Aging Auditory System: Presbycusis and Its Neural Bases

摘要/摘要--总体 我们的长期目标是改善年龄相关性听力损失(ARHL)或 老年性耳聋。ARHL是头号沟通障碍和头号神经退行性疾病 我们不断扩大的老龄化人口。大多数60岁以上的人都受到这种进步的影响 听觉敏感度下降，在噪音中难以理解语音。而ARHL是前三名之一 老年人的慢性疾病，目前还没有得到批准的预防或 逆转永久性听力损失(ARHL或其他类型)。尽管经过了几十年的研究和发现， 通过预防和治疗克服急性淋巴细胞性白血病的障碍仍然是一项重大的科学 和临床挑战。这项建议的主题重点是通过 生物疗法和神经可塑性的靶向诱导。这些方法的一个重要特征是 阐明外周功能和中枢听觉可塑性在听觉加工中的相关作用。这 开创性的研究使用创新的催化剂来诱导老化的听觉系统的功能变化。我们 在动物和人类中使用一系列测量技术来确定ARHL的主要后果 研究对象。从评估当前理论模型和项目具体假设中获得的见解将 在指导发展新的行为、技术和医疗方面发挥突出作用 延缓或阻止急性淋巴细胞性白血病的进展。 具体目标1.确定激素补充能在多大程度上预防或减缓 急性淋巴细胞性白血病的进展。实验方法：血清醛固酮及其他相关指标和生物标志物 将与行为、生理和分子指标一起进行定量测量，包括外周 以及中枢听力测量，在接受醛固酮激素治疗的老年受试者中。 具体目的2.确定丰富的声环境改善老年性耳聋的能力。 实验方法：丰富的声学环境将包括长期、可控的暴露于 在动物等待环境(老鼠)的自由场地中出现特定的人工产生的声音 间隔膜设施)，并通过人类定制的耳朵水平听力仪器。结果衡量标准将编制索引 急性淋巴细胞性白血病主要特征和生物标记物的外周和中枢成分。 具体目标3.确定老年人和动物的大脑可塑性与急性呼吸窘迫综合征的关系， 包括涉及的神经和分子机制。 实验方法：我们将建立在表明减少中枢抑制和/或塑料的工作的基础上 皮质活动的改变是ARHL的关键组成部分。实验的一个主要焦点将是链接 ARHL与中枢神经抑制和兴奋之间的关系，特别是在老年人和动物受试者中。

ABSTRACT/SUMMARY- Overall Our long-term goal is to ameliorate the debilitating consequences of age-related hearing loss (ARHL) or presbycusis. ARHL is the number one communication disorder and number one neurodegenerative condition of our expanding aging population. The vast majority of people over age 60 are affected by this progressive decline in auditory sensitivity and difficulty understanding speech in noise. While ARHL is one of the top three chronic medical conditions of the elderly, there currently are no approved medical treatments for preventing or reversing permanent hearing loss (ARHL or other types). Despite decades of research and discovery, overcoming the barriers of ARHL through prevention and treatment continues to represent a major scientific and clinical challenge. The thematic focus of this proposal is modulation of presbycusis through biotherapeutics and targeted induction of neural plasticity. An important feature of these approaches is elucidating the related roles of peripheral function and central auditory plasticity in auditory processing. This pioneering research uses innovative catalysts to induce functional changes in the aging auditory system. We target the primary consequences of ARHL using an array of measurement techniques in animal and human subjects. Insights gained from the evaluation of current theoretical models and project-specific hypotheses will play a prominent role in guiding development of new behavioral, technological and medical treatments aimed at slowing or preventing the progression of ARHL. Specific Aim 1. Determine the degree to which hormonal supplementation can prevent or slow the progression of ARHL. Experimental approach: Serum aldosterone and other related metrics and biomarkers will be quantitatively measured along with behavioral, physiological, and molecular indices, including peripheral and central hearing measures, in aging subjects undergoing aldosterone hormone therapies. Specific Aim 2. Determine the ability of enriched acoustic environments to ameliorate presbycusis. Experimental approach: Enriched acoustic environments will consist of extended, controlled exposure to specific artificially generated sounds presented in the free field in the animal holding environment (mouse vivarium facility) and via custom ear-level hearing instruments in humans. Outcome measures will index peripheral and central components of key features and biomarkers of ARHL. Specific Aim 3. Determine relations between brain plasticity and ARHL in older humans and animals, including the neural and molecular mechanisms that are involved. Experimental approach: We will build upon work indicating that reduced central inhibition and/or plastic changes in cortical activity are key components of ARHL. A major focus of experiments will be the link between ARHL and central neural inhibition and excitation, particularly in older human and animal subjects.