Causal examination of TRN role in neocortical spindle generation and function

TRN 在新皮质纺锤体生成和功能中的作用的因果检验

基本信息

批准号：
8424238
负责人：
Michael M Halassa
金额：
$ 9.07万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8424238
关键词：
Absence Epilepsy Animals Area Arousal Astrocytes Attenuated Behavior Behavioral Brain Cell Nucleus Cells Chronic Clinical Cognition Dependence Disease Disease model Dissection Dorsal Educational process of instructing Electrodes Electroencephalography Electrophysiology (science)Event Frequencies Functional disorder Future Generations Goals Hippocampus (Brain)Human Implanted Electrodes In Vitro Lead Learning Light Link Machine Learning Mediating Memory Mentors Mentorship Modality Modeling Mus Nature Neocortex Neurologic Neurons Neurosciences Optics Pathogenesis Pennsylvania Physicians Physiological Postdoctoral Fellow Preparation Process Property Research Rodent Rodent Model Role Schizophrenia Scientist Sensory Sensory Process Site Sleep Sleep Architecture Spatial Distribution Surface Techniques Testing Thalamic structure Training Transcend Translational Research Universities career computational neuroscience computerized data processing design endophenotype experience genetic manipulation implantation in vivo inhibitory neuron insight light weight neocortical neural prosthesis neuropsychiatry novel optogenetics post-doctoral training prevent programs relating to nervous system role model selective attention sensory gating sensory system sleep regulation somatosensory tool translational neuroscience transmission process

项目摘要

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.

描述（由申请人提供）：在哺乳动物的大脑中，在多个空间和时间尺度上观察到来自感觉处理的皮质脱离。在主动行为期间，此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合并有关。几条证据表明，皮层脱离接触是由丘脑皮层动力学（包括主轴振荡）介导的。纺锤体是离散的7-15Hz皮质振荡，与丘脑网核（TRN）的活化有关，一组GABA能细胞围绕背侧丘脑。在精神分裂症中观察到减毒纺锤体，并可能导致这种疾病中观察到的感觉门控赤字，而超同步纺锤体被认为代表了缺有癫痫的尖峰和波浪放电（SWD）。主动唤醒过程中感觉脱离接触的不当表达。尽管他们发现了七十年前的发现，但纺锤体的基本现象学正在进行重大修订。虽然麻醉动物中人类的表面电脑图（EEG）记录（LFP）记录表明，纺锤体在皮质区域之间是一致的，最近的人类磁性（MEG）和植入电极记录和植入电极记录已经显示了这些事件的局部表达，这表明这些事件具有局部计算值链接到局部计算值中的内部孔子和记录。使用新开发的轻质多电极微晶体，我将在自由行为的小鼠中记录并操纵TRN多个扇区的电生理活性。我将首先完善一种我所拥有的光遗传学方法一直用于确定可以控制TRN和相关新皮层的局部，特定于模式的控制的参数（AIM I）。在AIM II中，我将使用这些参数来因果关系控制主轴产生并探索主轴类型是否取决于TRN诱导的轨迹。在AIM III中，我将使用体感刺激来测试主轴表达是否以特异性方式减弱感觉输入。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缺勤的发病。此外，洞察丘脑射击模式有助于感官信息路由的原则将与设计神经假体有关以增强感觉功能和认知的影响。重要的是，该建议将使我能够在DR的指导下学习小鼠的光遗传学，电生理和行为技术。克里斯托弗·摩尔（Christopher Moore）和马修·威尔逊（Matthew Wilson）。我将在Emery Brown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，以领导超越物种边界的转化研究计划。我将使用人类模型来寻找神经精神疾病的电生理内表型，以及啮齿动物模型在生理状况和疾病模型中对这些过程进行电路级解剖。