Cellular Mechanisms of Auditory Information Processing

听力损失是一个普遍存在的问题，可能是由于暴露于响亮的声音，药物治疗 癌症和感染，衰老，或个体遗传因素。噪声性听力损失（NIHL）， 从职业和娱乐的原因，是一个日益严重的问题，目前被认为是影响 超过4000万美国人近25%的成年人有听力学迹象符合因果关系 的NIHL。听力损失导致沟通困难，社会孤立，并可能改变 认知.大多数听力损失的原因是由于耳蜗和螺旋的功能障碍性变化引起的 神经节细胞，这反过来又提供了一个退化的感觉代表耳蜗核（CN） 螺旋神经节细胞的轴突即听觉神经纤维（ANF）终止于此。后果 耳蜗NIHL然后传播到整个中枢听觉系统， 兴奋性增加并改变突触功能。CN由神经元网络组成， ANF的突触神经支配模式，这些神经元产生平行但交织的通路， 上游分析。虽然在CN的感觉加工已经在正常的动物中得到了很好的研究， 耳蜗，CN回路的机制和功能如何在听力损失后改变，以及 这些变化对感官加工的影响，还没有得到很好的理解。许多细胞 机制仅在发育敏感期的幼年小鼠中进行了研究。有一个 我们需要了解在成人中发生的NIHL的独特细胞机制。这里我们 我建议使用受控的NIHL来干扰到CN的ANF输入，然后检查特定的突触 以及CN中与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导致三个特定CN群体兴奋性增加的假设 神经元，其中两个还没有被研究过，一个只在非常年轻的动物身上研究过， 在成年小鼠的脑切片中。我们将确定哪些特定的机制和离子通道是因果关系， 兴奋性的变化。其次，我们将研究如何突触输入到CN的不同神经元， 受NIHL的影响，测试NIHL诱导放大残余树突状细胞的机制的假设， 兴奋性突触输入，并改变功能组织和抑制强度在特定的局部 连接.第三，我们将研究如何检测噪声中的声音是受NIHL在这三个 CN神经元群体，使用已建立的声学范式，在计算模型和 vivo.总之，这些研究的结果将为了解早期阶段如何处理 声音受听力损失的影响，可以帮助识别优化感官的方法， 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.