Physiological Studies of Age-Related Hearing Loss

描述（由申请人提供）：人类和动物老年性聋的一个主要因素是耳蜗外侧壁组织和血管纹的退化。这些组织以耳蜗内电位（EP）的形式向Corti器官提供能量。在年幼的动物中，这90 mV的电位已被证明是至关重要的操作耳蜗放大器和随后的听觉阈值的测定。安静状态下的沙鼠表现出与年龄相关的EP下降，EP是代谢性老年性聋的基础。在过去的赠款周期，我们已经开发了一个模型的老年耳朵在年轻的沙鼠使用慢性应用呋塞米的耳蜗，以阻止产生的EP。在此，我们进一步探讨急性和慢性EP操作对耳蜗传导和听觉神经纤维声音编码的影响。此外，我们探索细胞复制作为一种可能的机制，EP随着年龄的增长而下降。有三个具体目标。具体目标1检查EP调制的影响，通过直流电注入到中阶的正常，EP受损，和老年耳蜗。这一目的将测试的假设，即EP是控制神经阈值和耳声发射的主要因素。此外，它测试是否直流注入可以改善代谢性老年性聋。具体目标2侧重于神经纤维群如何对EP下降做出反应，特别是关于低和高自发频率（SR）纤维的阈值。这一目的验证了位于耳蜗底部的低SR纤维的阈值比相应的高SR纤维对EP下降更敏感的假设。它还将检查这些纤维的特性与EP受损的耳蜗中的声刺激。具体目标3研究了外侧壁纤维细胞在EP产生和维持中的作用。假设是纤维细胞增殖对于EP稳态是必不可少的，并且复制速率降低是在老年动物中观察到的EP下降的基础。这些实验将涉及有丝分裂抑制剂和间隙连接解偶联剂注入耳蜗。总的来说，这三个目标探索了代谢性老年性聋的主要原因和影响，并直接应用于未来的干预措施，以帮助恢复与年龄相关的听力损失。

DESCRIPTION (provided by applicant): A major factor in human and animal presbyacusis is the degeneration of the cochlear lateral wall tissues and stria vascularis. These tissues supply energy to the organ of Corti in the form of the endocochlear potential (EP). In young animals, this 90 mV potential has been shown to be of fundamental importance in the operation of the cochlear amplifier and subsequent determination of auditory thresholds. Gerbils aged in quiet show an age-related decline of EP, the basis of metabolic presbyacusis. Over the last grant cycle we have developed a model of the aged ear in young gerbils using the chronic application of furosemide to the cochlea to block the generation of the EP. Here we further explore the effects of acute and chronic EP manipulation on cochlear transduction and the encoding of sound in auditory-nerve fibers. Moreover, we explore cell replication as a possible mechanism fundamental to the EP decline with age. There are three specific aims. Specific Aim 1 examines the effects of EP modulation by direct current injection into the scala media of normal, EP-impaired, and aged cochleas. This aim will test the hypothesis that EP is the primary factor controlling neural thresholds and otoacoustic emissions. Moreover, it tests whether direct current injection can serve to ameliorate metabolic presbyacusis. Specific Aim 2 focuses on how populations of auditory-nerve fibers respond to EP decline, with specific regard to the thresholds of low- and high-spontaneous rate (SR) fibers. This aim tests the hypothesis that the thresholds of low-SR fibers located in the cochlear base are more sensitive to EP decline than corresponding high-SR fibers. It will also examine the characteristics of these fibers with acoustic stimuli in EP-impaired cochleas. Specific Aim 3 investigates the role of lateral wall fibrocytes in the production and maintenance of the EP. The hypothesis is that fibrocyte proliferation is essential for EP homeostasis, and a reduced rate of replication is the basis for the decline in EP observed in aged animals. These experiments will involve the infusion of mitotic inhibitors and gap junction uncouplers into the cochlea. Taken together, the three aims explore the major causes and effects of metabolic presbyacusis and have direct application to future interventions to help restore age-related hearing loss.