Causal examination of TRN role in neocortical spindle generation and function

描述(申请人提供)：在哺乳动物的大脑中，在多个空间和时间尺度上观察到皮质脱离感觉处理。在活跃的行为中，这一过程可能会改变与选择性注意相关的信息的路径，而在静止时，这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-皮质动力学调节的，包括纺锤体振荡。纺锤波是与丘脑网状核(TRN)的活动有关的离散的7-15赫兹的皮质振荡，一组GABA能细胞环绕在丘脑背侧。在精神分裂症中观察到减弱的纺锤波，这可能是这种疾病中观察到的感觉门控缺陷的原因之一，而超同步纺锤波被认为代表失神癫痫的棘波放电(SWD)；在活跃的觉醒过程中感觉分离的不适当表达。尽管他们在70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。虽然人类的表面脑电(EEG)记录和麻醉动物的局部场电位(LFP)记录显示纺锤波跨皮质区域是一致的，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，表明纺锤波具有与其在感觉过滤和记忆中的作用有关的局部计算值。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跨TRN多个扇区的电生理活动。我将首先改进我拥有的光遗传学方法 一直用于确定可控制局部、特定通道的TRN和相关新皮质的参数(目标一)。在AIM II中，我将使用这些参数来因果 控制纺锤体的产生，并探索纺锤体类型是否依赖于TRN诱导的基因座。在目标III中，我将测试纺锤体的表达是否会使用体感刺激以一种特定于通道的方式减弱感觉输入。这些目的将直接检验关于纺锤体表达和功能的一个重要假说，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传递感觉信息的原理，将与设计神经假体以增强感觉功能和认知有关。重要的是，这项提议将使我能够在克里斯托弗·摩尔博士和马修·威尔逊博士的指导下，在小鼠身上学习光遗传学、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障碍的电生理内表型，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电路水平的剖析。

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.