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

项目总结 睡眠和清醒等行为状态深刻地影响着体内的活动模式 新皮质回路，但这些状态的功能依赖于经验而改变 发育和可塑性仍然存在争议。一种有影响力的理论，突触动态平衡 假说(或害羞)，提出睡眠起到自稳作用，使突触重新正常化 力量/射击率被清醒状态中依赖经验的变化所扰乱。 我的实验室研究稳定视觉皮质内放电频率的稳态机制。 在自由活动的动物的初级视觉皮质(V1)中，可以跟踪这一过程。 我们已经证明，通过单眼视觉剥夺(MD)来扰乱大鼠的放电率 单眼V1最初抑制放电(1-2d MD)，但随后放电频率反弹以控制 在2天的时间内(MD3-4)的水平，尽管持续MD。这次恢复射击是 部分是通过突触放大兴奋性突触到锥体神经元来实现的 在V1中。我们可以使用慢性记录来跟踪这个放电率动态平衡的过程 行为自由的动物在短暂的睡眠和醒来之间骑车，允许我们 直接确定放电的动态平衡恢复是在睡眠期间还是在睡眠期间 醒醒吧。令人惊讶的是，我们发现向上的放电率动态平衡(向上的FRH)发生 在每一轮主动唤醒期间逐渐增加，但在相当清醒和睡眠期间被抑制 (Hengen等人，2016)。因此，与害羞假说形成鲜明对比的是，向上的自我平衡 可塑性发生在醒着的时候，而不是在睡眠中。在这里，我们建议将这些发现扩展到 向下稳态可塑性，探讨清醒/睡眠状态的特点 启用/抑制内稳态可塑性，并确定相反形式的可塑性 (如Hebbian LTP和Synaptic Down Scaling)被分为不同的行为状态。 这些实验有望阐明大脑皮层生理学的基本特征，并 阐明睡眠和清醒大脑状态在协调突触可塑性中的作用 新皮质环路内的感应。

PROJECT SUMMARY Behavioral states such as sleep and wake profound affect the patterns of activity within neocortical circuits, but the function of these state changes on experience-dependent development and plasticity remain controversial. An influential theory, the synaptic homeostasis hypothesis (or SHY), proposes that sleep serves to homeostatically “renormalize” synaptic strengths/firing rates that were perturbed by experience-dependent changes in the waking state. My lab studies the homeostatic mechanisms that stabilize firing rates within visual cortical microcircuits, and can track this process in primary visual cortex (V1) of freely behaving animals. We have shown that perturbing firing rates through monocular visual deprivation (MD) in monocular V1 initially suppresses firing (1-2d MD), but that firing rates then rebound to control levels over a 2 d period (MD3-4) despite continued MD. This restoration of firing is accomplished in part through synaptic scaling up of excitatory synapses onto pyramidal neurons within V1. We can follow this process of firing rate homeostasis using chronic recordings in freely behaving animals that are cycling between short bouts of sleep and wake, allowing us to directly determine whether the homeostatic restoration of firing occurs during sleep or during wake. Surprisingly, we found that upward firing rate homeostasis (upward FRH) occurs gradually during each bout of active wake, but is suppressed during quite wake and sleep (Hengen et al., 2016). Thus, in striking contrast to the SHY hypothesis, upward homeostatic plasticity happens during wake, not sleep. Here we propose to extend these findings to downward homeostatic plasticity, to explore the features of waking/sleeping states that enable/suppress homeostatic plasticity, and to determine whether opposing forms of plasticity (such as Hebbian LTP and synaptic downscaling) are segregated into distinct behavioral states. These experiments promise to illuminate a fundamental feature of cortical physiology, and to shed light on the function of sleeping and waking brain states in coordinating synaptic plasticity induction within neocortical circuits.