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

7.项目摘要 精神分裂症（SZ）患者患有基本的听觉处理缺陷，这可能是精神分裂症的根源。 更严重的认知缺陷听觉缺陷的神经相关性可以使用非侵入性记录， 脑电图（EEG）。例如，患有SZ的个体对以下各项的反应表现出迟钝的增强： 在长时间的沉默（N1不应期）或一系列的身体不适后出现的音调， 色调（失配负性，MMN）。在健康对照组和SZ中的研究将这两种EEG联系起来 SZ中听觉行为受损的标记物。N1的一个假定同源物的鉴定， 猕猴的MMN已将其确立为听觉障碍最相关的动物模型系统。 cits in SZ.然而，自从20世纪90年代最初的开创性报告以来，已经研究了猴子模型， 只是零星的留下了丰富的资源未被开发因为调节N1的精确神经机制是- 脆性和MMN仍然知之甚少，这个项目将提供一个详细的了解联合国， 为了更好地理解SZ的听觉缺陷，我们开发了神经网络，以提供坚实的基础。 本研究将采用以治疗为导向的研究方法， 相关性，如MMN作为同样重要的组成部分，在确定新的治疗目标，为听觉def. 在深圳，实验将分两个阶段进行。第一阶段是高密度的颅外 用于研究N1不应性的各种被动听力范例的恒河猴EEG记录， 人类的MMN。这些研究将确定任务和参数范围，这两个物种显示ho- martenses的回应第二阶段将测量上级颞叶不同听觉区域的反应 平面，以评估其对N1不应期和MMN的贡献，以及被认为是介导的行为 被底层的神经计算所控制这些问题将通过一种新的实验方法来解决 它结合了三种成熟的技术--猴子行为测试、脑电图和颅内层流记录-- 注射/显微注射-进入一个新的功能单位，我们称之为“侵入性脑电图”。侵入性脑电图实验- 将测量脑电图之前和之后调制神经活动的听觉皮层的补丁，而动物， MALS执行对听觉环境中的新事件的检测进行量化的听觉任务。 拟议的项目将建立一个单一的，高度相关的模型系统，集成两个非常有前途的- 在SZ（N1不应期和MMN）中使用电生理学候选听觉缺陷生物标志物， 延迟音调辨别的相关行为缺陷。该系统将使研究能够关闭 疾病的电生理学相关性和因果信息流之间的翻译间隙 在介导受影响的功能/行为并识别新的治疗靶点的网络中。

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.