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：
10609460
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/10609460
关键词：
Action Potentials Anterior Antimitotic Agents Area Astrocytes Behavioral Behavioral Paradigm Biological Models Birth Brain Brain region Cell Differentiation process Cell Maintenance Cells Coupling Cues Defect Development Disease Environment Etiology Functional disorder Glial Fibrillary Acidic Protein Health Housing Human Interneurons Knock-in Knowledge Lateral Life Maps Measures Mediating Molecular Mus Neuroanatomy 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 line 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 differentiation stem cell fate specification 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，全身信号和外部刺激可以改变神经发育程序，以及早期的发育缺陷成为行为后遗症的重要贡献者后来生活。尽管我们目前对神经发生控制的理解，但仍不清楚什么功能神经电路活动模式可能会在NSC增殖和分化上发挥作用发展。啮齿动物产后侧心（LV）生发基质/神经源性小众是一个专业环境住房GFAP+星形胶质细胞起作用，主要是GABA能中间神经元。它类似于产后人LV生发基质，其中鲁棒神经发生出生后长达两年。产后LV利基是一个出色的模型系统在健康和疾病状态下，研究调节神经发生的分子机制。产后LV 神经发生受NSC intrinsic机制的调节，与细胞外/利基驱动的提示相互作用。人们普遍认为，这些局部影响负责维持神经发生，尽管行为范式和疾病状态提出了神经回路级别的可能性调制。目前尚不清楚神经元组或离散神经回路的活动模式是可以应对外部刺激并控制产后大脑中的NSC增殖。我们已经确定了远程神经元预测，可以为产后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发现了以前的推定下游目标未描述的神经回路，静态的NSC，表明外部有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进一步探索这些观察结果：1）产后LV静态NSC的细胞身份； 2）哪些大脑区域可以作为继电器外部刺激诱导LV NSC增殖； 3）哪些产后径向神经胶质祖细胞及其依赖活动的成熟过程，负责构建神经回路以指导静止的NSC激活。我们的建议探讨了神经元活动模式之间的直接联系来自离散电路和产后NSC增殖。为了使这个研究问题可以解决，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发现将显着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的产后大脑。