Cellular Mechanisms of Auditory Information Processing

听力损失是一种普遍存在的问题，可能是由于暴露在嘈杂的声音中，以及治疗药物造成的。 癌症和感染，衰老，或个人遗传因素。噪声性听力损失(NIHL) 从职业和娱乐两个方面来说，这是一个日益严重的问题，目前被认为影响 超过4000万美国人。近25%的成年人有与病因相一致的听力体征 由NIHL提供。听力损失会导致沟通困难、社会孤立，可能还会导致 认知力。大多数听力损失的原因是由于耳蜗和螺旋的功能失调引起的。 神经节细胞，它反过来向耳蜗核(CN)提供退化的感觉表征 在那里，螺旋神经节细胞的轴突，即听神经纤维(ANF)，终止。后果是什么？ 然后，耳蜗性NIHL传播到整个中枢听觉系统，参与病理生理 兴奋性增加，突触功能改变。CN由神经元网络组成，这些神经元具有截然不同的 ANF的突触神经支配模式，这些神经元创建平行但相互交织的路径 用于上游分析。尽管CN中的感觉加工已经在正常的动物身上得到了很好的研究 耳蜗，听力损失后CN回路的机制和功能如何变化，以及 这些变化对感觉处理的影响还没有被很好地理解。许多手机 机制仅在发育敏感期的幼鼠身上进行了研究。有一个 未得到满足的需要了解发生在成人中的NIHL的独特细胞机制。在这里，我们 建议使用受控NIHL来干扰传入CN的ANF，然后检查特定的突触 以及与CN中噪声环境中的感觉处理相关的细胞兴奋性机制。第一, 我们将检验NIHL导致CN三个特定人群兴奋性增加的假设 神经元，其中两个还没有被研究，一个只在非常年轻的动物身上被研究过， 在成年小鼠的脑片中。我们将确定哪些特定机制和离子通道是导致 兴奋性的变化。其次，我们将研究如何将突触输入到CN的不同神经元 受NIHL的影响，检验NIHL诱导放大残存树突的机制的假设 兴奋性突触输入，并改变特定部位抑制的功能组织和强度 关系。第三，我们将研究噪声中的声音检测如何受到噪声中的NIHL的影响 使用已建立的声学范式，在计算模型和 活着。总而言之，这些研究的结果将为我们提供关于如何在早期阶段处理 声音会受到听力损失的影响，并有助于识别优化感觉的方法 听力损失后的歧视。

Hearing loss is a pervasive problem that can result from exposure to loud sounds, to drugs for treatment of cancer and infections, from aging, or from individual genetic factors. Noise-induce hearing loss (NIHL), from both occupational and recreational causes, is a growing issue that is currently is thought to affect more than 40 million Americans. Nearly 25% of adults have audiological signs consistent with causation by NIHL. Hearing loss leads to difficulties in communication, social isolation, and possibly to changes in cognition. Most causes of hearing loss are caused by dysfunctional changes in the cochlea and spiral ganglion cells, which in turn provided a degraded sensory representation to the cochlear nucleus (CN) where the axons of spiral ganglion cells, the auditory nerve fibers (ANFs), terminate. The consequences of cochlear NIHL then propagate throughout the central auditory system, engaging pathophysiological increases in excitability and altering synaptic function. The CN consists of networks of neurons with distinct patterns of synaptic innervation from ANFs, and these neurons create parallel, yet intertwined, pathways for upstream analysis. Although sensory processing in the CN has been well studied in animals with normal cochleae, how the mechanisms and functions of CN circuits change after hearing loss, and the consequences of those changes for sensory processing, is not as well understood. Many cellular mechanisms have only been studied in juvenile mice during a developmental sensitive period. There is an unmet need to understand the unique cellular mechanisms underlying NIHL that occur in adults. Here, we propose to use controlled NIHL to perturb the ANF inputs to the CN, and then to examine specific synapses and cellular excitability mechanisms related to sensory processing in noisy environments in the CN. First, we will examine the hypothesis that NIHL leads to increased excitability of three specific populations of CN neurons, two of which have not been studied, and one that has only been studied in very young animals, in brain slices in adult mice. We will determine which specific mechanisms and ion channels are causal to changes in excitability. Second, we will examine how the synaptic inputs to different neurons of the CN are affected by NIHL, testing the hypotheses that NIHL induces mechanisms that amplify residual dendritic excitatory synaptic inputs, and alter the functional organization and strength of inhibition at specific local connections. Third, we will examine how the detection of sounds in noise is affected by NIHL in these three populations of CN neurons, using an established acoustic paradigm, in both computational models and in vivo. Together the results from these studies will provide insights into how the early stage processing of sound is affected by hearing loss, and can contribute identifying approaches to optimize sensory discrimination after hearing loss.