Selective subplate vulnerability and cortical plasticity

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方式损害大脑。有证据表明，选择性细胞脆弱性有助于不同的模式与年龄相关的缺氧缺血性损伤。在人类脑室周围白色物质损伤的啮齿动物模型中，我们确定早期缺氧缺血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。亚板神经元需要活动依赖性的形成，完善和成熟的图案丘脑皮质连接，并可能发挥作用的独特能力的新生儿大脑的可塑性在定义的关键时期。我们已经开发了一种纯化亚板神经元的方法，代表了第一个层特异性皮层神经元培养物，并报道了促进亚板神经元存活的因素，包括一种新的p75 NTR依赖性神经酰胺信号通路。与它们在体内的选择性脆弱性相一致，培养的亚板神经元比年龄匹配的混合皮层神经元培养物对氧-葡萄糖剥夺更敏感。我们的目标是：1）确定选择性亚板神经元死亡对随后的皮质可塑性的意义; 2）利用纯化的亚板神经元来确定选择性亚板神经元脆弱性的机制。我们推测，选择性亚板神经元死亡后，早期缺氧缺血损害活动依赖性皮层可塑性。我们将量化早期缺氧缺血后的活动依赖性皮层可塑性和预防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的结果从改变神经营养因子介导的p75 NTR依赖性信号，我们将调查这与免疫纯化培养的亚板神经元暴露于氧葡萄糖剥夺。最后，我们假设在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。

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.