Type II Afferents and Cochlear Damage

项目摘要 听觉刺激通过I型和II型耳蜗传入从耳蜗传播到脑干。而 I型传入传递有关声音的频率、强度和时间的信息，II型传入的作用 传入仍然没有解决。听前大鼠耳蜗尖部Ⅱ型传入纤维的有限记录 表明它们可以被广泛的外毛细胞（OHC）刺激和由细胞释放的ATP激活。 急性组织损伤第二，II型纤维中的突触活动已被证明是突触能的，但输入 启动动作电位放电。最近的一项研究表明，II型传入神经 对非破坏性的声音做出反应，通过他们的神经元通路。此外，II型纤维表现出 类似于疼痛纤维，例如调节肽能和大麻素信号传导的表达 途径。最后，II型纤维表达炎症调节因子的受体基因，其中一些是 在噪声暴露后上调。这些综合数据表明，II型传入可能感觉到非- 破坏性和破坏性的声级，以及多个平行的路径可能有助于II型纤维 不同程度的反应，取决于声音暴露的历史。为了探索这个假设，我们有 开发了Ca 2+成像技术，揭示了整个耳蜗线圈的II型纤维活动，从顶点到 基地，成年小鼠。其次，我们建议使用II型传入纤维的松散贴片记录来监测 响应于OHC的光遗传学刺激的放电速率。这两种方法都用于确定 非损伤性和损伤性声暴露对II型耳蜗传入活动的影响。目标 这项建议的目的是了解多种途径（嘌呤能，多巴胺能， 神经调节和炎性）对这些病症的影响。我们最近的实验表明， 噪声暴露后的传入反应。这种敏感化可能反映了“功能获得” 病理学，如听觉过敏/听觉损伤。此处提议的综合办法旨在查明 药理学目标的功能获得病理学，可以遵循噪音暴露和噪音- 听力损失

Project Summary Auditory stimuli travel from the cochlea to the brainstem through type I and type II cochlear afferents. While type I afferents convey information about the frequency, intensity, and timing of sounds, the role of type II afferents remains unresolved. Limited recordings of type II afferents from the cochlear apex in pre-hearing rats reveal that they can be activated by widespread outer hair cell (OHC) stimulation and by ATP released by acute tissue damage. Secondly, synaptic activity in type II fibers has been shown to be glutamatergic but input from multiple OHCs is required to initiate action potential firing. A recent study suggests that type II afferents respond to non-damaging sound, via their glutamatergic pathway. Additionally, type II fibers exhibit properties similar to pain fibers, for example the expression of modulatory peptidergic and cannabinoid signaling pathways. Finally, type II fibers express receptor genes to inflammatory modulators, some of which are upregulated after noise exposure. These combined data suggest that type II afferents may sense non- damaging and damaging sound levels, and that multiple parallel pathways may contribute to the type II fiber response to different degrees, depending on history of sound exposure. To explore this hypothesis, we have developed Ca2+-imaging techniques that reveal type II fiber activity throughout the cochlear coil, from apex to base, of adult mice. Secondly, we propose to use loose patch recordings of type II afferent fibers to monitor firing rates in response to optogenetic stimulation of OHCs. Both approaches are utilized to determine the impact of non- damaging and damaging sound exposure on the activity of type II cochlear afferents. The goal of this proposal is to understand the contribution of multiple pathways (purinergic, glutamatergic, neuromodulatory and inflammatory) to these conditions. Our recent experiments show sensitization in the type II afferent response following noise exposure. Such sensitization might be reflective of a `gain-of-function pathology' like hyperacusis/noxacusis. The proposed comprehensive approach here aims to identify pharmacotherapeutic targets for such gain of function pathologies that can follow noise exposure and noise- induced hearing loss.