The effects of arousal on microglial motility

项目摘要：小胶质细胞是一种免疫细胞，可以迁移到大脑，在早期驻留 发展，并构成抵御脑部感染、疾病和损伤的第一道防线。然而，最近 研究表明，小胶质细胞是生理脑中必不可少的参与者，并在 正常功能，如网络发育、突触可塑性和成人神经发生。而当 对小胶质细胞在健康和疾病中的双重作用的理解刺激了大量的研究， 大多数研究病理和生理事件中的小胶质细胞动力学的研究都有 在麻醉动物身上进行了实验，这些动物表现出一种类似慢波睡眠的状态。考虑到这种慢波睡眠 是小胶质细胞参与的过程中的关键组成部分，如促进突触发育、网络 维持和损伤后的恢复，这为小胶质细胞在脑损伤中发挥不同作用提供了可能性。 大脑取决于唤醒状态。在这里，我们将调查假设去甲肾上腺素信号在 清醒状态会抑制小胶质细胞的动力学。了解觉醒状态如何调节小胶质细胞的行为 对于了解这些细胞如何促进正常的大脑功能和疾病进展至关重要。它是 众所周知，睡眠有助于维持大脑的动态平衡，促进正常的神经过程。 睡眠质量的中断会损害行为表现，抑制学习和记忆，并导致负面影响 在许多神经病理中的结果。虽然睡眠对大脑影响的生物学基础目前是 未知，我们假设小胶质细胞在睡眠状态下的稳态和免疫功能起着重要作用。 角色。小胶质细胞在基本生理条件下具有高度的运动性，动态观察突触和 在生理(如学习和记忆)过程中促进突触强度的变化 病理性(如兴奋性毒性)事件。我们的初步实验表明，小胶质细胞的运动性显著 在清醒的动物中减少，这表明小胶质细胞监视主要发生在睡眠中。在这里，我们将 通过比较小胶质细胞的动力学和它们与突触结构的相互作用来进一步探索这一点 体内麻醉、清醒和自然睡眠的动物Aim1。在目标2中，我们将确定 去甲肾上腺素能信号负责觉醒对小胶质细胞动力学的影响，以及 去甲肾上腺素直接向小胶质细胞传递信号，或通过改变细胞外间隙来传递信号。这两个目标是经过设计的 对觉醒在小胶质细胞动力学中所起的作用进行深入研究。

Project summary: Microglia are immune cells that migrate to the brain, taking up residency early in development, and constitute the first line of defense against brain infection, disease and injury. However, recent studies have shown that microglia are essential participants in the physiological brain and play critical roles in normal functions such as network development, synaptic plasticity and adult neurogenesis. While the understanding of the dual roles of microglia in health and disease has stimulated numerous lines of research, the majority of studies investigating microglial dynamics during both pathological and physiological events have been carried out in anesthetized animals, which exhibit a slow-wave sleep-like state. Given that slow-wave sleep is a critical component in microglia-implicated processes such as facilitating synaptic development, network maintenance, and post-injury recovery, this leaves open the possibility that microglia have different roles in the brain depending on arousal state. Here we will investigate the hypothesis that noradrenergic signaling during wakefulness dampens microglial dynamics. Understanding how arousal state modulates microglial behavior will be critical to understanding how these cells contribute to normal brain function and disease progression. It is well established that sleep helps maintain brain homeostasis and facilitates normal neurological processes. Disruptions in sleep quality can impair behavioral performance, inhibit learning and memory, and lead to negative outcomes in numerous neuropathologies. While the biological basis for sleep’s effects on the brain is currently unknown, we posit that homeostatic and immune functions of microglia during sleep states play an important role. Microglia are highly motile under basal physiological conditions, dynamically surveying synapses and contributing to changes in synaptic strength during both physiological (e.g. learning and memory) and pathological (e.g. excitotoxicity) events. Our preliminary experiments show that microglial motility is significantly reduced in awake animals, suggesting that microglial surveillance occurs primarily during sleep. Here we will explore this further by comparing the dynamics of microglia and their ability to interact with synaptic structure in vivo in anesthetized, awake and naturally sleeping animals in Aim1. In Aim 2 we will determine whether noradrenergic signaling is responsible for the effects of wakefulness on microglial dynamics and whether noradrenaline signals directly to microglia or through changes in extracellular space. The two aims are designed to provide a thorough investigation into the role arousal plays on microglial dynamics.