Network mechanisms for state-dependent consolidation of visual system plasticity

描述（由申请人提供）：摘要：本项目的长期目标是确定丘脑皮层网络机制参与巩固经验依赖的可塑性在视觉系统。睡眠对依赖于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，清醒感觉体验所涉及的皮层区域被“重新激活”，脑电图（EEG）振荡活动发生局部变化。由于这些EEG振荡是由丘脑和皮层神经元的节律性同步放电产生的，因此一个未经检验的假设是SWS丘脑皮层活动导致突触靶点的增强或抑制。小鼠视觉系统中的方向特异性反应增强（OSRP）涉及神经元对特定方向的视觉刺激的反应增强。OSRP通过短暂暴露于定向光栅刺激而启动，并且在视觉体验之后的几个小时内被“离线”巩固。我的初步数据表明，丘脑皮层纺锤体（7-14赫兹）活动在SWS可能发挥关键作用，在OSRP巩固。在建议奖励的指导阶段（目标1），我将：（a）测试SWS和SWS纺锤波振荡是否是OSRP所需的，以及（B）评估在巩固过程中，SWS纺锤波是否1）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的视觉皮层和外侧膝状体核中神经元群体的持续活动和视觉反应特性来做到这一点，在基线，清醒的视觉体验和随后的巩固期：随意睡眠，完全睡眠剥夺，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之前的多电极记录和数据分析研究经验的基础上，在Marcos Frank博士（我目前的博士后顾问，睡眠和视觉皮层可塑性领域的专家）和Diego Contreras（视觉相关的状态依赖性丘脑皮层网络特性和网络机制领域的专家）的共同指导下。在该奖项的指导阶段，我还将发展在自由行为小鼠中使用光遗传学技术与多电极记录相结合的专业知识，为目标2中概述的实验做准备。在该奖项的独立阶段（目标2），我将使用这种最先进的技术的组合，以沉默特定状态（清醒，REM或SWS）丘脑皮质，网状丘脑或皮质丘脑神经元的定义群体，以测试在每个状态下的丘脑皮质活动的必要性OSRP巩固。我推测，在SWS过程中，这些神经元群体的纺锤体的产生和协调对这一过程至关重要。总之，这些研究将揭示状态依赖的网络机制，巩固可塑性的视觉体验。 公共卫生相关性：相关性：这些研究将为睡眠和清醒状态如何独特地促进视觉系统中的突触可塑性提供新的见解。由于记忆形成等认知过程依赖于类似的可塑性机制，这些实验的发现可能最终导致认知和睡眠模式受到不利影响的疾病的新治疗方法-如阿尔茨海默病，精神分裂症和自闭症。

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.