Cellular Mechanisms of Auditory Information Processing

描述(申请人提供)：听觉环境的中央处理始于在大脑的第一听觉中枢，即耳蜗核的水平上产生不同的、并行的信息流。这些流是由具有不同突触输入和投射模式的神经元群体创建的。为了完成它们特定的功能，每条神经流中的神经元利用不同的细胞机制，包括控制内在兴奋性的离子通道和靶点依赖的突触输入。最近的研究表明，抑制在形成腹侧耳蜗核(VCN)神经元对声音的反应中起着比以往认识到的更重要的作用。抑制可以用于增强声音属性的频谱和时间处理，这对于声音识别和定位以及语音处理是重要的。我们的研究表明，即使是来自单一来源的抑制，在两种主要的细胞类型，丛生细胞和星状细胞中，抑制的时间过程也是不同的。这一建议的第一个目的是阐明VCN中两个局部抑制性突触回路的功能突触组织。第二个目的是验证不同细胞类型上的突触电流是由不同的甘氨酸受体亚基介导的假设。我们还将研究在持续活动中调节释放时间进程的突触前机制。第三个目标是将这些信息合并到一个详细的计算模型中，该模型将用于探索抑制在VCN的时间和频谱处理中的不同方面的重要性。第四个目标是确定听力损失如何影响这些抑制回路的功能。所有这些实验都将在成年小鼠的脑片上进行。总体而言，我们的研究将确定早期听觉信息处理的关键机制，并确定这些机制如何有助于复杂声音的分析。然后，我们将确定这些机制是如何受到听力损失的影响的，这将为听力障碍者和人工耳蜗使用者提供替代刺激策略的见解。大脑中感觉处理的神经机制是我们正常感知能力的基础，包括识别声源和通过声音进行交流的能力。这些机制会因感觉器官受损而改变，因此，残留的感知能力往往会受到不利影响。在这个项目中，我们试图了解功能性突触组织和在听觉通路的早期阶段有助于听力的潜在机制。我们还将确定这些基本机制如何受到听力损失的影响，以及听力损失如何影响大脑中的高级感觉处理。这些实验最终将为重听人和人工耳蜗使用者提供替代刺激策略的见解。

DESCRIPTION (provided by applicant): Central processing of the auditory environment begins with the generation of diverse, parallel, streams of information processing at the level of the first auditory center of the brain, the cochlear nucleus. These streams are created by populations of neurons with distinct patterns of synaptic inputs and projections. In order to accomplish their specific functions, the neurons in each stream utilize different cellular mechanisms, including ion channels that govern intrinsic excitability, and target-dependent synaptic inputs. Recent studies have shown that inhibition plays a much more important role in sculpting the responses of ventral cochlear nucleus (VCN) neurons to sound than previously appreciated. Inhibition can serve to enhance both the spectral and temporal processing of sound attributes that are important for sound identification and localization as well as speech processing. Our studies have revealed that the time course of inhibition, even from a single source, is different in the two principal cell types, the bushy and stellate cells. The first aim of this proposal is to clarify the functional synaptic organization of two local inhibitory synaptic circuits in the VCN. The second aim is to test the hypothesis that the synaptic currents on different cell types are mediated by different glycine receptor subunits. We will also investigate the presynaptic mechanisms that regulate the time course of release during sustained activity. The third aim is to incorporate this information into a detailed computational model, which will be used to explore the importance of different aspects of inhibition in temporal and spectral processing in the VCN. The fourth aim is to determine how the function of these inhibitory circuits is affected by hearing loss. All of these experiments will be performed in brain slices of adult mice. Overall, our studies will identify critical mechanisms in early auditory information processing, and determine how those mechanisms contribute to the analysis of complex sounds. We will then determine how these mechanisms are affected by hearing loss, which will provide insights for alternative stimulation strategies for the hard-of-hearing and for cochlear implant users. The neural mechanisms of sensory processing in the brain underlie our normal perceptual abilities, including the identification of sound sources and the ability to communicate through sound. These mechanisms are changed by damage to the sensory organs, and consequently, residual perceptual abilities are often adversely affected. In this project, we seek to understand the functional synaptic organization and the underlying mechanisms that contribute to hearing at early stages of the auditory pathway. We will also determine how these basic mechanisms are affected by hearing loss, and how hearing loss affects higher-order sensory processing in the brain. These experiments will ultimately generate insights for alternative stimulation strategies for the hard-of-hearing, and for cochlear implant users.