Synaptic mechanisms of temporal pattern recognition

描述(由申请人提供)：这项提议的长期目标是了解大脑中的感觉回路如何从包含在计时码中的信息中提取与行为相关的线索。刺激的时机几乎在每一种感觉通道中都承载着信息。例如，声音的定时提示对于人类语音感知的各个方面至关重要，例如音高和音素辨别。此外，时序模式也可能在一种被称为新颖性检测或识别新感觉刺激的现象中发挥作用。阅读障碍、中枢听觉处理障碍和自闭症都与定时和新奇提示的听觉处理障碍有关。在听觉和电感中，时间线索的解码是由中脑神经元根据连续刺激之间的时间间隔进行的。此外，在哺乳动物的听觉和鱼类的电感觉通路中也发现了单神经元新奇探测器。几个假说试图描述神经回路如何建立区间调谐和新颖性检测，但这些假说的核心兴奋和抑制的潜在行为仍然不确定。使用尖端电生理学和计算方法的组合，这一建议将识别兴奋和抑制输入的相互作用，这些输入在弱电鱼类的中脑电感觉神经元中产生间隔调谐和新颖性检测。目的1确定兴奋性和抑制性短时突触可塑性在建立间期调谐中的作用。在体内，在不同的电流注入水平下，将收集不同刺激间隔的感觉刺激期间的全细胞膜片钳记录。下一步，将计算每个神经元反应背后的兴奋性和抑制性突触电导，以揭示短期抑制和/或促进如何有助于产生间期调谐。最后，改变兴奋性和抑制性输入到漏电整合放电模式神经元的时间常数和可塑性强度，并测量模型神经元对不同间隔刺激的反应。这些方法将检验这样一个假设，即间隔调谐可能是由于兴奋性和抑制性通路的抑郁时间进程的不同而导致的。目的2将确定短时突触可塑性在检测新刺激中的作用。目标1中使用的电生理学和计算方法将被用来揭示当神经元被呈现由常见(更频繁的)和罕见(不太频繁的)刺激脉冲组成的刺激序列时的兴奋和抑制行为。我们将测量不同的可塑性兴奋和抑制时间进程对模型漏电整合和放电神经元的影响，以响应相同的刺激。这些方法将检验这样一种假设，即经历短期兴奋抑制的神经元子集将能够检测到新的刺激。这项建议的结果将提供对中央电路在社会交流途径中处理计时信息所使用的突触机制的描述，以及进一步了解几种疾病的神经基础。 公共卫生相关性：该项目对理解涉及感觉处理的基本神经过程具有相关性，并可能为阅读障碍、中枢听觉处理障碍、自闭症和精神分裂症等情况下神经回路的功能障碍提供洞察。彻底了解完整的神经通路如何执行对感官感知至关重要的操作，对于寻求确定复杂人类疾病的根本原因的研究至关重要。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand how sensory circuits in the brain extract behaviorally relevant cues from information contained within a timing code. The timing of stimuli carries information in almost every sensory modality. For example, the timing cues of sounds are critical for aspects of human speech perception such as pitch and phoneme discrimination. Further, timing patterns may also play a role in a phenomenon called novelty detection, or the identification of a new sensory stimulus. Disruptions in the auditory processing of timing and novelty cues have been implicated in dyslexia, Central Auditory Processing Disorder, and autism. In audition and electrosensation, the decoding of timing cues is performed by midbrain neurons tuned to the time intervals between successive stimuli. Additionally, single-neuron novelty detectors have been found in mammalian auditory and fish electrosensory pathways. Several hypotheses attempt to describe how neural circuits can establish interval tuning and novelty detection, but the underlying behaviors of excitation and inhibition central to these hypotheses remain uncertain. Using a combination of cutting-edge electrophysiological and computational methods, this proposal will identify the interactions of excitatory and inhibitory inputs that produce interval tuning and novelty detection in electrosensory midbrain neurons of weakly electric fish. Aim 1 will determine the role of short-term synaptic plasticity of excitation and inhibition in establishing interval tuning. In vivo whole-cell patch clamp recordings during sensory stimulation with varying interstimulus intervals will be collected at different levels of current injection. Next, the excittory and inhibitory synaptic conductances underlying each neuron's responses will be calculated to reveal how short-term depression and/or facilitation contribute to producing interval tuning. Finally, the time constant and strength of plasticity of excitatory and inhibitory inputs onto mode leaky integrate-and-fire neurons will be varied and the response of the model neurons to varying-interval stimulation measured. These methods will test the hypothesis that interval tuning can result from differences in the time course of depression of excitatory and inhibitory pathways. Aim 2 will determine the role of short-term synaptic plasticity in detecting novel stimuli. The electrophysiological and computational methods employed in Aim 1 will be used to reveal the behavior of excitation and inhibition when a neuron is presented with a stimulus train consisting of common (more frequent) and rare (less frequent) stimulus pulses. The effect of varying the time courses of plastic excitation and inhibition onto model leaky integrate-and-fire neurons in response to the same stimuli will be measured. These methods will test the hypothesis that a subset of neurons that experience short-term depression of excitation will be able to detect novel stimuli. The results of this proposal will provide a description of the synaptc mechanisms employed by central circuits for the processing of timing information in a social communication pathway as well as further our understanding of the neural basis of several disorders. PUBLIC HEALTH RELEVANCE: This project holds relevance for understanding fundamental neural processes involved in sensory processing, and may provide insight into the dysfunction of neural circuits in conditions such as dyslexia, Central Auditory Processing Disorder, autism, and schizophrenia. A thorough knowledge of how intact neural pathways perform operations critical for sensory perception is vital to research that seeks to identify the underlying causes o complex human disorders.