Network mechanisms for state-dependent consolidation of visual system plasticity

摘要：该项目的长期目标是确定丘脑皮质的网络机制。 巩固视觉系统中依赖经验的可塑性。睡眠对进程有有益的影响 依赖于突触的可塑性，如记忆巩固。最近的研究表明，大脑皮质 在随后的慢波睡眠(SWS)期间，由觉醒的感觉体验所涉及的区域被重新激活， 伴随着脑电(EEG)振荡活动的局部变化。因为这些脑电振荡是 由丘脑和皮质神经元有节奏的同步放电产生的，一个未经检验的假设是 SWS丘脑皮质活动导致突触靶点的增强或抑制。特定于方向 小鼠视觉系统中的反应增强(OSRP)涉及神经元对视觉反应的增强 特定方向的刺激。OSRP是通过短暂暴露于定向光栅刺激而启动的，并且是 在紧随视觉体验之后的几个小时内整合了“离线”。我的初步数据显示 SWS期间丘脑皮质纺锤体(7-14赫兹)的活动可能在OSRP的巩固中起关键作用。在 在拟议奖项的指导阶段(目标1)，我将：(A)测试SWS和SWS主轴振荡是否 OSRP所需的，以及(B)评估在巩固过程中，SWS纺锤体1)激活丘脑皮质 以非特定方式连接，或2)以某种方式调节丘脑皮质连接的“重新激活” 与之前的视觉体验一致。我将通过记录正在进行的活动和视觉反应来做到这一点 自由活动小鼠视皮质和外侧膝状体神经元群体的特性 在基线期间，清醒的视觉体验，以及随后的整合期：临时睡眠，总计 睡眠剥夺、快速眼动睡眠(REM)剥夺或选择性中断SWS纺锤波。 这些研究将建立在我以前在多电极记录和数据分析方面的研究经验的基础上， 在Marcos Frank博士(我目前的博士后导师和以下领域的专家)的共同指导下 睡眠和视觉皮质可塑性)和Diego Contrera(状态依赖领域的专家 涉及视觉的丘脑皮质网络特性和网络机制)。在指导阶段 获奖后，我还将发展与多电极相结合的光遗传技术的专业知识。 在行为自由的小鼠中进行记录，为目标2中概述的实验做准备。在独立阶段 对于奖项(目标2)，我将使用这种最先进的技术组合来让特定的人群保持沉默 特定状态(WAKE、REM或SWS)的丘脑皮质、网状丘脑或皮质丘脑神经元 测试每个州内丘脑皮质活动对OSRP巩固的必要性。我假设 在SWS过程中，这些神经元群体产生和协调纺锤体是这一过程的关键。 总之，这些研究将揭示巩固塑性所必需的依赖于状态的网络机制 遵循视觉体验。

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.