimate goal is to establish research to determine critical behavioral, molecular and genetic neural mechanisms of auditory learning and memory. A particular focus is on cortical plasticity. Learning to understanding the meaning of sounds by their linkage to other events and significant stimuli enables auditory comprehension. Abilities of auditory comprehension in normal adults, or in adults after rehabilitation following hearing loss or cochlear implantation, all depend on enduring auditory memory - that is, the stable information storage about sound. To understand processes underlying auditory memory function, it is important to identify neuroplasticity that enables the formation of long-term auditry memory and information storage. Auditory cortex is key for auditory memory. Even early auditory cortex can undergo experience-dependent physiological plasticity throughout a lifetime. The relationship between auditory memory and cortical plasticity is open to investigation from molecules, to genes, cells, circuits in systems, and behavior. This proposal is to determine molecular and genetic neural mechanisms that control cortical plasticity and, thereby, the transformation of auditory experiences into auditory memory. Future multi-level approaches will discover how these molecules and which particular genes function in their neural circuits and systems to ultimately establish robust auditory memory. The initial plan is to investigate in two Specific Aims epigenetic mechanisms of auditory memory formation and experience-dependent auditory cortical plasticity. Experience-dependent mechanisms that underlie auditory cortical plasticity require transcription - that is, the expression of genes that enable stable changes in neuronal function, and ultimately animal behavior. An exciting new avenue to approach the role of transcription for auditory cortical plasticity and memory is through the power of epigenetic control. A primary epigenetic mechanism is histone modification, specifically histone acetylation, which generally promotes transcription. Histone deacetylases (HDACs) repress transcription by down-regulating this process, so are critical and powerful negative regulators of experience-dependent neural plasticity. Currently completely unknown, is whether HDACs regulate auditory cortical plasticity and, thereby, change the formation of auditory memory in ways that may make memories stronger and more specific. To address this important question, the role of HDAC3 will be initially determined over the course of this proposal at molecular, neurophysiological and behavioral levels, using pharmacological (AIM 1) and targeted viral (AIM 2) techniques to manipulate HDAC3 in a rodent model of auditory associative learning. These studies promote the entry of Dr. Bieszczad and her research on auditory memory processes to the new field of behavioral epigenetics. Future R01s will extend this work to establish independence in a high-caliber, important, and completely novel niche of laboratory research.

 描述（由应用程序提供）：本申请将播种最近在罗格斯大学（ASST。教授，2015年1月）雇用的早期研究人员的研究计划，Kasia M. Bieszczad博士（Bee-Yesh-Chad）。最终目标是建立研究，以确定听觉学习和记忆的关键行为，分子和遗传神经机制。特别的重点是皮质可塑性。学会通过与其他事件的联系来理解声音的含义，并具有重大的刺激能够获得听觉理解。听力损失或人工耳蜗后，正常成年人或康复后的成年人的听觉理解能力都取决于结束听觉记忆 - 也就是说，关于声音的稳定信息存储。要了解听觉记忆功能的基础过程，重要的是要确定能够形成长期审核记忆和信息存储的神经塑性。听觉皮层是听觉内存的关键。即使是早期的听觉皮层也可以在一生中都具有经验依赖的物理可塑性。听觉记忆与皮质可塑性之间的关系对分子，基因，细胞，系统和行为的电路的研究开放。该建议是确定控制皮质可塑性的分子和遗传神经力学，从而将听觉体验转化为听觉记忆。未来的多层次方法将发现这些分子以及哪些特定基因在其神经元电路和系统中如何起作用，以最终建立强大的听觉记忆。最初的计划是在两个特定的目标中研究听觉记忆形成和经验依赖的听觉皮质可塑性的表观遗传机制。依赖经验的听觉皮质可塑性的机制需要转录 - 即，基因的表达能够使神经元功能稳定变化，最终是动物行为。一种令人兴奋的新途径来攻读听觉皮质可塑性和记忆的转录作用，这是通过表观遗传控制的力量。主要的表观遗传机制是组蛋白修饰，特别是组蛋白乙酰化，通常促进转录。组蛋白脱乙酰基酶（HDACS）通过下调该过程来抑制转录，因此具有经验依赖性神经塑性的关键和强大的负调节剂。目前完全未知的是HDAC是否调节听觉皮层可塑性，从而改变听觉记忆的形成方式可能会使记忆更加强，更具体。为了解决这个重要问题，使用药物（AIM 1）和靶向病毒（AIM 2）技术，在该提案的过程中，将在该提案的整个过程中确定HDAC3的作用。这些研究促进了Bieszczad博士的进入及其在听觉记忆过程中的研究到新的行为表观遗传学领域。未来的R01将扩展这项工作，以在实验室研究的高素质，重要且完全新颖的利基市场中建立独立性。