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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.

项目总结及摘要