Epigenetic rescue of age-related deficits in auditory processing of vocal communication signals

表观遗传学拯救声音通讯信号听觉处理中与年龄相关的缺陷

基本信息

批准号：
10730818
负责人：
CAROLYN Liv PYTTE
金额：
$ 47.77万
依托单位：
QUEENS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730818
关键词：
Address Adopted Adult Age Age Factors Age-associated memory impairment Aging Alzheimer&apos s disease related dementia Animal Model Anxiety Area Auditory Behavior Biological Assay Biological Models Biomedical Research Birds Brain region Chromatin Structure Chronic Cognitive Communication Complex Corpus striatum structure Cues Development Disease model Electrophysiology (science)Enzyme Inhibitor Drugs Enzymes Epigenetic Process Excision Female Fright Gene Expression Gene Expression Profile Generations Genes Genetic Transcription Goals HDAC3 gene Health Hippocampus Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Homologous Gene Human Human Characteristics Immunohistochemistry Impaired cognition Impairment Individual Inflammaging Inflammation Information Dissemination Infrastructure Institution Intervention Investigation Learning Longevity Measures Memory Memory Loss Mental Depression Mental Health Modeling Molecular Motor Nature Nerve Degeneration Neurons Pathogenesis Physiological Process Recording of previous events Research Research Personnel Rodent Rodent Model Role Sensory Sex Differences Signal Transduction Social Well-Being Songbirds Source Speech Students System Techniques Testing Therapeutic Intervention Training Universities Work adult neurogenesis age related age related neurodegeneration aging brain auditory processing behavioral study brain tissue college comorbidity cost critical period differential expression epigenetic regulation experience experimental study human old age (65+)improved inflammatory marker loss of function male manufacture memory retrieval middle age mild cognitive impairment neural neurogenesis neuroinflammation neuromechanism normal aging novel response senescence sex side effect social social communication social metrics sound targeted treatment tool transcriptome transcriptome sequencing undergraduate research undergraduate student university student vocal learning vocalization young adult zebra finch

项目摘要

PROJECT SUMMARY A critical component of cognitive decline during aging is impairment in auditory processing and memory formation for speech and speaker identity. Because of its social nature, decline in this domain has been associated with increasing social avoidance, isolation, and other comorbidities that increase with age, such as depression and anxiety. Moreover, because of its nearly uniquely human nature, no animal model system has been established in which to study age-related decline in neural mechanisms underlying auditory processing of complex, learned vocal sounds. The model system best suited to address this need is the songbird, which learns its vocal signals in much the same manner as do humans. Here we propose to establish a songbird model system of aging and test a promising mechanism of targeted epigenetic manipulation in improving memories for auditory communication signals. We will also examine the effects of epigenetic manipulation on the age-related increased inflammation and decreased neurogenesis in the neural substrate underlying auditory processing of vocalizations. The songbird model has historically been central to our understanding of the dynamics of neurogenesis and new neuron incorporation into telencephalic circuits corresponding to varied and tractable behaviors and cognitive domains. Developmental models of songbirds have also been at the forefront of our understanding of critical periods in sensory, motor, and sensorimotor learning and memory. Surprisingly, songbirds have not been used much at the end of the lifespan to study behavioral and neural substrate changes, and interventions, during aging and senescence. In the few examples of such use, findings have led to new avenues of investigation adopted by researchers for studies in rodent aging. Thus, a songbird model of aging provides opportunities for discoveries relevant to understanding human aging that may not be available in rodent models. The use of epigenetic tools to regulate gene expression is at the forefront of research on brain aging and cognitive decline and is emerging as a promising treatment in a wide range of disease models of neurodegeneration. One means of epigenetic regulation targets histone deacetylases (HDACs), enzymes that suppress gene transcription by catalyzing the removal of histone acetyl groups, resulting in a closed chromatin structure. HDAC inhibitors (HDIs) block this process, promoting transcription. However, until recently, HDIs were limited in translational use because available HDIs targeted a broad range of HDACs, resulting in widespread side effects. A new generation of HDAC-specific HDIs is leading the way in establishing promising treatments with limited side effects. Here we will describe the effects of blocking HDAC3 specifically on gene expression profiles, neural inflammation, neurogenesis, and parameters of auditory memory for vocalizations in aging male and female zebra finches. The results of this work will advance our understanding of the role of epigenetics in modulating inflammation, neurogenesis, and memory with an aim toward establishing interventions for age-related memory loss.

项目概要衰老过程中认知能力下降的一个关键因素是听觉处理和记忆力受损语音和说话者身份的形成。由于其社会性质，该领域的衰落已经与社交回避、孤立以及其他随着年龄增长而增加的合并症有关，例如抑郁和焦虑。此外，由于其几乎独特的人性，没有任何动物模型系统具有建立了研究与年龄相关的听觉处理神经机制衰退的方法复杂的、习得的声音。最适合满足这一需求的模型系统是鸣禽，它它学习声音信号的方式与人类非常相似。在这里我们建议建立一个鸣禽衰老模型系统并测试靶向表观遗传操作在改善衰老方面的有前途的机制听觉交流信号的记忆。我们还将研究表观遗传操作对与年龄相关的炎症增加和神经基质中神经发生的减少发声的听觉处理。鸣禽模型在历史上一直是我们理解的核心神经发生的动力学和新神经元融入端脑回路对应于不同的以及易于处理的行为和认知领域。鸣禽的发育模型也已在我们对感觉、运动和感觉运动学习和记忆关键时期的理解最前沿。令人惊讶的是，鸣禽在生命结束时并没有被太多地用来研究行为和神经衰老和衰老过程中的底物变化和干预措施。在这种使用的几个例子中，发现导致研究人员采用新的研究途径来研究啮齿动物的衰老。于是，一只鸣禽衰老模型为与理解人类衰老相关的发现提供了机会，而这些发现可能并不存在提供啮齿动物模型。使用表观遗传学工具来调节基因表达处于最前沿关于大脑衰老和认知能力下降的研究，正在成为广泛领域的一种有前途的治疗方法神经变性疾病模型。表观遗传调控的一种手段是针对组蛋白脱乙酰酶 (HDAC)，通过催化去除组蛋白乙酰基来抑制基因转录的酶，从而形成封闭的染色质结构。 HDAC 抑制剂 (HDI) 阻断这一过程，促进转录。然而，直到最近，HDI 的转化应用还受到限制，因为可用的 HDIs 的目标范围很广。 HDAC，导致广泛的副作用。新一代 HDAC 专用 HDI 在以下方面处于领先地位建立具有有限副作用的有前景的治疗方法。这里我们将描述阻断 HDAC3 的影响特别是关于基因表达谱、神经炎症、神经发生和听觉参数老年雄性和雌性斑胸草雀的发声记忆。这项工作的成果将推动我们了解表观遗传学在调节炎症、神经发生和记忆中的作用制定针对与年龄相关的记忆丧失的干预措施。