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

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

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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.

项目摘要和摘要该项目的这个目标是调查可以确保声音有意义的表观遗传神经机制在成人的听觉大脑中忠实而适应性地代表。这项研究的一个重要方面涉及记忆中声学内容的精度，这对于学习和执行微调很重要听觉歧视。第二，涉及通过学习引起的长期维护经验具有强大听觉记忆的神经可塑性，这与维持学习的听觉能力有关。动物（包括人类）使用联想学习将声音提示与显着事件联系起来（例如奖励或其他重要的结果）。遵循这些记忆形成的神经机制经验 - 从分子到基因再到电路和系统的机制 - 缔合记忆是形成，这又提供了具有可获得意义的任意声音。例如，在试镜中沟通能力要求声音与他们所学的含义完全相关，这取决于神经塑性和持久的听觉记忆，持续时间为几分钟，数小时或一生。几十年研究表明联想学习系统地改变了感觉皮层以改变表示具有学识渊博的行为显着性的感官提示。如何？该建议是通过多层次的方法确定如何调节基因组的分子（尤其是控制染色质的表观遗传机制）组蛋白脱乙酰基酶（HDACS）的乙酰化 - 控制基因的功能，最终建立了对该基因的变化听觉系统有助于其可塑性和随后的长期听觉记忆。确实，HDAC是能够通过有意义的学习经验来使听觉皮层能够改变，这可能会提供对整个听觉系统的启发性控制，以进行自适应（或有时不良适应）功能。目前未知的是HDAC调节听觉的下游基因和电路机制皮质可塑性。这很重要，因为它可以从遗传层面解释为什么有些人自然形成听觉记忆比其他人更强烈，更具体。电生理，药物（AIM1）在听觉关联学习的啮齿动物行为模型中操纵HDAC3的病毒（AIM2）技术将有助于确定HDAC如何改变强大听觉存储器的获取和初始存储。潜在的 HDAC效应的胆碱能确定剂将通过基因靶向和全基因组测序进行测试技术（AIM1＆2）。转基因CHAT :: CRE大鼠与胆碱能电路中的激活的恐惧者将挑战 HDAC功能（AIM3）。研究将解释HDAC如何调节基因，分子，通过系统更好地“调整”重要声音的电路和系统。这研究促进了神经毛皮材料和基因发现，作为听觉神经科学的重要新领域。