Network mechanisms for state-dependent consolidation of visual system plasticity

摘要：本项目的长期目标是确定参与巩固视觉系统经验依赖可塑性的丘脑皮质网络机制。睡眠对依赖突触可塑性的过程有有益的影响，如记忆巩固。最近的研究表明，在随后的慢波睡眠（SWS）中，由清醒感觉体验参与的皮层区域被“重新激活”，并伴有脑电图（EEG）振荡活动的局部变化。由于这些脑电图振荡是由丘脑和皮层神经元有节奏的同步放电产生的，一个未经验证的假设是，SWS丘脑皮层活动导致突触目标的增强或抑制。定向特异性反应增强（orientation -specific response potentiation， OSRP）是小鼠视觉系统中神经元对特定方向的视觉刺激反应的增强。OSRP是由短暂暴露于定向光栅刺激引发的，并在视觉体验后的几个小时内“离线”巩固。我的初步数据表明，在SWS期间，丘脑皮质纺锤体（7-14 Hz）的活动可能在OSRP巩固中起关键作用。在拟议奖励的指导阶段（目标1），我将：（a)测试OSRP是否需要SWS和SWS纺锤波振荡，(b)评估在巩固过程中，SWS纺锤波是否以非特异性方式激活丘脑皮质连接，或2）以与先前视觉经验一致的方式介导丘脑皮质连接的“再激活”。我将通过记录自由行为小鼠在基线、清醒的视觉体验和随后的巩固期（随机睡眠、完全睡眠剥夺、快速眼动睡眠剥夺或选择性地中断SWS纺锤波）期间视觉皮层和外侧束状核神经元群的持续活动和视觉反应特性来做到这一点。这些研究将建立在我之前的研究经验，多电极记录和数据分析，在博士的共同指导下。马科斯·弗兰克（Marcos Frank）（我目前的博士后导师，睡眠和视觉皮层可塑性领域的专家）和迭戈·孔特雷拉斯（Diego Contreras）（视觉中状态依赖性丘脑皮层网络特性和网络机制领域的专家）。在该奖项的指导阶段，我还将开发将光遗传学技术与自由行为小鼠的多电极记录相结合的专业知识，为Aim 2中概述的实验做准备。在该奖项的独立阶段（目标2），我将结合最先进的技术，在特定状态（清醒、REM或SWS）中沉默丘脑皮质、网状丘脑或皮质丘脑神经元的特定群体，以测试每种状态下丘脑皮质活动对OSRP巩固的必要性。我推测，这些神经元群在SWS过程中产生和协调纺锤体对这一过程至关重要。总之，这些研究将揭示巩固视觉经验后可塑性所必需的状态依赖网络机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Relevance: The proposed studies will provide new insights into how sleep and wake states uniquely contribute to synaptic plasticity in the visual system. Because cognitive processes such as memory formation rely on similar plasticity mechanisms, findings from these experiments may ultimately lead to novel treatments for disorders where both cognition and sleep patterns are adversely affected - such as Alzheimer's disease, schizophrenia, and autism.