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: 10117595
• 负责人: Kasia Bieszczad
• 金额: $ 33.15万
• 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/10117595
• 关键词: Acetylesterase; Acoustics; Adult; Anesthesia procedures; Animals; Auditory; Auditory area; Auditory system; Behavior; Behavioral; Behavioral Assay; Behavioral Model; Brain; Candidate Disease Gene; Categories; Cholinergic Receptors; Chromatin; Chronic; Cochlear Implants; Communication; Complex; Coupled; Cues; Data; Deacetylase; Desire for food; Discrimination; Discrimination Learning; Electrophysiology (science); Ensure; Enzymes; Epigenetic Process; Event; Family; Food; Future; Gene Chips; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Hearing; Hearing problem; Histone Acetylation; Histone Deacetylase; Histones; Hour; Human; Individual; Instruction; Lead; Learning; Life; Link; Maintenance; Mediating; Medical; Memory; Molecular; Molecular Conformation; Molecular Genetics; Neuronal Plasticity; Neurosciences; Outcome; Persons; Pharmacology; Physiological; Physiology; Process; Quantitative Reverse Transcriptase PCR; Rattus; Recording of previous events; Regulation; Rehabilitation therapy; Research; Rewards; Rodent; Role; Sensory; Signal Transduction; Site; Sleep; Specificity; System; Techniques; Testing; Therapeutic; Training; Transgenic Organisms; Viral; aging brain; auditory discrimination; cholinergic; classical conditioning; designer receptors exclusively activated by designer drugs; experience; gene discovery; genetic approach; genome-wide; inhibitor/antagonist; learned behavior; mutant; neuromechanism; precision medicine; relating to nervous system; remediation; response; sensory cortex; small molecule; sound; stem; synergism; tool; transcriptome sequencing; virus genetics

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.

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。怎么做？这一建议是用多层次的方法来确定 调节基因组的分子，特别是控制染色质的表观遗传机制， 组蛋白去乙酰化酶（HDAC）的乙酰化作用-控制基因的功能，最终建立改变 听觉系统，有助于其可塑性和随后的长期听觉记忆。事实上，HDAC是 能够使听觉皮层随着有意义的学习经历而改变，这可能会提供一个 对整个听觉系统进行指导性控制，以实现自适应（或有时适应不良）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 听觉记忆比其他记忆更强更具体电生理学、药理学（AIM 1） 和病毒（AIM 2）技术来操纵听觉联想学习的啮齿动物行为模型中的HDAC 3 将有助于确定HDAC如何改变稳健听觉记忆的获取和初始存储。潜在 HDAC效应的胆碱能决定因素将使用基因靶向和全基因组测序进行检测 技术（AIM 1&2）。在胆碱能回路中具有激活的DREADD的转基因ChAT：：Cre大鼠将激发 HDAC功能（AIM 3）。这些研究将解释HDAC如何从基因，分子， 电路和系统，用于稳健的听觉行为，其中系统更好地“调谐”到重要的声音。这 研究促进神经表观遗传学和基因发现作为听觉神经科学的一个重要的新的利基。