Neural Circuit Control of Postnatal Quiescent Neural Stem Cell Activation

摘要 越来越清楚的是，系统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的理解，但在很大程度上仍然不清楚 神经回路活动模式可能对神经干细胞增殖和分化的作用 发展啮齿类动物出生后侧脑室（LV）生殖基质/神经源性生态位是一个重要的神经系统， 专门的环境，容纳GFAP+星形胶质细胞作为NSC，主要产生GABA能 中间神经元它类似于出生后的人左心室胚基质， 持续到出生后两年。出生后左心室龛作为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。出生后LV 神经发生受NSC-intrinsic机制调节，与细胞外/生态位驱动的线索相互作用。 人们普遍认为，这些局部效应是维持神经发生的原因， 尽管行为模式和疾病状态已经暗示了神经回路水平的可能性， 调制目前尚不清楚神经元组或离散神经回路的活动模式， 能够对外界刺激做出反应并控制出生后大脑中的NSC增殖。我们已经确定 长距离神经元投射，可为出生后LV内的局部神经元提供兴奋性驱动 利基我们的初步结果已经揭示了这一假定的下游目标， 未描述的神经回路，静止的神经干细胞，表明外部神经元之间存在令人兴奋的联系。 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LV NSC增殖;和3）出生后放射状胶质祖细胞，及其 活动依赖的成熟过程，负责构建神经回路， 静止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 和出生后神经干细胞的增殖。为了使这个研究问题易于处理，我们有 开发了新的小鼠试剂，以及实验平台，以测量 神经元活动和NSC增殖的模式。我们相信这些实验的结果 显著推进了我们对神经回路活动如何控制干细胞增殖的理解。 产后大脑的健康和疾病。

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.