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

项目总结与摘要 这个项目的目标是研究表观遗传神经机制，以确保有意义的声音 在成人的听觉大脑中忠实地和适应性地表现出来。这项研究的一个重要方面 关系到记忆中声学内容的精确度，这对学习和执行精细任务是重要的 听觉辨别。第二，关注通过学习诱导的长期经验保持 强听觉记忆的神经可塑性，这与终生保持习得的听觉能力有关。 动物(包括人类)使用联想学习将声音提示与显著事件联系起来(如奖励或 其他重大成果)。当记忆形成的神经机制被激活时， 经验--从分子到基因再到电路和系统的机制--联想记忆是 这反过来又提供了具有后天意义的、本来是任意的声音。比如，在试镜的时候， 交流能力要求声音与其习得的意义精确地联系在一起，这取决于 神经可塑性和持久的听觉记忆，持续时间从几分钟到几小时、几天或一生。几十年 研究表明，联想学习会系统地改变感觉皮质，从而改变表征 感官线索和习得的行为突显。但为什么有些人会自然而然地形成听觉记忆 比其他人更强大、更具体？组蛋白控制染色质乙酰化的表观遗传机制 脱乙酰酶(HDAC)可能控制最终改变听觉系统的基因 这有助于它的可塑性和随后的长期听觉记忆。事实上，HDAC能够 通过有意义的体验控制听觉皮质的变化，这可能会提供一个有启发性的 对整个听觉系统的控制，以适应(或有时不适应)功能。目前未知 是HDACs调节听觉皮质可塑性的下游基因和回路机制。 这项提议是为了一个行政补充，以促进研究团队的多样性 在整个领域，这里特别支持博士前实习生关恩·格雷厄姆女士 最后几年的博士学位。她的研究在完成行为药理学的范围内，也是至关重要的。 和分子工作(亲本AIM1)以及病毒(AIM2)技术在啮齿动物行为中操纵HDAC3 听觉联想学习模型确定HDAC如何改变稳健的获得和初始存储 听觉记忆。这些研究将从基因、分子、回路等方面解释HDAC如何调节神经可塑性。 以及健壮的听觉行为系统，其系统对重要声音有更好的“调谐”。这项研究 促进神经表观遗传学和基因发现，成为听神经科学的重要新利基。实习生 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 寻找一个博士后实验室，在那里她将在未来的K01提案中继续寻求NIH级别的资金。

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.