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

描述（由申请人提供）：内毛细胞（IHC）是听觉系统的主要感觉受体。在发育中的耳蜗中，内毛细胞接受传出输入，这被认为是其内在尖峰行为的模式。在出生后的第二周，IHC失去了它们的传出联系。在成熟的耳蜗中，转导电流和内源性基底外侧钾电流控制着IHC的受体电位，使其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，传出神经支配返回到患有听力损失的小鼠的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返回到IHC。在表征了三个年龄段（以及听力障碍的水平）受神经支配的IHC的比例后，我们将确定这些突触的分子组成部分。为了确定这些突触形成的具体病理因素，我们将选择性地消融外毛细胞（由内侧传出神经接触）和1型螺旋神经节神经元（由外侧传出神经接触），并测试这些操作（单独或一起）是否诱导IHC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、静纤毛损伤和传入突触丢失。然而，很少有人注意传出纤维在受损耳蜗中的作用。我们的初步数据表明，在受损的耳蜗中，与内毛细胞接触的传出神经是功能抑制性的。传出活动可能通过减少从外周到中枢神经系统的信息传递而进一步加剧听力障碍。另一方面，传出抑制的IHC可能有助于保护传入神经元兴奋性毒性回缩。通过表征这些突触和构成其形成基础的特定耳蜗病理学，我们正在迈出理解传出-IHC突触在听觉处理中的作用的第一步。 如果我们 能够诱导IHC的传出神经支配（通过外毛细胞和/或螺旋神经节消融），可以作为成年动物中突触发生的有价值的模型。目前尚不清楚神经系统对突触形成的损伤做出反应的程度，但我们的工作表明这样的过程发生在耳蜗中。另外令人感兴趣的是，神经系统可能通过假设在发育过程中发现的特征来对损伤做出反应，并且我们观察到的强大的传出-IHC神经支配概括了耳蜗的发育突触组织。

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.