Physiological Studies of Age-Related Hearing Loss

描述（由申请人提供）：人类和动物耳蜗老年性耳聋的一个主要因素是耳蜗外侧壁组织和血管纹的退化。这些组织以耳蜗电位（endocochlear potential， EP）的形式向耳蜗供能。在幼龄动物中，这个90毫伏电位已被证明对耳蜗放大器的操作和随后的听觉阈值的确定至关重要。在安静环境中衰老的沙鼠表现出与年龄相关的EP下降，EP是代谢性耳聋的基础。在上一个拨款周期中，我们开发了一种年轻沙鼠的老年耳朵模型，使用速尿对耳蜗的慢性应用来阻止EP的产生。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，我们还探索了细胞复制作为EP随年龄下降的可能机制。有三个具体目标。特异性目的1研究了将直流电注入正常耳蜗、耳蜗受损耳蜗和老年耳蜗的耳蜗中，对耳蜗电位调制的影响。这一目的将检验假设，即EP是控制神经阈值和耳声发射的主要因素。同时测试直流注射是否可以改善代谢性老年性耳聋。具体目标2侧重于听神经纤维群体如何对EP下降做出反应，具体考虑到低自发率和高自发率（SR）纤维的阈值。本研究旨在验证位于耳蜗基底的低sr纤维阈值比相应的高sr纤维对EP下降更敏感的假设。它还将研究这些纤维在ep受损耳蜗的声学刺激下的特征。特异性目的3研究外侧壁纤维细胞在EP的产生和维持中的作用。假设是纤维细胞增殖对EP稳态至关重要，而在老年动物中观察到的EP下降的基础是复制速率的降低。这些实验将涉及有丝分裂抑制剂和间隙连接解耦剂注入耳蜗。综上所述，这三个目的探讨代谢性老年性耳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.