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（由申请人提供）：本申请将为罗格斯大学最近聘用的早期研究员 Kasia M. Bieszczad 博士（bee-YESH-chad）（助理教授，2015 年 1 月）的研究项目提供种子。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。特别关注皮质可塑性。学习通过声音与其他事件和重要刺激的联系来理解声音的含义可以实现听觉理解。正常成年人、或听力损失或人工耳蜗植入后康复后的成年人的听觉理解能力，都取决于持久的听觉记忆，即关于声音的稳定信息存储。为了了解听觉记忆功能的基本过程，重要的是要确定能够形成长期听觉记忆和信息存储的神经可塑性。听觉皮层是听觉记忆的关键。即使是早期的听觉皮层也可以在一生中经历依赖于经验的生理可塑性。听觉记忆和皮质可塑性之间的关系可以从分子、基因、细胞、系统回路和行为等方面进行研究。该提议旨在确定控制皮质可塑性的分子和遗传神经机制，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如何在其神经回路和系统中发挥作用，以最终建立强大的听觉记忆。 最初的计划是在两个特定目标中研究听觉记忆形成和经验依赖性听觉皮层可塑性的表观遗传机制。听觉皮层可塑性背后的依赖经验的机制需要转录——也就是说，基因的表达能够实现神经元功能的稳定变化，并最终实现动物行为的稳定变化。研究转录对听觉皮层可塑性和记忆的作用的一个令人兴奋的新途径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，它通常促进转录。组蛋白脱乙酰酶 (HDAC) 通过下调这一过程来抑制转录，因此是经验依赖性神经可塑性的关键且强大的负调节因子。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，使记忆变得更强、更具体。为了解决这个重要问题，在本提案的过程中，将在分子、神经生理学和行为水平上初步确定 HDAC3 的作用，使用药理学 (AIM 1) 和靶向病毒 (AIM 2) 技术在听觉联想学习的啮齿动物模型中操纵 HDAC3。这些研究促进了 Bieszczad 博士及其对听觉记忆过程的研究进入行为表观遗传学新领域。未来的 R01 将扩展这项工作，以在高水平、重要且全新的实验室研究领域建立独立性。