Cellular Mechanisms of Auditory Information Processing

听觉信息处理的细胞机制

基本信息

批准号：
10399541
负责人：
Paul B Manis
金额：
$ 49.5万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10399541
关键词：
Acoustic Nerve Acoustics Adolescent Adult Affect Age Aging American Animals Auditory Auditory system Axon Bilateral Brain Cell Nucleus Cells Cochlea Cochlear nucleus Code Cognition Communication Complex Computer Models Dendrites Detection Development Dorsal Environment Environmental Risk Factor Etiology Exposure to Fiber Frequencies Functional disorder Genetic Goals Hair Cells Hearing problem Human Hyperacusis Individual Infection Interneurons Ion Channel Ions Knowledge Literature Loudness Maps Masks Measures Modeling Molecular Mus Nerve Fibers Neuraxis Neurons Noise Noise-Induced Hearing Loss Occupational Output Pathway interactions Pattern Perception Peripheral Persons Pharmacotherapy Population Poverty Process Pyramidal Cells Rattus Residual state Sensory Sensory Thresholds Signal Transduction Slice Social isolation Speech Speech Discrimination Synapses Synaptic Transmission Testing Training United States Work auditory processing cancer therapy cell type dorsal cochlear nucleus ganglion cell hearing impairment hippocampal pyramidal neuron in vivo information processing insight juvenile animal mature animal nerve supply neural circuit novel programs receptor response sensory discrimination sensory input sensory integration sound spiral ganglion stellate cell stimulus processing synaptic function virtual

项目摘要

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.

听力损失是一个普遍存在的问题，可能因暴露于大声的声音或治疗药物而导致癌症和感染、衰老或个体遗传因素。噪音引起的听力损失（NIHL），由于职业和娱乐原因，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% 的成年人有与因果关系一致的听力学体征由 NIHL 提供。听力损失会导致沟通困难、社交孤立，并可能导致生活习惯的改变认识。听力损失的大多数原因是由耳蜗和螺旋的功能失调变化引起的神经节细胞，进而向耳蜗核提供退化的感觉表征 (CN) 螺旋神经节细胞的轴突（听觉神经纤维（ANF））终止于此。后果然后耳蜗 NIHL 的信号传播到整个中枢听觉系统，参与病理生理学兴奋性增加并改变突触功能。 CN 由具有不同特征的神经元网络组成 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。尽管中枢神经系统的感觉处理已在具有正常功能的动物身上进行了充分研究耳蜗，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得到很好的理解。许多蜂窝仅在发育敏感期的幼年小鼠中研究了其机制。有一个了解成人 NIHL 背后独特的细胞机制的需求尚未得到满足。在这里，我们建议使用受控 NIHL 扰乱 ANF 对 CN 的输入，然后检查特定突触以及与中枢神经系统噪声环境中的感觉处理相关的细胞兴奋机制。第一的，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，其中两种尚未被研究，另一种仅在非常年幼的动物中进行过研究，在成年小鼠的脑切片中。我们将确定哪些具体机制和离子通道导致兴奋性的变化。其次，我们将研究 CN 不同神经元的突触输入是如何的受 NIHL 影响，检验 NIHL 诱导放大残余树突的机制的假设兴奋性突触输入，并改变特定局部的功能组织和抑制强度连接。第三，我们将研究这三个方面的 NIHL 如何影响噪声中声音的检测 CN 神经元群体，使用已建立的声学范式，在计算模型和体内。这些研究的结果将提供关于早期处理如何进行的见解。声音会受到听力损失的影响，并且有助于识别优化感官的方法听力损失后的歧视。