Functional consequences of in vivo ablation of NG2 cells

NG2 细胞体内消融的功能后果

基本信息

批准号：
8189685
负责人：
DWIGHT E BERGLES
金额：
$ 24.6万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189685
关键词：
Ablation Accounting Action Potentials Acute Adult Anxiety Astrocytes Axon Behavior Biochemical Brain CSPG4 gene Cells Cessation of life Chronic Chronic Disease Cicatrix Corpus Callosum Demyelinations Development Disease Excision Exhibits Extracellular Space Hippocampus (Brain)Homeostasis Infarction Injury Interneurons Ischemia Knowledge Life Long-Term Potentiation Maps Membrane Membrane Potentials Memory Microglia Morphology Mus Myelin Sheath NG2 antigen Nerve Degeneration Neuraxis Neuroglia Neuronal Injury Neurons Neuropil Neurotransmitter Receptor Neurotransmitters Oligodendroglia Optic Nerve Paralysed Pathway interactions Physiological Population Population Heterogeneity Process Proliferating Property Pyramidal Cells Recovery Reflex action Resistance Rest Role Series Signal Transduction Site Slice Spinal Cord Stroke Synapses Synaptic Transmission Testing Therapeutic Transgenic Mice Visual Cortex behavior test central nervous system injury extracellular gray matter hippocampal pyramidal neuron in vivo information processing insight ischemic lesion neural circuit neuroregulation oligodendrocyte precursor postnatal precursor cell prevent progenitor repaired response response to injury therapeutic target white matter

项目摘要

DESCRIPTION (provided by applicant): The mammalian CNS contains an abundant, widely distributed population of glial progenitors known as NG2 cells (also termed oligodendrocyte precursor cells or polydendrocytes) that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although these cells retain the capacity to generate oligodendrocytes in the adult brain and spinal cord, most NG2 cells in the adult CNS do not differentiate and remain in a "progenitor" state. NG2 cells are arranged in a grid-like manner in all gray and white matter regions, extend highly ramified processes into the surrounding neuropil, and form direct synapses with neurons, raising the possibility that they modulate the activity of neurons and the flow of information through neural circuits. Moreover, NG2 cells proliferate, increase expression of NG2, and contribute to the formation of glial scars in response to both acute and chronic injury, suggesting that they may help limit neurodegeneration and promote repair. Nevertheless, our knowledge about the roles of these abundant glial cells, and the consequences of their change in behavior following ischemic injury, is very limited. To define the functions of NG2 cells in the adult brain, we recently developed transgenic mice that allow selective ablation of NG2 cells in vivo. Using these mice, NG2 cells can be removed from the brain without inducing reactive changes in astrocytes or microglial cells, or causing paralysis or death, indicating that this approach can be used to help define the functions of these ubiquitous glial cells. In the proposed studies, we will selectively ablate NG2 cells from the CNS in vivo, and examine whether their absence results in alterations in neuronal activity, signaling at synapses, axonal conduction, or specific aspects of behavior, such as spatial memory, anxiety, or sensorimotor control. In addition, we will examine whether removal of NG2 cells alters the response of other glial cells to focal ischemia and the extent of neuronal injury. Together, these exploratory studies have the potential to reveal new roles for this enigmatic population of glial cells in the adult brain, and deepen our understanding of interactions that occur between neurons and glial cells in physiological and pathological conditions. If NG2 cells participate in neuromodulation and CNS repair, they would represent an additional therapeutic target with the potential to reduce abnormal neuronal activity, prevent neurodegeneration in chronic disease, and promote recovery and repair following stroke. PUBLIC HEALTH RELEVANCE: This proposal seeks to determine whether an abundant, widely distributed population of glial cells in adult CNS influences the flow of information through neural circuits and promotes repair following ischemia. These studies have the potential to identify new pathways for regulating abnormal neuronal activity, as well as reducing injury and accelerating recovery after stroke.

描述（由申请人提供）：哺乳动物中枢神经系统含有丰富、分布广泛的神经胶质祖细胞群，称为 NG2 细胞（也称为少突胶质细胞前体细胞或多突胶质细胞），它们能够发育成少突胶质细胞，并在响应损伤和损伤时发生巨大变化。脱髓鞘。尽管这些细胞保留了在成人大脑和脊髓中生成少突胶质细胞的能力，但成人中枢神经系统中的大多数 NG2 细胞不会分化并保持在“祖细胞”状态。 NG2细胞在所有灰质和白质区域中以网格状排列，将高度分支的过程延伸到周围的神经纤维，并与神经元形成直接突触，这增加了它们通过调节神经元活动和信息流的可能性。神经回路。此外，NG2细胞会增殖，增加NG2的表达，并有助于急性和慢性损伤时神经胶质疤痕的形成，这表明它们可能有助于限制神经退行性变并促进修复。然而，我们对这些丰富的神经胶质细胞的作用以及缺血性损伤后行为变化的后果的了解非常有限。为了定义 NG2 细胞在成人大脑中的功能，我们最近开发了转基因小鼠，可以在体内选择性消融 NG2 细胞。使用这些小鼠，可以从大脑中去除 NG2 细胞，而不会引起星形胶质细胞或小胶质细胞的反应性变化，也不会导致瘫痪或死亡，这表明这种方法可用于帮助定义这些无处不在的胶质细胞的功能。在拟议的研究中，我们将选择性地在体内去除中枢神经系统中的 NG2 细胞，并检查它们的缺失是否会导致神经元活动、突触信号传导、轴突传导或行为的特定方面（例如空间记忆、焦虑或焦虑）的改变。感觉运动控制。此外，我们将检查去除 NG2 细胞是否会改变其他神经胶质细胞对局灶性缺血的反应以及神经元损伤的程度。总之，这些探索性研究有可能揭示成人大脑中这一神秘神经胶质细胞群的新作用，并加深我们对生理和病理条件下神经元和神经胶质细胞之间发生的相互作用的理解。如果NG2细胞参与神经调节和中枢神经系统修复，它们将代表一个额外的治疗靶点，有可能减少异常神经元活动，预防慢性疾病中的神经退行性变，并促进中风后的恢复和修复。公共健康相关性：该提案旨在确定成人中枢神经系统中丰富且分布广泛的神经胶质细胞群是否会影响神经回路的信息流动并促进缺血后的修复。这些研究有可能确定调节异常神经元活动、减少损伤和加速中风后恢复的新途径。