Neural Circuit Control of Postnatal Quiescent Neural Stem Cell Activation

摘要 越来越清楚的是，全身信号和外部刺激可以改变神经发育。 早期发育缺陷成为行为后遗症的重要因素 在以后的生活中。尽管我们目前对神经发生控制有了了解，但在很大程度上仍不清楚 神经回路活动模式在神经干细胞增殖和分化中的作用 发展。啮齿动物出生后侧脑室(LV)生发基质/神经源性壁龛是一种 专门的环境容纳GFAP+星形胶质细胞作为神经干细胞发挥功能，主要产生GABA能 中间神经元。它类似于出生后的人类LV生发基质，在那里有强大的神经发生 在出生后持续两年。出生后的LV生态位是一个很好的模型系统 研究在健康和疾病状态下调节神经发生的分子机制。产后LV 神经发生受NSC内在机制的调控，与细胞外/生态位驱动的信号相互作用。 人们普遍认为，这些局部效应是维持神经发生的原因， 虽然行为模式和疾病状态表明了神经回路水平的可能性 调制。目前尚不清楚是神经元组的活动模式，还是离散的神经回路， 能对外界刺激做出反应，控制神经干细胞在出生后脑内的增殖。我们已经确定了 可为出生后左室内局部神经元提供兴奋性驱动的远程神经元投射 利基市场。我们的初步结果已经揭示了这一假设的下游目标 未描述的神经回路，静止的神经干细胞，表明外部和外部之间存在兴奋的联系 输入和NSC激活。我们计划通过确定以下内容来进一步探索这些观察结果：1) 出生后LV静止神经干细胞的细胞特性；2)哪些脑区可以作为 外部刺激诱导左室神经干细胞增殖；3)出生后哪些放射状神经胶质前体细胞及其 依赖活动的成熟过程，负责构建神经回路来指导 静止的NSC激活。我们的建议探索了神经元活动模式之间的直接联系 来自离散电路和出生后NSC的增殖。为了让这个研究问题变得容易理解，我们有 开发了新的老鼠试剂，以及测量相互作用的实验平台 神经元活动和神经干细胞增殖的模式。我们相信这些实验的发现将会 显著提高了我们对神经回路活动如何控制干细胞增殖的理解 健康和疾病中的出生后大脑。

ABSTRACT It has become increasingly clear that systemic signals and external stimuli can alter neurodevelopmental programs, and that early developmental defects become significant contributors to behavioral sequelae later in life. Despite our current understanding of neurogenesis control, it remains largely unclear what functions neural circuit activity patterns may exert on NSC proliferation and differentiation during development. The rodent postnatal lateral ventricular (LV) germinal matrix/neurogenic niche is a specialized environment housing GFAP+ astrocytes functioning as NSCs, producing mainly GABAergic interneurons. It is analogous to the postnatal human LV germinal matrix, where robust neurogenesis persists for up to two years after birth. The postnatal LV niche serves as an excellent model system to study molecular mechanisms regulating neurogenesis, both in health and in disease states. Postnatal LV neurogenesis is regulated by NSC-intrinsic mechanisms, interacting with extracellular/niche-driven cues. It has been generally accepted that these local effects are responsible for sustaining neurogenesis, though behavioral paradigms and disease states have suggested possibilities for neural circuit-level modulations. It is currently unclear if activity patterns from groups of neurons, or discrete neural circuits, can respond to external stimuli and control NSC proliferation in the postnatal brain. We have identified long-range neuronal projections that can provide excitatory drive to local neurons within the postnatal LV niche. Our preliminary results have uncovered putative downstream targets of this previously undescribed neural circuit, the quiescent NSCs, suggesting an exciting connection between external inputs and NSC activation. We plan to further explore these observations by determining the following: 1) the cellular identity of the postnatal LV quiescent NSCs; 2) which brain regions can serve as a relay for external stimuli to induce LV NSC proliferation; and 3) which postnatal radial glial progenitors, and their activity-dependent maturation process, are responsible for constructing the neural circuits to direct quiescent NSC activation. Our proposal explores a direct connection between neuronal activity patterns from discrete circuits and postnatal NSC proliferation. To make this research question tractable, we have developed new mouse reagents, as well as experimental platforms to measure the interactions between patterns of neuronal activity and NSC proliferation. We believe findings from these experiments will significantly advance our understanding of how neural circuit activity controls stem cell proliferation in the postnatal brain in health and disease.