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。时态代码使用精确计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代码，其中事件是尖峰时间。在这种情况下，神经元首先在相对于声音到达每只耳朵的特定时间发出尖峰。然后，时间比较神经元整合这些尖峰时间，这样特定的细胞只有在声音从特定位置发出时才会做出反应。时间编码对于识别人类语音的特征也很重要，例如元音持续时间、音素辨别和停顿长度；所有这些都涉及非常精确的、微小的时序差异。这一建议特别关注抑制在时间代码中的作用，该代码用于处理尖峰时间的非常小的差异。尽管时间编码对感觉加工很重要，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区分出中枢听觉处理障碍(CAPD)的许多原因中看出。CAPD是一组定义不清的听觉缺陷，由中枢神经系统功能障碍引起。这里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。这项拟议的研究将检验这一假设，即抑制不仅产生对尖峰时间差异的敏感性，还通过改变神经元的调谐方式来塑造这种敏感性的表征。具体地说，这项研究将分析神经回路中三个不同位置的抑制作用：向时间比较器神经元提供输入的细胞，时间比较器神经元本身，以及整合时间比较器神经元输出的细胞。首先，将结合免疫组织化学和电生理学来评估抑制细胞上的抑制输入是否会影响对峰时差的敏感性。然后，一种新的细胞外轴突记录方法将与抑制的药物阻滞剂一起使用，以直接测试抑制的存在或不存在如何影响时间比较器神经元的调谐特性。最后，免疫组织化学和电生理学将被用来评估兴奋和抑制输入到神经元的时间、强度和位置，这些神经元整合了时间比较器神经元的输出。所有这些实验都将使用弱电鱼类作为模型系统，因为它们的感觉处理使用微小的尖峰时序差异，在专用于这种感觉通道的可访问神经电路中编码与行为相关的信号。该方案中的实验将提供对抑制在时间编码中的不同作用的关键洞察，从而导致对听觉信息的神经处理的更好的理解。 与公共健康相关：这项提案中描述的研究与大脑如何处理感觉信息，特别是声音持续时间和位置有关。具体地说，它将分析抑制性和兴奋性连接是如何汇聚到脑细胞上的，这些细胞使用这些信号的时序来调节对刺激的感知，时序差异非常小。这一结果将促进我们对基于时间的神经编码的理解。

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. PUBLIC HEALTH RELEVANCE: The research described in this proposal is relevant to how the brain processes sensory information, particularly sound duration and location. Specifically, it will analyze how inhibitory and excitatory connections converge onto brain cells that use the timing of those signals to mediate perception of stimuli with very small timing differences. The results will advance our understanding of time-based neural coding.