Molecular epigenetics of auditory memory and cortical plasticity

 描述（由申请人提供）：本申请将为罗格斯大学最近聘请的早期研究员（助理教授，2015年1月），Kasia M. Bieszczad（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。一个特别的重点是皮质可塑性。学习通过与其他事件和重要刺激的联系来理解声音的意义，使听觉理解成为可能。正常成年人的听觉理解能力，以及听力损失或人工耳蜗植入后康复的成年人的听觉理解能力，都依赖于持久的听觉记忆，即关于声音的稳定信息存储。为了理解听觉记忆功能的基础过程，重要的是要识别能够形成长期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会在一生中经历依赖经验的生理可塑性。听觉记忆和皮层可塑性之间的关系是开放的调查从分子，基因，细胞，电路系统和行为。这个建议是为了确定控制皮质可塑性的分子和遗传神经机制，从而将听觉经验转化为听觉记忆。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回路和系统中发挥作用，最终建立强大的听觉记忆。 初步计划是在两个特定的目标调查的听觉记忆形成和经验依赖的听觉皮层可塑性的表观遗传机制。听觉皮层可塑性的基础依赖于经验的机制需要转录--也就是说，基因的表达使神经元功能和最终动物行为发生稳定变化。一个令人兴奋的新途径，以接近转录的作用，听觉皮层可塑性和记忆是通过权力的表观遗传控制。主要的表观遗传机制是组蛋白修饰，特别是组蛋白乙酰化，其通常促进转录。组蛋白去乙酰化酶（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和强大的负调节因子。目前完全未知的是，HDACs是否调节听觉皮层的可塑性，从而改变听觉记忆的形成方式，使记忆更强大，更具体。为了解决这个重要的问题，HDAC 3的作用将在分子，神经生理学和行为水平上，使用药理学（AIM 1）和靶向病毒（AIM 2）技术在啮齿动物听觉联想学习模型中操纵HDAC 3的过程中初步确定。这些研究促进了Bieszczad博士和她对听觉记忆过程的研究进入行为表观遗传学的新领域。未来的R 01将扩展这项工作，以在高素质，重要和全新的实验室研究领域建立独立性。

 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.