Neural Circuit Control of Postnatal Quiescent Neural Stem Cell Activation

产后静态神经干细胞激活的神经回路控制

基本信息

批准号：
10386923
负责人：
Henry Yin
金额：
$ 51.37万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-19 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10386923
关键词：
Action Potentials Anterior Antimitotic Agents Area Astrocytes Behavioral Behavioral Paradigm Biological Models Birth Brain Brain region Cell Differentiation process Cells Coupling Cues Defect Development Disease Environment Etiology Functional disorder Glial Fibrillary Acidic Protein Health Housing Human Interneurons Knock-in Knowledge Lateral Life Maintenance Measures Mediating Molecular Mus Neurons Neurophysiology - biologic function Pathway interactions Pattern Play Population Process Production Property Rabies Radial Reagent Research Resistance Resolution Rodent Role Signal Transduction Stimulus Subependymal Testing Ventricular cholinergic cholinergic neuron cingulate cortex developmental neurobiology experimental study extracellular in vivo insight lateral ventricle nerve stem cell neural circuit neural network neurogenesis neuronal patterning neuropsychiatric disorder neuroregulation newborn neuron novel optogenetics postnatal postnatal human postsynaptic progenitor programs public health relevance stem cell proliferation thrombospondin 4 transcriptomics

项目摘要

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.

抽象的越来越清楚的是，系统信号和外部刺激可以改变神经发育计划，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所了解，但仍不清楚到底是什么神经回路活动模式可能对 NSC 增殖和分化产生影响发展。啮齿动物出生后侧脑室（LV）生发基质/神经源性生态位是特殊环境容纳 GFAP+ 星形胶质细胞，充当 NSC，主要产生 GABA 能中间神经元。它类似于出生后的人类左心室生发基质，其中有强大的神经发生出生后持续长达两年。产后 LV 利基作为一个优秀的模型系统研究健康和疾病状态下调节神经发生的分子机制。产后左心室神经发生受到 NSC 内在机制的调节，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负责维持神经发生，尽管行为范式和疾病状态表明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是否可以对外部刺激做出反应并控制出生后大脑中 NSC 的增殖。我们已经确定长距离神经元投射，可为出生后左室的局部神经元提供兴奋驱动利基。我们的初步结果揭示了先前的假定下游目标未描述的神经回路，即静止的神经干细胞，表明外部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) 出生后左室静止 NSC 的细胞特性； 2）哪些大脑区域可以充当中继外部刺激诱导左室 NSC 增殖； 3）哪些出生后放射状胶质祖细胞及其依赖于活动的成熟过程，负责构建神经回路来指导 NSC 静态激活。我们的提案探讨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 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测量之间相互作用的实验平台神经元活动和 NSC 增殖的模式。我们相信这些实验的结果将显着增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。