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

项目总结 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害。 形成语音和说话人身份。由于其社会性，这一领域的衰落 与越来越多的社交回避、孤立和其他随年龄增加的共病有关，例如 抑郁和焦虑。此外，由于其近乎独特的人类本性，没有任何动物模型系统 已经建立了一个研究与年龄相关的听觉加工神经机制衰退的实验室 复杂的、习得的声音。最适合满足这一需求的模型系统是Songbird，它 它学习声音信号的方式与人类大致相同。在这里，我们提议建立一只鸣鸟 衰老模型系统的建立和测试一种有前景的靶向表观遗传操作改善机制 用于听觉通信信号的记忆。我们还将研究表观遗传操作对 与年龄相关的炎症增加，神经基质中的神经发生减少 发声的听觉处理。在历史上，鸣鸟模型一直是我们理解 神经发生和新神经元并入端脑回路的动力学对应于不同的 以及易于控制的行为和认知域。鸣禽的发育模型也一直处于 处于我们对感觉、运动和感觉运动学习和记忆的关键时期的理解的前沿。 令人惊讶的是，鸣禽在生命的末期并没有被大量用于研究行为和神经。 在衰老和衰老过程中底物的变化和干预。在为数不多的几个这样使用的例子中，发现 为研究人员提供了研究啮齿动物老化的新的调查途径。因此，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，而这些发现可能不是 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处于 对大脑衰老和认知能力下降的研究，并正在成为一种有希望的治疗方法，在广泛的 神经退行性变的疾病模型。以组蛋白脱乙酰基酶为靶点的表观遗传调控手段之一 (HDACs)，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，人类发展指数在翻译方面的使用受到限制，因为可用的人类发展指数目标范围很广 HDAC的使用，导致了广泛的副作用。新一代HDAC专用HDI正在引领 建立副作用有限、前景看好的治疗方法。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 老年雄性和雌性斑马雀对发声的记忆。这项工作的成果将推动我们的 有目的地理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.