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

• 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
• 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' 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

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.

项目摘要 衰老期间认知能力下降的关键组成部分是听觉处理和记忆的损害 言语和说话者身份的形成。由于其社会性质，该领域的下降一直是 与随着年龄的增长而增加的社会回避，隔离和其他合并症的增加相关，例如 抑郁和焦虑。而且，由于其几乎独特的人性，没有动物模型系统 建立了研究与年龄相关的与年龄相关的神经机制下降的衰落 复杂的，学习的声音。最适合满足此需求的模型系统是鸣禽 以与人类几乎相同的方式学习其声音信号。在这里，我们建议建立一只鸣禽 衰老和测试靶向表观遗传操作的有希望的机制在改善 听觉通信信号的回忆。我们还将检查表观遗传操作对 与年龄有关的增加的炎症增加和神经发生下的神经发生降低 发声的听觉处理。从历史上看，鸣禽模型是我们对 神经发生和新神经元的动力学与对应于不同的尾脑电路 以及可进行的行为和认知领域。鸣禽的发展模型也在 我们对感官，运动和感觉运动学习和记忆中关键时期的理解的最前沿。 令人惊讶的是，在寿命结束时，鸣禽没有被太多用于研究行为和神经 在衰老和衰老过程中，底物变化和干预措施。在这种使用的几个示例中 导致研究人员通过研究啮齿动物衰老的研究采用了新的调查途径。因此，鸣禽 衰老模型为与了解人类衰老有关的发现提供了机会 可在啮齿动物型号中使用。使用表观遗传学工具来调节基因表达是 研究大脑衰老和认知能力下降，并在广泛的范围内成为一种有前途的治疗 神经退行性的疾病模型。一种表观遗传调节的一种方法是组蛋白脱乙酰基酶 （HDACS），通过催化组蛋白乙酰基的去除来抑制基因转录的酶， 导致封闭的染色质结构。 HDAC抑制剂（HDIS）阻止了此过程，从而促进转录。 但是，直到最近，HDI在翻译中仍受到限制，因为可用的HDI针对广泛范围 HDAC，导致广泛的副作用。新一代的HDAC特异性HDI处于领先地位 建立有限副作用的有希望的治疗方法。在这里，我们将描述阻止HDAC3的效果 特别是基因表达谱，神经炎症，神经发生和听觉参数 衰老的男性和女性斑马雀科的发声记忆。这项工作的结果将推动我们的 了解表观遗传学在调节炎症，神经发生和记忆中的作用 建立与年龄相关的记忆损失的干预措施。