Network mechanisms for state-dependent consolidation of visual system plasticity

翻译后摘要：本项目的长期目标是确定丘脑皮质网络机制参与 巩固视觉系统中依赖经验的可塑性。睡眠对过程有好处 依赖于突触可塑性，如记忆巩固。最近的研究表明， 清醒感觉体验所涉及的区域在随后的慢波睡眠（SWS）期间被“重新激活”， 脑电图（EEG）振荡活动的局部变化。因为这些脑电振荡 由丘脑和皮层神经元有节奏的同步放电产生，一个未经验证的假设是， SWS丘脑皮质活动导致突触靶点的增强或抑制。取向特定 小鼠视觉系统中的反应增强（OSRP）涉及对视觉刺激的神经元反应的增强。 特定方向的刺激。OSRP通过短暂暴露于定向光栅刺激来启动，并且 在视觉体验之后的几个小时内巩固“离线”。我的初步数据显示 SWS时丘脑皮质纺锤体（7-14 Hz）活动在OSRP巩固中可能起关键作用。在 在建议奖励的指导阶段（目标1），我将：（a）测试SWS和SWS主轴振荡是否 （B）评估在巩固过程中，SWS纺锤体1）激活丘脑皮质 以非特异性方式介导丘脑皮质连接的“再激活”， 与先前的视觉体验一致。我将通过记录正在进行的活动和视觉反应来做到这一点 自由行为小鼠视觉皮层和外侧膝状体核神经元群体的特性 在基线、清醒视觉体验和随后的巩固期：随意睡眠，总 睡眠剥夺、快速眼动睡眠（REM）剥夺或SWS纺锤波的选择性中断。 这些研究将建立在我以前的多电极记录和数据分析研究经验的基础上， 在马科斯·弗兰克博士（我现任的博士后顾问和领域的专家）的共同指导下 睡眠和视觉皮层可塑性）和迭戈孔特雷拉斯（在国家依赖领域的专家 丘脑皮层网络特性和视觉中涉及的网络机制）。在指导阶段， 该奖项，我还将开发使用光遗传学技术与多电极相结合的专业知识 在自由行为的小鼠中进行记录，为目标2中概述的实验做准备。在独立阶段 奖项（目标2），我将使用这种最先进的技术相结合，以沉默定义的人群， 丘脑皮质、网状丘脑或皮质丘脑神经元在特定状态（清醒、REM或SWS）下， 测试在每个状态下丘脑皮质活动对于OSRP巩固的必要性。我假设 在SWS期间由这些神经元群体产生和协调纺锤体对于该过程是关键的。 总之，这些研究将揭示巩固可塑性所必需的状态依赖网络机制 根据视觉体验。

Abstract: The long-term goal of this project is to identify thalamocortical network mechanisms involved in consolidating experience-dependent plasticity in the visual system. Sleep has beneficial effects for processes dependent upon synaptic plasticity, such as memory consolidation. Recent studies have shown that cortical areas engaged by waking sensory experience are "reactivated" during subsequent slow wave sleep (SWS), with local changes in electroencephalogram (EEG) oscillatory activity. Because these EEG oscillations are generated by rhythmic, synchronous firing of thalamic and cortical neurons, one untested hypothesis is that SWS thalamocortical activity leads to potentiation or depression of synaptic targets. Orientation-specific response potentiation (OSRP) in the mouse visual system involves potentiation of neuronal responses to visual stimuli of a specific orientation. OSRP is initiated by brief exposure to an oriented grating stimulus, and is consolidated "offline" in the hours immediately following visual experience. My preliminary data suggest that thalamocortical spindle (7-14 Hz) activity during SWS may play a critical role in OSRP consolidation. In the mentored phase of the proposed award (Aim 1), I will: (a) test whether SWS and SWS spindle oscillations are required for OSRP, and (b) assess whether during consolidation, SWS spindles 1) activate thalamocortical connections in a non-specific manner, or 2) mediate "reactivation" of thalamocortical connections in a manner consistent with prior visual experience. I will do this by recording ongoing activity and visual response properties in populations of neurons in the visual cortex and lateral geniculate nucleus of freely-behaving mice during baseline, waking visual experience, and a subsequent consolidation period of either: ad lib sleep, total sleep deprivation, rapid eye movement sleep (REM) deprivation, or selective interruption of SWS spindles. These studies will build upon the my prior research experience with multielectrode recording and data analysis, under the co-mentorship of Drs. Marcos Frank (my current postdoctoral advisor and an expert in the areas of sleep and visual cortex plasticity) and Diego Contreras (an expert in the areas of state-dependent thalamocortical network properties and network mechanisms involved in vision). During the mentored phase of the award, I will also develop expertise in using optogenetic techniques in combination with multielectrode recording in freely-behaving mice, in preparation for experiments outlined in Aim 2. In the independent phase of the award (Aim 2), I will use this combination of state of the art techniques to silence defined populations of thalamocortical, reticular thalamic, or corticothalamic neurons during particular states (wake, REM, or SWS), to test the necessity of thalamocortical activity within each state for OSRP consolidation. I hypothesize that generation and coordination of spindles by these neuronal populations during SWS is critical for this process. Together, these studies will reveal state-dependent network mechanisms necessary for consolidating plasticity following visual experience.