Causal examination of TRN role in neocortical spindle generation and function

描述（由申请人提供）：在哺乳动物大脑中，在多个空间和时间尺度上观察到皮质脱离感觉处理。在活跃行为期间，这个过程可能会改变与选择性注意相关的信息路由，而在安静期间，它可能与睡眠稳定性和记忆巩固有关。多项证据表明，皮质脱离是由丘脑皮质动力学（包括纺锤体振荡）介导的。纺锤体是离散的 7-15Hz 皮质振荡，与丘脑网状核 (TRN) 的活动相关，丘脑网状核是一组围绕背侧丘脑的 GABA 能细胞。在精神分裂症中观察到减弱的纺锤体，并且可能导致在这种疾病中观察到的感觉门控缺陷，而超同步纺锤体被认为代表失神性癫痫的棘波放电（SWD）；主动醒来时感觉脱离的不恰当表达。尽管七十年前就发现了纺锤体，但纺锤体的基本现象学正在经历重大修订。虽然人类表面脑电图（EEG）记录和麻醉动物局部场电位（LFP）记录显示纺锤体在整个皮质区域是一致的，但最近的人类脑磁图（MEG）和植入电极记录揭示了这些事件的局部表达，这表明纺锤体具有与其在感觉过滤和记忆中的作用相关的局部计算价值。使用新开发的轻型多电极微驱动器，我将记录和操纵自由行为小鼠 TRN 多个部分的电生理活动。我将首先完善我拥有的光遗传学方法 已用于确定可以控制 TRN 和相关新皮质的局部、特定模式控制的参数（目标 I）。在目标 II 中，我将使用这些参数来因果关系 控制纺锤体的产生并探讨纺锤体类型是否依赖于 TRN 诱导位点。在目标 III 中，我将使用体感刺激来测试纺锤体表达是否以特定方式减弱感觉输入。这些目标将直接检验有关纺锤体表达和功能的重要假设，从而更深入地了解精神分裂症和失神发作的发病机制。此外，深入了解丘脑放电模式有助于感觉信息路由的原理将与设计用于增强感觉功能和认知的神经修复体相关。重要的是，这个提案将使我能够在小鼠身上学习光遗传学、电生理学和行为技术。克里斯托弗·摩尔和马修·威尔逊。我将在埃默里·布朗博士的指导下学习统计和分析技术。我未来的职业目标是将我的临床经验与啮齿动物研究相结合，领导一个超越物种界限的转化研究项目。我将使用人类模型来寻找神经精神疾病的电生理内表型，并使用啮齿动物模型来在生理条件和疾病模型中对这些过程进行电路级解剖。 公共健康相关性：该项目将研究丘脑机制如何产生某种类型的皮质振荡（纺锤体），以及它们的表达对睡眠和感觉功能有何功能意义。纺锤体被认为对于睡眠稳定性、睡眠期间的感觉过滤和睡眠依赖性记忆巩固很重要。纺锤体减弱被认为与精神分裂症的病理生理学有关，而纺锤体过多则导致失神发作时尖峰放电和波放电的产生。因此，拟议的研究将对理解疾病机制和理性纠正方法产生广泛的影响。

DESCRIPTION (provided by applicant): In the mammalian brain, cortical disengagement from sensory processing is observed at multiple spatial and temporal scales. During active behavior, this process may alter routing of information relevant to selective attention, while during quiescence, it may be relevant for sleep stability and memory consolidation. Several lines of evidence suggest that cortical disengagement is mediated by thalamo-cortical dynamics, including spindle oscillations. Spindles are discrete 7- 15Hz cortical oscillations linked to activty of the thalamic reticular nucleus (TRN), a group of GABAergic cells surround the dorsal thalamus. Attenuated spindles are observed in schizophrenia, and may contribute to the sensory gating deficits observed in this disorder, while hypersynchronous spindles are thought to represent spike and wave discharges (SWDs) of absence epilepsy; the inappropriate expression of sensory disengagement during active waking. Despite their discovery seven decades ago, the basic phenomenology of spindles is undergoing major revision. While surface electroencephalographic (EEG) recordings in humans and local field potential (LFP) recordings in anesthetized animals have shown spindles to be coherent across cortical areas, recent human magnetoencephalographic (MEG) and implanted electrode recordings have revealed local expression of these events, suggesting that spindles have a local computational value linked to their roles in sensory filtering and memory. Using newly developed light-weight multi-electrode microdrives, I will record and manipulate electrophysiological activity across multiple sectors of the TRN in freely behaving mice. I will first refine an optogenetic approach that I have been using to determine the parameters under which local, modality-specific, control of TRN and related neocortex can be controlled (Aim I). In Aim II, I will use these parameters to causally control spindle generation and explore whether spindle type is dependent on the locus of TRN induction. In Aim III, I will test whether spindle expression attenuates sensory input in a modality-specific manner using somatosensory stimulation. These aims will directly test an important hypothesis about spindle expression and function, leading to greater insight into the pathogenesis of schizophrenia and absence seizures. In addition, insight into the principles by which thalamic firing modes contribute to routing of sensory information will be relevant to designing neural prosthetics for augmenting sensory function and cognition. Importantly, this proposal will allow me to learn optogenetic, electrophysiological, and behavioral techniques in mice, under the mentorship of Drs. Christopher Moore and Matthew Wilson. I will learn statistical and analytic techniques under the mentorship of Dr. Emery Brown. My future career goal is to combine my clinical experience with rodent studies to lead a translational research program that transcends species boundaries. I will use the human model to look for electrophysiological endophenotypes of neuropsychiatric disorders, and the rodent model to perform circuit-level dissection of these processes under physiological conditions and in models of disease. PUBLIC HEALTH RELEVANCE: This project will investigate how a certain type of cortical oscillation, spindles, are generated by thalamic mechanisms, and what functional significance their expression has on sleep and sensory function. Spindles are thought to be important for sleep stability, sensory filtering during sleep and sleep-dependent memory consolidation. Attenuated spindles are thought to contribute to the pathophysiology of schizophrenia, while excess spindles underlie the generation of spike and wave discharges of absence seizures. The proposed research, therefore, will have broad implications in understanding disease mechanisms and approach to rational correction.