Molecular epigenetic mechanisms that transform the auditory system for learning and memory

项目概要和摘要 这个项目的目标是调查表观遗传神经机制，可以确保有意义的声音 在成年人的听觉大脑中被忠实地、适应性地呈现出来。这项研究的一个重要方面是 记忆中声学内容的精确性，对于学习和精细操作非常重要 听觉辨别第二，关于通过学习诱导的经验的长期维持 神经可塑性的强大的听觉记忆，这是相关的，以保持学习听觉能力的生活。 动物（包括人类）使用联想学习将声音线索与突出事件（如奖励或奖励）联系起来。 其他重要成果）。当记忆形成的神经机制被激活后， 经验--从分子到基因再到电路和系统的机制--联想记忆是 形成，这反过来又提供了具有获得意义的任意声音。例如，在试镜中， 交流能力要求声音与它们的学习意义精确地联系起来，这取决于 神经可塑性和持久的听觉记忆，持续从几分钟到几小时和几天，甚至一生。几十年 的研究表明，联想学习系统地改变了感觉皮层， 与习得的行为显著性相结合。但为什么有些人会自然地形成听觉记忆呢 比其他人更强更具体组蛋白控制染色质乙酰化的表观遗传机制 去乙酰化酶（HDAC）的功能可能是控制基因，最终建立听觉系统的变化 这有助于其可塑性和随后的长期听觉记忆。事实上，HDAC能够 控制听觉皮层在有意义的经历中的变化，这可能会提供一个有指导意义的 控制听觉系统作为一个整体的适应（或有时适应不良）功能。目前未知 是HDACs调节听觉皮层可塑性的下游基因和回路机制。 这项建议是为了增加行政补助，以促进研究小组的多样性。 在整个领域，特别是在这里支持博士前实习生，关恩格雷厄姆女士，在她的 最后的PhD岁月她的研究属于行为药理学的范围， 和分子工作（亲本AIM 1）以及病毒（AIM 2）技术来操纵啮齿动物行为中的HDAC 3。 模型的听觉联想学习，以确定如何HDAC改变收购和初始存储的鲁棒 听觉记忆这些研究将解释HDAC如何从基因，分子，电路 以及具有更好地“调谐”到重要声音的系统的用于鲁棒听觉行为的系统。本研究 促进神经表观遗传学和基因发现作为一个重要的新的利基听觉神经科学。见习 支持将为关恩的研究和职业培训奠定基础，使她在比赛中处于领先地位，因为她 寻找一个博士后实验室，她将继续在未来的K 01提案中寻求NIH级资金。

PROJECT SUMMARY & ABSTRACT This goal of this project is to investigate epigenetic neural mechanisms that can ensure meaningful sounds are faithfully and adaptively represented in the adult auditory brain. One important aspect of this research concerns the precision of acoustic content in memory, which is important for learning and performing fine-tine auditory discriminations. A second, concerns long-term maintenance of experience via learning-induced neuroplasticity for strong auditory memory, which is relevant to maintain learned auditory abilities for life. Animals (including humans) use associative learning to link sound cues to salient events (like rewards or other significant outcomes). When neural mechanisms of memory formation are activated following these experiences—mechanisms that span from molecules to genes to circuits and systems—associative memory is formed, which in turn provides otherwise arbitrary sound with acquired significance. For example, in audition, communication abilities require that sounds are precisely linked with their learned meaning, which depends on neuroplasticity and enduring auditory memory that lasts from minutes, to hours and days, or a lifetime. Decades of research indicate that associative learning systematically changes the sensory cortex to alter representation of sensory cues with learned behavioral salience. But why do some individuals naturally form auditory memories stronger and more specifically than others? Epigenetic mechanisms that control chromatin acetylation by histone deacetylases (HDACs) likely function to control genes that ultimately establish changes to the auditory system that contribute to its plasticity and subsequent long-term auditory memory. Indeed, HDACs are capable of controlling how much auditory cortex changes with meaningful experiences, which may provide an instructive control on the auditory system as a whole for adaptive (or sometimes maladaptive) function. Currently unknown are the downstream gene and circuit mechanisms with which HDACs regulate auditory cortical plasticity. This proposal is for an administrative supplement that would promote diversity in the research team and in the field at large, here in particular to support a predoctoral trainee, Ms. Guan-En Graham, in her final PhD years. Her research is within the scope and critical to the completion of behavioral pharmacological and molecular work (parent AIM1) as well as viral (AIM2) techniques to manipulate HDAC3 in a rodent behavioral model of auditory associative learning to determine how HDACs alter the acquisition and initial storage of robust auditory memory. The studies will explain how HDACs regulate neuroplasticity from genes, molecules, circuits and systems for robust auditory behaviors with a system better “tuned-in” to important sounds. This research promotes neuroepigenetics and gene-discovery as an important new niche for auditory neuroscience. Trainee support will set the stage for Guan-En’s research and career training to put her at the top of her game as she searches for a postdoctoral lab where she will continue to pursue NIH-level funding in a future K01 proposal.