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

改变学习和记忆听觉系统的分子表观遗传机制

• 批准号: 10666170
• 负责人: Kasia Bieszczad
• 金额: $ 8.32万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666170
• 关键词: Acoustics; Administrative Supplement; Adult; Animals; Auditory; Auditory area; Auditory system; Behavior; Behavioral; Behavioral Model; Brain; Chromatin; Cochlear Implants; Communication; Complex; Cues; Doctor of Philosophy; Ensure; Epigenetic Process; Event; Family; Funding; Future; Genes; Genetic; Goals; HDAC3 gene; Hearing; Hearing problem; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Hour; Human; Individual; Instruction; Lead; Learning; Life; Link; Maintenance; Medical; Memory; Molecular; Neuronal Plasticity; Neurosciences; Outcome; Parents; Persons; Rehabilitation therapy; Research; Rewards; Rodent; Sensory; Signal Transduction; System; Techniques; Therapeutic; Training; United States National Institutes of Health; Viral; Work; aging brain; auditory discrimination; behavioral pharmacology; career; cholinergic; classical conditioning; experience; gene discovery; neuromechanism; pre-doctoral; precision medicine; relating to nervous system; remediation; sensory cortex; small molecule; sound; tool

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.

项目概要和摘要 该项目的目标是研究可确保有意义的声音的表观遗传神经机制 这项研究的一个重要方面是在成人听觉大脑中忠实且适应性地表现。 涉及记忆中声音内容的精确度，这对于精细学习和表现非常重要 第二，涉及通过学习引起的经验的长期维持。 神经可塑性强的听觉记忆，与终生维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线索与显着事件（例如奖励或 当记忆形成的神经机制被激活时，这些结果 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，这反过来又为其他任意声音提供了后天的意义，例如，在试听中， 沟通能力要求声音与其学到的含义精确联系起来，这取决于 神经可塑性和持久的听觉记忆可以持续几分钟、几小时、几天甚至几十年。 的研究表明联想学习系统地改变感觉皮层以改变表征 但为什么有些人会自然地形成听觉记忆呢？ 通过组蛋白控制染色质乙酰化的表观遗传机制更强、更特异？ 脱乙酰酶 (HDAC) 可能具有控制基因的功能，最终改变听觉系统 事实上，HDAC 具有可塑性和长期听觉记忆的能力。 控制听觉皮层随着有意义的经历而变化的程度，这可能提供指导性的 对整个听觉系统的适应性（有时是适应不良）功能的控制目前未知。 是 HDAC 调节听觉皮层可塑性的下游基因和电路机制。 该提案是一项行政补充，旨在促进研究团队的多样性 在整个领域，特别是在这里支持博士前实习生，Guan-En Graham 女士， 她的博士最后几年的研究属于行为药理学的范围，并且对于完成行为药理学至关重要。 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，以确定 HDAC 如何改变鲁棒性的获取和初始存储 这些研究将解释 HDAC 如何通过基因、分子、回路调节神经可塑性。 以及具有鲁棒听觉行为的系统，该系统更好地“调谐”到重要的声音。 促进神经表观遗传学和基因发现成为听觉神经科学的重要新领域。 支持将为冠恩的研究和职业培训奠定基础，使她在她的职业生涯中处于领先地位。 寻找一个博士后实验室，她将在未来的 K01 提案中继续寻求 NIH 级别的资助。