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

项目摘要 诸如睡眠和清醒的行为状态深刻地影响活动模式和神经调节张力 在新皮层回路，但这些国家的功能变化的学习和经验的依赖 可塑性仍然存在争议。有人假设尾流是赫布机制起作用的时候， 虽然睡眠用于稳态地“重新正常化”突触强度/放电速率， 清醒状态下的经验依赖性变化。我们研究了体内稳态可塑性机制， 稳定初级视觉皮层（V1）内的放电率和回路功能，并可以自由地跟踪这一过程 行为啮齿动物。通过单眼视觉剥夺（MD）的干扰放电最初抑制放电（1- 2d MD），但放电率然后反弹到控制水平，在2天的时间内，尽管继续MD。此外，我们可以 在另一个方向上使用MD然后再睁眼（ER）范例扰动放电，并观察到， 通过ER增强放电速率，并再次缓慢地返回到基线值。这种“放电率稳态”是 这部分是通过兴奋性突触在锥体神经元上的突触放大或缩小来实现的 在V1。我们可以在行为自由的动物中观察到这一过程， 唤醒，以直接确定何时发生放电的稳态恢复。在上一个融资期， 令人惊讶的发现，向上和向下的放电率稳态是相反的调节， 睡眠和清醒状态：向上在每次活跃清醒期间逐渐发生并且被睡眠抑制， 而向下则由睡眠启用并由唤醒抑制。我们的工作表明，睡眠和清醒状态是 对于门控稳态可塑性至关重要，并起到隔离向上和向下稳态的作用。 形成不同的行为状态。这是如何机械地完成是完全未知的，因为 这种隔离可能发挥的作用。在这里，我们建议确定清醒/睡眠状态的特征， 激活/抑制放电率稳态，并测试潜在的突触可塑性是否 这些机制本身直接由睡眠和清醒控制。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觉醒如何编排Hebbian 以及视觉依赖性学习任务中V1内的稳态可塑性。这些实验承诺， 阐明视觉皮层生理学的基本特征，并阐明睡眠的功能， 在学习过程中协调突触可塑性的唤醒状态。

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.