Causal examination of TRN role in neocortical spindle generation and function

描述（由申请人提供）： 在哺乳动物的大脑中，皮层脱离感觉处理观察到在多个空间和时间尺度。在主动行为期间，这个过程可能会改变与选择性注意相关的信息的路由，而在静止期间，它可能与睡眠稳定性和记忆巩固有关。一些证据表明，皮质脱离是由丘脑-皮质动力学，包括纺锤体振荡介导的。Spectrometry是与丘脑网状核（TRN）活动相关的7- 15 Hz的离散皮层振荡，TRN是一组围绕背侧丘脑的GABA能细胞。在精神分裂症中观察到衰减的纺锤体，并且可能有助于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癫痫的棘波和波放电（SWD）;在主动清醒期间感觉脱离的不适当表达。尽管纺锤体的发现已有70年，但它的基本现象学正在经历重大的修正。虽然人类的表面脑电图（EEG）记录和麻醉动物的局部场电位（LFP）记录显示，纺锤波在皮层区域是连贯的，但最近的人类脑磁图（MEG）和植入电极记录显示了这些事件的局部表达，这表明纺锤波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。使用新开发的轻质多电极微驱动器，我将记录和操纵自由行为小鼠TRN多个部分的电生理活动。我将首先完善一种光遗传学方法， 已被用来确定参数下，局部，模态特异性，控制TRN和相关的新皮层可以控制（目的I）。在目标II中，我将使用这些参数来因果地 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。在目的III中，我将测试是否纺锤体表达减弱感觉输入的特定方式使用体感刺激。这些目标将直接测试一个重要的假设，纺锤体的表达和功能，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，洞察丘脑放电模式有助于路由的感觉信息的原则，将相关的设计神经假体增强感觉功能和认知。重要的是，这个建议将使我能够在克里斯托弗摩尔和马修威尔逊博士的指导下学习小鼠的光遗传学，电生理学和行为技术。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联合收割机结合我的临床经验与啮齿动物研究，领导一个超越物种界限的转化研究计划。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在生理条件下和疾病模型中对这些过程进行回路水平的解剖。

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.