Physiological Studies of Age-Related Hearing Loss

描述(申请人提供)：人类和动物老年性耳聋的一个主要因素是耳蜗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器官供应能量。在幼年动物中，这种90 mV的电势已被证明对耳蜗放的操作和随后的听阈值的确定具有基本的重要性。安静老化的沙土鼠表现出与年龄相关的EP下降，EP是代谢性老聋的基础。在上一个资助周期中，我们开发了一种年轻沙土鼠老化耳朵的模型，使用慢性应用速尿来阻止EP的产生。在这里，我们进一步探讨了急性和慢性EP操作对耳蜗神经传导和听神经纤维中声音编码的影响。此外，我们探讨了细胞复制作为EP随年龄下降的一个可能的基本机制。有三个具体目标。具体目的1研究通过将直流电注入正常、EP受损和老年耳蜗人的中阶对EP调制的影响。这一目标将检验EP是控制神经阈值和耳声发射的主要因素的假设。此外，它还测试了直流电注射是否可以改善代谢性老聋。具体目标2集中于听神经纤维群体如何对EP下降作出反应，特别是关于低自发性和高自发性(SR)纤维的阈值。这一目的验证了一种假设，即位于耳蜗基底部的低SR纤维的阈值比相应的高SR纤维对EP下降更敏感。它还将在EP受损的耳蜗中检查这些纤维在声刺激下的特征。具体目的3研究侧壁成纤维细胞在EP的产生和维持中的作用。该假说认为，纤维细胞的增殖对EP的动态平衡是必不可少的，而复制速度的降低是老年动物EP下降的基础。这些实验将包括将有丝分裂抑制物和缝隙连接解偶联剂注入耳蜗内。综上所述，这三个目标探索了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.