Corticosterone effects on the stability and vulnerability of the IHC synapse and sound processing

每当我们体内生理过程的平衡受到干扰时，就会触发压力反应，以恢复体内平衡并促进适应。已知由环境需求、正压力以及创伤性、破坏性压力引起的生理挑战影响人类的声音感知的敏锐度以及动物的听觉信号的皮层处理的敏锐度。这些影响被认为起源于中央大脑区域。我们最近观察到皮质酮对听力的有益和恶化影响，可能是由于直接影响内毛细胞（IHC）突触。在本申请中，我们解决了这样的压力对听觉处理的影响的性质和功能的问题。我们的目的是确定皮质类固醇激素受体类型，盐皮质激素（MR）和糖皮质激素受体（GR）在内毛细胞水平的作用（1）通过在耳蜗或大脑缺失的条件小鼠模型中细胞特异性缺失MR和GR，（2）通过研究MR/GR激动剂/拮抗剂对成熟器官中听力和声音处理的影响，（3）通过测试推测的急性MR/GR对皮层处理的单根听觉纤维反应的影响。一个假定的应力诱导的影响IHC突触的完整性或脆弱性将有助于确定一个本地化的药物治疗和治疗性临床intervention.We的目标有证据表明，改变皮质酮水平在啮齿动物直接影响稳定的IHC丝带号码前和后声创伤相关的相应的变化在阈上ABR波和活动依赖性基因表达的听觉通路上升。由于IHC条带定义了尖峰频率的精确度，并且阈上ABR波的大小反映了总听神经的放电率和同步性，我们的项目期望在最好的情况下提供关于压力的大量新信息-我们目前应用的主要假设表明，通过MR或GR受体的不同皮质类固醇受体活性可能通过对IHC突触的活动影响中枢听觉处理的完整性和脆弱性，从而可以影响声音敏感性以及适应性或非适应性可塑性变化。

Whenever the balance of physiological processes in our body is disturbed, a stress response can be triggered to restore homeostasis and to facilitate adaptation. Physiological challenge by environmental demands, positive stress and also traumatizing, damaging stress are known to influence acuity of sound perception in humans as well as acuity of cortical processing of auditory signals in animals. These influences are considered to originate in central brain regions. We recently observed beneficial and deteriorating effects of corticosterone on hearing that may result from directly affecting the inner hair cell (IHC) synapse. In the present application we address the question to the nature and function of such stress influences on auditory processing. We aim to identify the role of corticosteroid hormone receptor types, mineralocorticoid (MR) and glucocorticoid receptor (GR), at the inner hair cell level (1) through cell-specific deletion of MR and GR in conditional mouse models with deletions in either cochlea or brain, (2) through investigating the effect of MR/GR agonists/antagonists on hearing and sound processing in the mature organ, and (3) through testing presumptive acute MR/GR effects on single auditory fiber responses on cortical processing. A presumptive stress-induced effect on IHC synapse integrity or vulnerability would help to define a localized target for drug therapies and therapeutic clinical intervention.We have evidence that altered corticosterone levels in rodents directly influence the stability of IHC ribbon numbers pre- and post acoustic trauma correlated with correspondent shifts in supra-threshold ABR waves and activity-dependent gene expression in the ascending auditory pathway. As IHC ribbons define precision of spike rates and the size of supra-threshold ABR waves mirror the discharge rate and synchronicity of the summed auditory nerve, our project is expecting to provide in the best case substantial new information about stress-induced influences on temporal precise auditory information processing.Our main hypothesis of the current application suggests that differential corticosteroid receptor activities through MR or GR receptors may influence through activities on IHC synapses the integrity and vulnerability of central auditory processing and thereby can influence sound sensitivity as well as adaptive or non-adaptive plasticity changes.