Multiple roles of inhibition in temporal coding of sensory information

描述（由申请人提供）：本提案的目的是确定控制抑制在时间编码中的作用的具体机制。时间代码使用精确定时的事件来表示信息。例如，鸟类、哺乳动物和其他脊椎动物的声音定位依赖于时间编码，其中事件是峰值时间。在这种情况下，神经元首先在相对于声音到达每只耳朵的时间的特定时间发射脉冲。然后，时间比较神经元将这些尖峰时间整合起来，这样特定的细胞只对来自特定位置的声音做出反应。时间编码对于识别人类语言的特征也很重要，如元音持续时间、音素辨别和停顿长度；所有这些都涉及到非常精确，时间上的微小差异。这一建议特别感兴趣的是抑制在用于处理峰值时间非常小的差异的时间代码中的作用。虽然时间编码对感觉处理很重要，但我们对时间编码背后的细胞机制知之甚少。这种缺陷的相关性可以从我们无法分离出中枢性听觉处理障碍（CAPD）的许多原因中看出，CAPD是一组由中枢神经系统功能障碍引起的定义不清的听觉缺陷。本文提出的实验将通过具体解决抑制在时间编码中的作用，向阐明人类听觉加工迈出重要的一步。这项提议的研究将检验这样一个假设，即抑制不仅会产生对脉冲时间差异的敏感性，而且还会通过改变神经元的调节方式来塑造这种敏感性的表征。具体来说，本研究将分析神经回路中三个不同位置的抑制作用：向时间比较神经元提供输入的细胞，时间比较神经元本身，以及整合时间比较神经元输出的细胞。首先，免疫组织化学和电生理学的结合将用于评估抑制细胞的抑制输入是否影响对尖峰时间差异的敏感性。然后，一种新的体内细胞外轴突记录方法将与抑制药物阻滞剂一起使用，以提供抑制存在或不存在如何影响时间比较神经元调谐特性的直接测试。最后，免疫组织化学和电生理学将用于评估神经元的兴奋性和抑制性输入的时间、强度和位置，这些输入整合了时间比较神经元的输出。所有这些实验都将使用弱电鱼作为模型系统，因为它们的感觉处理使用小的脉冲时间差异在专门用于这种感觉模式的可访问的神经回路中编码与行为相关的信号。本提案中的实验将为抑制在时间编码中的不同作用提供关键的见解，从而提高对听觉信息的神经处理的理解。

DESCRIPTION (provided by applicant): The objective of this proposal is to identify specific mechanisms governing the role of inhibition in temporal coding. A temporal code uses precisely timed events to represent information. For example, sound localization in birds, mammals, and other vertebrates relies on temporal codes in which the events are spike times. In this case, neurons first fire spikes at specific times relative to the time at which the sound arrives at each ear. Then, time-comparing neurons integrate those spike times such that specific cells only respond when sound comes from certain locations. Temporal coding is also important for recognizing features of human speech such as vowel sound duration, phoneme discrimination, and pause length; all of which involve very precise, small differences in timing. This proposal is specifically interested in the role of inhibition in temporal codes used to process very small differences in spike times. Although it is clear that temporal codes are important for sensory processing, we know relatively little about the cellular mechanisms underlying temporal codes. The relevance of this deficit can be seen in our inability to separate out the many causes of Central Auditory Processing Disorder (CAPD), a group of ill-defined auditory deficiencies resulting from central nervous system dysfunction. The experiments proposed here will take an important step towards elucidating human auditory processing by specifically addressing the role of inhibition in temporal coding. The proposed research will test the hypothesis that inhibition not only generates sensitivity to spike timing differences, but also shapes the representation of that sensitivity by altering how neurons are tuned. Specifically, this research will analyze the role of inhibition at three distinct locations in a neural circuit: the cells providing input to the time-comparator neurons, the time-comparator neurons themselves, and the cells that integrate the outputs of time-comparator neurons. First, a combination of immunohistochemistry and electrophysiology will be used to assess if inhibitory inputs onto inhibitory cells affect sensitivity to spike timing differences. Then, a novel in vivo extracellular axon recording approach will be used along with a pharmacological blocker of inhibition to provide a direct test of how the presence or absence of inhibition affects the tuning properties of time-comparator neurons. Finally, immunohistochemistry and electrophysiology will be used to assess the timing, strength, and location of excitatory and inhibitory inputs onto the neurons that integrate the outputs of time-comparator neurons. All of these experiments will be done using weakly electric fish as a model system because their sensory processing uses small spike timing differences to encode behaviorally relevant signals in an accessible neural circuit devoted exclusively to this sensory modality. The experiments in this proposal will provide critical insight into the diverse roles of inhibition in temporal coding, thus leading to an improved understanding of neural processing of auditory information.