Aging Auditory System: Presbycusis and Its Neural Bases

 描述(由申请人提供)：我们的长期目标是改善年龄相关性听力损失(ARHL)或老年性耳聋的衰弱后果。ARHL是我们日益增长的老龄化人口中的头号沟通障碍和头号神经退行性疾病。大多数60岁以上的人都受到这种渐进性听觉敏感度下降和在噪音中理解语言困难的影响。虽然ARHL是老年人的三大慢性疾病之一，但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)的药物。尽管经过了几十年的研究和发现，通过预防和治疗克服ARHL的障碍仍然是一项重大的科学和临床挑战。这一应用的主题重点是通过生物疗法和定向诱导神经可塑性来调节老年性耳聋。这些方法的一个重要特点是阐明了外周功能和中枢听觉可塑性在听觉加工中的相关作用。这项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。我们针对ARHL的主要后果，在动物和人类受试者中使用了一系列测量技术。通过对现有理论模型和特定项目假说的评估所获得的见解，将在指导旨在减缓或预防ARHL进展的新的行为、技术和医学治疗方法的开发中发挥重要作用。具体目标1。确定激素补充可以预防或减缓急性淋巴细胞性白血病进展的程度。实验方法：在接受醛固酮激素治疗的老年受试者中，将定量测量血清醛固酮和其他相关指标和生物标志物，以及行为、生理和分子指标，包括外周和中枢听力测量。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、可控地暴露在动物饲养环境(小鼠隔膜设施)的自由场中出现的特定人工产生的声音，以及通过人类定制的耳朵水平的听力仪器。结果测量将索引急性淋巴细胞性白血病关键特征和生物标记物的外周和中央成分。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之间的关系，包括涉及的神经和分子机制。实验方法：我们将建立在表明中枢抑制减少和/或皮质活动的可塑性改变是ARHL的关键组成部分的工作的基础上。实验的一个主要焦点将是ARHL与中枢神经抑制和兴奋之间的联系，特别是在老年人和动物受试者中。

 DESCRIPTION (provided by applicant): 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 application 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 ar 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.