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

项目摘要 衰老过程中认知能力下降的一个重要组成部分是听觉处理和记忆的损伤 言语和说话者身份的形成。由于其社会性质，这一领域的衰落一直是 与社交回避、孤立和其他随年龄增加的合并症相关，如 抑郁和焦虑此外，由于其几乎独特的人性，没有动物模型系统 已经建立了一个研究年龄相关的听觉处理神经机制的下降， 复杂的，习得的声音最适合满足这一需求的模型系统是鸣鸟， 学习声音信号的方式和人类差不多。在这里，我们建议建立一个鸣禽 模型系统的老化和测试有希望的机制，有针对性的表观遗传操作，在改善 听觉交流信号的记忆我们还将研究表观遗传操纵对 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。鸣鸟模型在历史上一直是我们理解 神经发生的动力学和新的神经元纳入端脑回路对应于不同的 和易驾驭的行为和认知领域。鸣禽的发育模型也在 我们对感觉、运动和感觉运动学习和记忆关键期的理解的前沿。 令人惊讶的是，鸣禽在生命的最后阶段并没有被用于研究行为和神经系统。 基质变化和干预，在老化和衰老。在这类使用的少数例子中， 为研究人员研究啮齿动物衰老开辟了新的研究途径。因此，一种鸣禽 衰老模型提供了与理解人类衰老相关的发现的机会， 在啮齿动物模型中可用。使用表观遗传工具来调节基因表达是最前沿的 研究大脑老化和认知能力下降，并正在成为一个有前途的治疗在广泛的 神经退行性疾病模型。表观遗传调控的一种方式是靶向组蛋白脱乙酰酶 （HDAC），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）阻断这一过程，促进转录。 然而，直到最近，HDIs在翻译中的使用受到限制，因为可用的HDIs针对广泛的范围， 导致广泛的副作用新一代HDAC专用的HDI在 建立了副作用有限的有希望的治疗方法。在这里，我们将描述阻断HDAC3 特别是基因表达谱，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。这项工作的结果将促进我们的 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丧失的干预措施。

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.