Functional consequences of in vivo ablation of NG2 cells

NG2 细胞体内消融的功能后果

• 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
• 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

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包含大量的，广泛分布的神经胶质祖细胞种群，称为NG2细胞（也称为少突胶质细胞前体细胞或多发性核细胞），它们具有发展为少突胶质细胞和遭受损伤和DemeLination响应的巨大变化的能力。尽管这些细胞保留在成年大脑和脊髓中产生少突胶质细胞的能力，但成年中枢神经系统中的大多数NG2细胞都没有区分并保持在“祖细胞”状态。 NG2细胞在所有灰色和白质区域中以网格状的方式排列，将高度分支的过程扩展到周围的神经胶体中，并用神经元形成直接的突触，从而提高了它们调节神经元活性和通过神经电路的信息流的可能性。此外，NG2细胞增殖，增加NG2的表达，并有助于响应急性和慢性损伤的胶质疤痕形成，这表明它们可能有助于限制神经变性并促进修复。然而，我们对这些丰富的神经胶质细胞的作用的了解以及它们在缺血性损伤后行为变化的后果非常有限。 为了定义成人大脑中NG2细胞的功能，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，而不会诱导星形胶质细胞或小胶质细胞的反应性变化，或引起麻痹或死亡，表明该方法可用于帮助定义这些无处不在的神经胶质细胞的功能。在拟议的研究中，我们将从体内选择性地从中枢神经系统中赋予NG2细胞，并检查它们的缺失是否导致神经元活性的改变，突触，轴突传导处的信号传导或行为的特定方面，例如空间记忆，焦虑，焦虑或感觉运动动物控制。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和神经元损伤的程度。总之，这些探索性研究有可能揭示成人大脑中神经胶质细胞的新作用，并加深我们对生理和病理条件下神经元与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，具有降低异常神经元活性，预防慢性疾病中神经退行性的潜力，并促进中风后康复和修复。 公共卫生相关性：该提案旨在确定成人中枢神经系统中大量的，广泛分布的神经胶质细胞种群是否会通过神经回路影响信息流，并在缺血后促进维修。这些研究有可能确定调节异常神经元活性的新途径，并减少中风后损伤和加速恢复。