Network mechanisms for state-dependent consolidation of visual system plasticity

描述(申请人提供)：摘要：这个项目的长期目标是确定丘脑皮质网络机制，涉及巩固视觉系统中经验依赖的可塑性。睡眠对依赖突触可塑性的过程有有益的影响，例如记忆巩固。最近的研究表明，在随后的慢波睡眠(SWS)中，与觉醒感觉体验有关的大脑皮层区域被重新激活，脑电(EEG)振荡活动发生局部变化。由于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目标的增强或抑制。小鼠视觉系统中的方位特异性反应增强(OSRP)涉及神经元对特定方向视觉刺激的反应增强。OSRP是通过短暂暴露于定向栅格刺激而启动的，并在紧接视觉体验后的几个小时内被“离线”巩固。我的初步数据表明，SWS期间丘脑皮质纺锤体(7-14赫兹)的活动可能在OSRP巩固中发挥关键作用。在拟议奖项的指导阶段(目标1)，我将：(A)测试OSRP是否需要SWS和SWS纺锤摆动，以及(B)评估在巩固过程中，SWS纺锤1)以非特定方式激活丘脑皮质连接，或2)以与先前视觉体验一致的方式介导丘脑皮质连接的“重新激活”。为此，我将记录自由行为小鼠在基线、清醒视觉体验和随后的巩固期间：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纺锤波时，视皮层和外侧膝状体中神经元群体的持续活动和视觉反应特性。这些研究将建立在我之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，睡眠和视觉皮质可塑性领域的专家)和Diego Contrera博士(视觉相关的丘脑皮质网络特性和网络机制领域的专家)的共同指导下进行的。在奖项的指导阶段，我还将在自由行为的小鼠身上发展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。在奖项的独立阶段(目标2)，我将使用这种最新技术的组合来在特定状态(WAKE、REM或SWS)期间使特定人群的丘脑皮质、网状丘脑或皮质丘脑神经元静音，以测试每个状态中丘脑皮质活动的必要性，以巩固OSRP。我推测，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。总而言之，这些研究将揭示状态依赖的网络机制，这是巩固视觉经验后的可塑性所必需的。 公共卫生相关性：相关性：拟议的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会导致对认知和睡眠模式都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.