Selective subplate vulnerability and cortical plasticity

选择性底板脆弱性和皮质可塑性

• 批准号: 6866027
• 负责人: Patrick Sean McQuillen
• 金额: $ 16.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866027
• 关键词: biological signal transduction; brain derived neurotrophic factor; cerebral ischemia /hypoxia; developmental neurobiology; early experience; gel mobility shift assay; growth factor receptors; hypoglycemia; hypoxia; immunocytochemistry; laboratory rat; neocortex; nerve growth factors; neural degeneration; neural plasticity; neurogenesis; neuroprotectants; neuroregulation; receptor expression; somesthetic sensory cortex; visual cortex; western blottings

DESCRIPTION (provided by applicant): Hypoxia-ischemia damages the brain in a developmental stage-specific and region selective manner. Evidence suggests that selective cellular vulnerability contributes to differing patterns of age-related hypoxicic schemic injury. In a rodent model of human periventricular white matter injury, we determined that early hypoxia-ischemia leads to the selective cell death of sub-plate neurons, a cell population unique to the developing brain. Sub-plate neurons are required for activity-dependent formation, refinement and maturation of patterned thalamocortical connections, and may play a role in the unique capacity of the neonatal brain for plasticity during defined critical periods. We have developed a method for purifying sub-plate neurons, representing the first lamina-specific cortical neuronal cultures and have reported the factors that promote sub-plate neuron survival including a novel p75NTR dependent ceramide signaling pathway. Consistent with their selective vulnerability in vivo, cultured sub-plate neurons are more sensitive to oxygen-glucose deprivation than age matched mixed cortical neuronal cultures. Our objectives in this proposal are 1) to determine the significance of selective sub-plate neuron death for subsequent cortical plasticity and 2) utilize purified sub-plate neurons to determine the mechanism of selective sub-plate neuron vulnerability. We hypothesize that selective sub-plate neuron death following early hypoxia-ischemia impairs activity-dependent cortical plasticity. We will quantify activity dependent cortical plasticity following early hypoxia-ischemia and interventions that prevent sub-plate neuron cell death. We hypothesize further that sub-plate neuron selective vulnerability results from altered neurotrophin-mediated p75NTR-dependent signaling and we will investigate this with immunopurified cultures of sub-plate neurons exposed to oxygen glucose deprivation. Finally, we hypothesize that treatments that protect sub-plate neurons in vitro will also prevent sub-plate neuron cell death following early hypoxia ischemia.

描述（由申请人提供）：缺氧缺血以发育阶段特异性和区域选择性的方式损害大脑。有证据表明，选择性细胞脆弱性导致了与年龄相关的缺氧缺血性损伤的不同模式。在人类脑室周围白质损伤的啮齿动物模型中，我们确定早期缺氧缺血会导致亚板神经元的选择性细胞死亡，亚板神经元是发育中大脑特有的细胞群。亚板神经元是丘脑皮层连接模式的活动依赖性形成、细化和成熟所必需的，并且可能在新生儿大脑在特定关键时期的独特可塑性能力中发挥作用。我们开发了一种纯化亚板神经元的方法，代表了第一个层板特异性皮质神经元培养物，并报告了促进亚板神经元存活的因素，包括新型 p75NTR 依赖性神经酰胺信号通路。与它们在体内的选择性脆弱性一致，培养的亚板神经元比年龄匹配的混合皮质神经元培养物对氧-葡萄糖剥夺更敏感。我们在此提案中的目标是 1）确定选择性亚板神经元死亡对随后皮质可塑性的重要性；2）利用纯化的亚板神经元确定选择性亚板神经元脆弱性的机制。我们假设早期缺氧缺血后选择性亚板神经元死亡会损害活动依赖性皮质可塑性。我们将量化早期缺氧缺血后的活动依赖性皮质可塑性以及防止亚板神经元细胞死亡的干预措施。我们进一步假设亚板神经元选择性脆弱性是由神经营养蛋白介导的 p75NTR 依赖性信号传导改变引起的，我们将通过暴露于氧糖剥夺的亚板神经元的免疫纯化培养物来研究这一点。最后，我们假设体外保护亚板神经元的治疗也将防止早期缺氧缺血后亚板神经元细胞死亡。