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。多么?这项建议是用多层次的方法来确定的 调控基因组的分子--特别是控制染色质的表观遗传机制 组蛋白脱乙酰酶(HDAC)的乙酰化作用-控制基因，最终建立改变 有助于其可塑性和随后的长期听觉记忆的听觉系统。事实上，HDAC是 能够使听觉皮质随着有意义的学习经历而改变，这可能提供 对整个听觉系统的指导性控制，以适应(或有时不适应)功能。 目前尚不清楚HDAC调节听觉的下游基因和电路机制。 皮质可塑性。这一点很重要，因为它可以从基因水平上解释为什么有些人自然形成 听觉记忆比其他人更强、更具体。电生理学、药理学(AIM1) 和病毒(AIM2)技术在听觉联想学习的啮齿动物行为模型中操纵HDAC3 将有助于确定HDAC如何改变强健听觉记忆的获取和初始存储。潜力 将使用基因靶向和全基因组测序来测试HDAC效应的胆碱能决定因素 技巧(AIM1和2)。胆碱能回路DREADDS激活的转基因ChAT：：CRE大鼠将挑战 HDAC功能(AIM3)。这些研究将解释HDAC如何从基因、分子、 用于强健听觉行为的电路和系统，其中系统对重要声音有更好的“调谐”。这 研究促进了神经表观遗传学和基因发现，成为听神经科学的一个重要的新利基。

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. How? This proposal is to determine with multi-level approaches how molecules that regulate the genome—in particular epigenetic mechanisms that control chromatin acetylation by histone deacetylases (HDACs)—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 enabling the auditory cortex to change with meaningful learning 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 is important as it could explain from a genetic level why some individuals naturally form auditory memories stronger and more specifically than others. Electrophysiological, pharmacological (AIM1) and viral (AIM2) techniques to manipulate HDAC3 in a rodent behavioral model of auditory associative learning will help determine how HDACs alter the acquisition and initial storage of robust auditory memory. Potential cholinergic determinants of HDAC effects will be tested using gene-targeted and genome-wide sequencing techniques (AIM1&2). Transgenic ChAT::Cre rats with activated DREADDs in cholinergic circuitry will challenge HDAC function (AIM3). 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.