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层脱离感觉处理。在活动时，这一过程可能会改变与选择性注意相关的信息路径，而在静止时，这一过程可能与睡眠稳定性和记忆巩固有关。一些证据表明，皮层脱离是由丘脑-皮层动力学介导的，包括纺锤波振荡。纺锤波是离散的7- 15Hz皮层振荡，与丘脑网状核（TRN）的活动有关，TRN是一组环绕丘脑背侧的gaba能细胞。在精神分裂症中观察到减弱的纺锤波，并可能导致这种疾病中观察到的感觉门控缺陷，而超同步纺锤波被认为代表缺席癫痫的尖峰和波放电（SWDs）；清醒时不恰当的感觉脱离的表现。尽管它们在70年前就被发现了，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，这表明纺锤波具有局部计算价值，与其在感觉过滤和记忆中的作用有关。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多个部门的电生理活动。我将首先完善我现有的光遗传学方法

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.