Gating of Firing Rate Homeostasis by Sleep and Wake States During Experience-Dependent Plasticity

经验依赖性可塑性期间睡眠和清醒状态对放电率稳态的门控

• 批准号: 10396620
• 负责人: GINA G TURRIGIANO
• 金额: $ 48.43万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396620
• 关键词: Affect; Amblyopia; Animals; Arousal; Attention; Behavior; Behavioral; Brain; Excitatory Synapse; Eye; Funding; Gryllidae; Homeostasis; Human; Image; Influentials; Learning; Light; Long-Evans Rats; Neocortex; Pattern; Physiology; Population; Process; Resolution; Rodent; Role; Sensory; Sleep; Source; Synapses; Synaptic plasticity; Testing; V1 neuron; Vision; Visual; Visual Cortex; Visual impairment; Work; area striata; basal forebrain; cholinergic; design; effective therapy; experience; experimental study; hippocampal pyramidal neuron; improved; in vivo; insight; learned behavior; monocular; neocortical; neuroregulation; non rapid eye movement; optogenetics; response; restoration; scale up; segregation; theories; visual deprivation

Project Summary Behavioral states such as sleep and wake profoundly affect the patterns of activity and neuromodulatory tone within neocortical circuits, but the function of these state changes on learning and experience-dependent plasticity remain controversial. It has been postulated that wake is when Hebbian mechanisms are engaged, while sleep serves to homeostatically “renormalize” synaptic strengths/firing rates that were perturbed by experience-dependent changes in the waking state. We study the homeostatic plasticity mechanisms that stabilize firing rates and circuit function within primary visual cortex (V1), and can track this process in freely behaving rodents. Perturbing firing through monocular visual deprivation (MD) initially suppresses firing (1- 2d MD), but firing rates then rebound to control levels over a 2 d period despite continued MD. Further, we can perturb firing in the other direction using an MD followed by eye re-opening (ER) paradigm, and observed that firing rates are potentiated by ER and again slowly return to baseline values. This ‘firing rate homeostasis’ is accomplished in part through synaptic scaling up or down of excitatory synapses onto pyramidal neurons within V1. We can follow this process in freely behaving animals cycling between natural bouts of sleep and wake, to directly determine when the homeostatic restoration of firing occurs. In the last funding period we made the surprising discovery that upward and downward firing rate homeostasis are oppositely regulated by sleep and wake states: upward occurs gradually during each bout of active wake and is suppressed by sleep, while downward is enabled by sleep and suppressed by wake. Our work reveals that sleep and wake states are critically important for gating homeostatic plasticity, and act to segregate upward and downward homeostatic processes into distinct behavioral states. How this is accomplished mechanistically is entirely unknown, as is the function this segregation might serve. Here we propose to determine the features of waking/sleeping states that enable/suppress firing rate homeostasis, and to test whether the underlying synaptic plasticity mechanisms are themselves directly gated by sleep and wake. Finally, to gain insight into the behavioral/functional consequences of this gating, we propose to test how sleep and wake orchestrate Hebbian and homeostatic plasticity within V1 during a vision-dependent learning task. These experiments promise to illuminate fundamental features of visual cortical physiology, and to shed light on the function of sleep and wake states in coordinating synaptic plasticity during learning.

项目摘要 睡眠和清醒等行为状态深刻地影响着活动模式和神经调节张力 在新皮质回路内，但这些状态的功能改变对学习和经验依赖 可塑性仍然存在争议。据推测，觉醒是当Hebbian机制接合时， 而睡眠起到的作用是使受到干扰的突触强度/放电率自恒定地重新正常化 清醒状态中依赖经验的变化。我们研究了动态平衡的可塑性机制 稳定初级视觉皮质(V1)内的放电频率和电路功能，并可以自由跟踪这一过程 表现得像啮齿类动物。通过单眼视觉剥夺(MD)干扰放电最初抑制放电(1- 2D MD)，但尽管MD仍在持续，但射速随后在2 d时间内反弹至控制水平。此外，我们还可以 使用MD的另一个方向的扰动放电，然后是眼睛重新睁开(ER)范式，并观察到 发射频率被ER增强，并再次缓慢地返回到基准值。这种‘射击率动态平衡’是 部分是通过突触放大或缩小兴奋性突触到锥体神经元来实现的 在V1中。我们可以在自由行为的动物身上遵循这个过程，在自然睡眠和 唤醒，以直接确定何时发生放电的动态平衡恢复。在上一个资助期，我们 令人惊讶的发现，向上和向下的射率动态平衡是相反的调节 睡眠和觉醒状态：在每一轮活跃的觉醒过程中逐渐出现向上，并被睡眠抑制， 而向下则由睡眠启用，并由唤醒抑制。我们的研究表明，睡眠和清醒状态 对于控制动态平衡可塑性至关重要，并起到隔离向上和向下动态平衡的作用 过程进入不同的行为状态。这是如何机械地实现的，这是完全未知的。 这种隔离可能起到的作用。在这里，我们建议确定清醒/睡眠状态的特征 启动/抑制放电速率的动态平衡，并测试潜在的突触可塑性 机制本身直接由睡眠和觉醒控制。最后，为了深入了解 这种门控的行为/功能后果，我们建议测试睡眠和醒来是如何协调Hebbian的 在视觉依赖的学习任务中，V1内的稳态可塑性。这些实验承诺 阐明视觉皮质生理学的基本特征，并阐明睡眠和睡眠的功能 学习过程中协调突触可塑性的觉醒状态。