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

基本信息

批准号：
10682563
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
项目类别：
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/10682563
关键词：
Acceleration Acoustics Adult Anesthesia procedures Animals Association Learning 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 Expression Gene Targeting Genes Genetic Genetic Transcription Genome Genomics Goals Hearing Hearing problem Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Hour Human Individual Learning Life Link Maintenance Mediating Medical Memory Molecular Molecular Conformation Neuronal Plasticity Neurosciences Outcome Persons 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 designer receptors exclusively activated by designer drugs experience gene discovery gene interaction genetic approach genome-wide inhibitor learned behavior member mutant neural neuromechanism pharmacologic precision medicine remediation response sensory cortex small molecule sound stem synergism tool transcriptome sequencing

项目摘要

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具有习得行为显着性的感官线索如何确定？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脱乙酰酶 (HDAC) 的乙酰化作用——控制基因，最终改变 HDAC 是听觉系统的一个重要组成部分，有助于其可塑性和随后的长期听觉记忆。能够使听觉皮层随着有意义的学习经历而改变，这可能会提供一种对整个听觉系统的适应性（有时是适应不良）功能的指导性控制。目前尚不清楚 HDAC 调节听觉的下游基因和电路机制这很重要，因为它可以从基因水平解释为什么有些个体会自然形成。听觉记忆比其他记忆更强、更具体。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 如何改变强大的听觉记忆的获取和初始存储。 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测试胆碱能回路中 DREADD 被激活的转基因 ChAT::Cre 大鼠将面临挑战。 HDAC 功能 (AIM3) 将解释 HDAC 如何从基因、分子、电路和系统具有稳健的听觉行为，系统可以更好地“调谐”到重要的声音。研究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。