Possible roles for sleep states and neuromodulation in sleep-dependent plasticity

描述（由申请人提供）：睡眠存在的根本问题是有争议的。睡眠在神经元可塑性中起作用的假设已经得到了皮质可塑性的一个典型模型的支持，即猫脑中的眼优势可塑性（ODP）。在猫的视觉皮层（VI）中，大多数神经元对两只眼睛的反应都一样好；然而，在生命早期剥夺一只眼睛的视觉输入（单眼剥夺，MD）会增加优先响应非被剥夺眼睛的细胞数量[3,4]。MD诱导的ODP在随后的睡眠中得到增强，表明睡眠在可塑性[2]的巩固中起作用。此外，一些与可塑性有关的蛋白质在md后睡眠期间被激活。然而，快速眼动（REM）和非快速眼动（NREM）睡眠状态在这一过程中的作用尚不清楚。这些状态都具有独特的神经调节音调和离子通道激活的特征，并可能在可塑性[6]中发挥不同但互补的作用。因此，本研究的目的是研究每种睡眠状态的需求（目的1）以及睡眠期间神经调节剂和离子通道活动（目的2）对睡眠依赖性ODP巩固的贡献。这些实验将深入了解神经回路发展的基本机制，以及新皮层记忆巩固，这被认为是长期记忆bbb形成和维持的基础。为了解决这些问题，猫将被植入电极来监测睡眠，并在醒着的时候接受6小时的MD治疗。在第一阶段，接下来是正常睡眠、剥夺快速眼动睡眠或非快速眼动睡眠碎片化睡眠。非快速眼动断裂是对快速眼动剥夺非特异性影响的一种控制。在Aim 2中，MD之后是睡眠，在此期间将神经调节剂和离子通道的特异性拮抗剂注入V1。对于这两个目标，将使用两种实验方法来量化操作对ODP巩固的影响。首先，操作对神经元活动的影响将通过皮质固有信号的光学成像和单单元记录进行评估。其次，操作对可塑性相关蛋白激活的影响将使用Western blot分析和免疫组织化学进行量化。睡眠不足与许多身心健康问题有关，是影响当今社会的一个主要公共卫生问题。这项研究将有助于阐明儿童时期睡眠不足对大脑发育的影响，以及对成人认知功能和记忆形成和维持的影响。

DESCRIPTION (provided by applicant): The fundamental question of why sleep exists is controversial [1]. The hypothesis that sleep plays a role in neuronal plasticity has been supported by work on a canonical model of cortical plasticity, ocular dominance plasticity (ODP) in the cat [2]. In the the cat visual cortex (VI), most neurons respond equally well to either eye; however, depriving one eye of visual input (monocular deprivation, MD) early in life increases the number of cells that respond preferentially to the non-deprived eye [3, 4]. ODP induction by MD is enhanced by subsequent sleep, indicating that sleep plays a role in the consolidation of plasticity [2]. Furthermore, several proteins involved in plasticity are activated during post-MD sleep [5]. However, the roles of rapid eye movement (REM) and non-REM (NREM) sleep states in this process are not understood. These states are both characterized by unique neuromodulatory tone and ion channel activation, and may play distinct but complementary roles in plasticity [6]. Therefore, the goal of this proposal is to investigate the requirement for each sleep state (Aim 1) and the contribution of neuromodulators and ion channel activity during sleep (Aim 2) to sleep-dependent ODP consolidation. These experiments will provide insight into fundamental mechanisms underlying the development of neural circuits, as well as neocortical memory consolidation, which is thought to underlie the formation and maintenance of long-term memory [7]. To address these questions, cats will be implanted with electrodes to monitor sleep and will undergo 6 hours of MD during waking. In Aim 1, this will be followed by normal, REM-deprived, or NREM-fragmented sleep. NREM fragmentation is a control for the nonspecific effects of REM deprivation. In Aim 2, MD will be followed by sleep during which specific antagonists of neuromodulators and ion channels will be infused into V1. For both aims, two experimental approaches will be used to quantify the impact of the manipulation on ODP consolidation. First, the effects of the manipulations on neuronal activity will be assessed using optical imaging of intrinsic cortical signals and single unit recording. Second, the effect of the manipulation on the activation of plasticity-related proteins will be quantified using Western blot analysis and immunohistochemistry. Getting inadequate amounts of sleep is linked to many physical and mental health issues and is a major public health problem that affects today's society [8]. This research will help elucidate the impact of sleep loss during childhood on brain development, as well as demonstrating the impact on cognitive function and the formation and maintenance of memories in adults.