Efferent innervation of inner hair cells in the aged/damaged cochlea

描述（由申请人提供）：内毛细胞（IHCs）是听觉系统的主要感觉受体。在发育中的耳蜗中，IHCs接收的输出输入被认为是其固有尖峰行为的模式。在产后第二周，ihc失去其传出接触。在成熟耳蜗中，传导电流和固有的基底外侧钾电流控制ihc的受体电位，使它们能够准确地编码和传递声学信息。然而，有超微结构证据表明，在听力损失的小鼠中，传出神经支配返回到ihc。我们将对患有年龄相关性听力损失的动物的ihc进行全细胞膜片钳记录，以确定功能性传出神经支配是否确实恢复到ihc。在描述了三个年龄段（和听力损伤水平）受神经支配的间质干细胞的比例后，我们将确定这些突触的分子成分。为了确定这些突触形成的具体病理因素，我们将选择性地切除外毛细胞（通过内侧传出神经接触）和1型螺旋神经节神经元（通过外侧传出神经接触），并测试这些操作（单独或共同）是否诱导IHCs的传出神经支配。许多外周因素与听力损失有关，包括外毛细胞死亡、立体纤毛损伤和传入突触丧失。然而，很少有人注意到传出纤维在受损耳蜗中的作用。我们的初步数据表明，在受损耳蜗中接触ihc的传出信号具有功能抑制性。传出活动可能通过减少从外周神经系统到中枢神经系统的信息传递进一步加剧听力障碍。另一方面，ihc的传出抑制可能有助于保护传入神经元免受兴奋性毒性收缩。通过表征这些突触及其形成背后的特定耳蜗病理，我们在理解传出-免疫组化突触在听觉处理中的作用方面迈出了第一步。如果我们是

DESCRIPTION (provided by applicant): Inner hair cells (IHCs) are the primary sensory receptors of the auditory system. In the developing cochlea, IHCs receive efferent input that is thought to pattern their intrinsic spiking behavior. During the second postnatal week, IHCs lose their efferent contacts. In the mature cochlea, transduction currents and intrinsic basolateral potassium currents govern the receptor potential of IHCs, allowing them to accurately encode and transmit acoustic information. There is ultrastructural evidence, however, that efferent innervation returns to IHCs in mice suffering hearing loss. We will perform whole cell patch clamp recordings of IHCs from animals suffering age-related hearing loss in order to determine if functional efferent innervation does indeed return to IHCs. After characterizing the proportion of IHCs innervated at three ages (and levels of hearing impairment), we will identify the molecular components of these synapses. In order to determine the specific pathological factors underlying the formation of these synapses, we will selectively ablate outer hair cells (which are contacted by medial efferents) and Type 1 spiral ganglion neurons (which are contacted by lateral efferents) and test if these manipulations (in isolation or together) induce efferent innervation of IHCs. A number of peripheral factors have been implicated in hearing loss, including outer hair cell death, stereocilia damage, and afferent synaptic loss. Little attention hs been paid, however, to the role of efferent fibers in the damaged cochlea. Our preliminary data indicate that the efferents contacting IHCs in the damaged cochlea are functionally inhibitory. It is possible that efferent activity further exacerbates hearing impairment by reducing information transfer from the periphery to the central nervous system. On the other hand, efferent inhibition of IHCs might serve to protect afferent neurons from excitotoxic retraction. By characterizing these synapses and the specific cochlear pathology that underlies their formation, we are taking the first steps in understanding the efferent-IHC synapse's role in auditory processing. If we are able to induce efferent innervation of IHCs (via outer hair cell and/or spiral ganglia ablation), i may serve as a valuable model of synaptogenesis in the adult animal. The extent to which the nervous system responds to insults with synaptic formation is currently unknown, but our work suggests that such a process occurs in the cochlea. Of additional interest is the idea that the nervous system might respond to damage by assuming characteristics that are found during development, and the robust efferent-IHC innervation we observe recapitulates the developmental synaptic organization of the cochlea.