Neural networks of auditory refractoriness and mismatch generation in the rhesus macaque

恒河猴听觉不应性和失配产生的神经网络

• 批准号: 9295151
• 负责人: Tobias Teichert
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295151
• 关键词: Acute; Address; Affect; Anatomy; Animal Model; Animals; Anterolateral; Auditory; Auditory area; Auditory system; Behavior; Behavioral; Biological Models; Biological Neural Networks; Brain region; Cognitive deficits; Correlative Study; Data; Detection; Discrimination; Disease; Dura Mater; Electroencephalography; Electrophysiology (science); Environment; Etiology; Event; Exhibits; Foundations; Functional disorder; Future; Generations; Homologous Gene; Hot Spot; Human; Impairment; Individual; Intervention; Knowledge; Lateral; Link; Literature; Macaca; Macaca mulatta; Maps; Measures; Mediating; Methodology; Methods; Microinjections; Modeling; Molecular; Molecular Target; Monkeys; N-Methyl-D-Aspartate Receptors; Network-based; Neurobehavioral Manifestations; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phencyclidine; Pitch Discrimination; Plant Roots; Receptor Signaling; Refractory; Reporting; Research; Resources; Role; Schizophrenia; Solid; Speech; Stream; Synapses; System; Techniques; Testing; Translational Research; Translations; auditory processing; base; behavior test; behavioral impairment; candidate marker; clinically relevant; cognitive process; density; experimental study; neural correlate; neuromechanism; novel; phenomenological models; prevent; psychotic symptoms; relating to nervous system; response; sound; vesicular release

7. PROJECT SUMMARY Individuals with schizophrenia (SZ) suffer from basic auditory processing deficits that may be at the root of more severe cognitive deficits. Neural correlates of auditory deficits can be recorded non-invasively using elec- troencephalography (EEG). For example, individuals with SZ show a blunted enhancement of responses for tones presented either after long periods of silence (N1 refractoriness) or after sequences of physically dis- tinct tones (mismatch negativity, MMN). Studies in healthy controls and SZ have linked both of these EEG markers to auditory behaviors that are impaired in SZ. The identification of a presumed homolog of N1 and MMN in macaque monkeys has established them as the most relevant animal model system for auditory defi- cits in SZ. However, since the initial groundbreaking reports in the 1990s, the monkey model has been studied only sporadically, leaving a rich resource untapped. Since the precise neural mechanisms that mediate N1 re- fractoriness and MMN are still poorly understood, this project will provide a detailed understanding of the un- derlying neural networks in order to provide a solid foundation to better understand auditory deficits in SZ. This project will employ a treatment-oriented research approach that views auditory function and neural correlates such as MMN as equally important components in identifying new treatment targets for auditory def- icits in SZ. Experiments will be performed in two stages. Stage one will consist of high-density extra-cranial rhesus EEG recordings over a wide range of passive listening paradigms used to study N1 refractoriness and MMN in humans. These studies will identify tasks and parameter ranges for which the two species show ho- mologous responses. Stage two will measure responses of different auditory regions in the superior temporal plane to assess their contribution to N1 refractoriness and MMN, as well as behaviors believed to be mediated by the underlying neural computations. These questions will be addressed with a new experimental approach that combines three established techniques – monkey behavioral testing, EEG, and intracranial laminar record- ings/microinjections – into a new functional unit that we refer to as `invasive EEG'. The invasive EEG experi- ments will measure EEG before and after modulating neural activity in a patch of auditory cortex while the ani- mals perform an auditory task that quantifies the detection of novel events in the auditory environment. The proposed project will establish a single, highly relevant model system that integrates two very promis- ing electrophysiological candidate bio-markers of auditory deficits in SZ (N1 refractoriness and MMN) with the associated behavioral deficit of delayed tone-discrimination. This system will then enable studies that can close the translational gap between electrophysiological correlates of the disease and the causal flow of information in the network that mediates the affected function/behavior and identify novel treatment targets.

7。项目摘要 精神分裂症（SZ）患有基本听觉处理的人可以定义 更严重的认知缺陷。听觉缺陷的神经相关性可以使用ELEC-无创地记录 TRONCEPHALOGHAPHY（EEG）。例如，患有SZ的个体显示出对响应的增强 长时间的静音（N1耐火）或物理上序列后，呈现的音调 Tinct语调（不匹配谈判，MMN）。在健康对照和SZ方面的研究已将这两个脑电图联系在一起 SZ中受损的听觉行为的标记。识别N1和N1的预览同源物 猕猴中的MMN已将它们确立为听觉障碍的最相关的动物模型系统 SZ中的CIT。但是，自1990年代最初的开创性报告以来，猴子模型已经研究了 只有零星，就没有开发丰富的资源。由于介导N1的精确神经机制 断裂性和MMN的理解仍然很差，该项目将提供对不合理的详细理解 衍生神经网络以提供坚实的基础以更好地了解SZ中的听觉定义。 该项目将采用以治疗为导向的研究方法，该方法观看听觉功能和神经 将MMN作为同等重要组成部分的相关性，以确定听觉的新治疗目标 SZ中的ICIT。实验将分为两个阶段。第一阶段将由高密度的外颅组成 用于研究N1难治性和 MMN在人类中。这些研究将确定两个物种显示的任务和参数范围 感动的反应。第二阶段将测量上级临时性不同听觉区域的响应 评估其对N1耐火和MMN的贡献的飞机，以及被认为是介导的行为 通过基础神经计算。这些问题将通过一种新的实验方法解决 结合了三种已建立的技术 - 猴子行为测试，脑电图和颅内层流记录 - INS/显微注射 - 进入一个新功能单元，我们称为“侵入性脑电图”。侵入性脑电图实验 - 在调节一块听觉皮层中的神经活动之前和之后，MENTS将测量脑电图 MALS执行听觉任务，该任务量化了听觉环境中新事件的检测。 拟议的项目将建立一个单一的，高度相关的模型系统，该系统整合了两个非常诺言 - 与SZ（N1难治性和MMN）的听觉缺陷的电生理候选生物标志物 相关的行为不足延迟歧视。然后，该系统将启用可以关闭的研究 电生理学相关性与信息因果流动之间的转化差距 在介导受影响功能/行为并确定新颖治疗目标的网络中。