Selective subplate vulnerability and cortical plasticity

描述(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，选择性的细胞脆弱性导致了与年龄相关的不同类型的缺氧性缺血损伤。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-缺血导致板下神经元的选择性细胞死亡，板下神经元是发育中的大脑特有的细胞群体。下丘脑板下神经元是形成、完善和成熟丘脑皮质连接所必需的活动依赖性神经元，在特定的关键时期，它可能在新生儿大脑独特的可塑性能力中发挥作用。我们开发了一种纯化板下神经元的方法，代表了第一个板层特异性皮质神经元培养，并报道了促进板下神经元存活的因素，包括一种新的p75NTR依赖的神经酰胺信号通路。与体内选择性弱点一致，培养的下层神经元对缺氧-葡萄糖剥夺比年龄匹配的混合皮质神经元培养更敏感。我们的目标是1)确定选择性板下神经元死亡对随后皮质可塑性的意义，以及2)利用纯化的板下神经元来确定选择性板下神经元易损性的机制。我们假设，早期缺氧缺血后选择性板下神经元死亡会损害依赖活动的皮质可塑性。我们将量化早期缺氧-缺血和预防板下神经细胞死亡的干预措施后活动依赖的皮质可塑性。我们进一步假设，神经营养素介导的p75NTR依赖信号的改变导致了板下神经元的选择性脆弱性，我们将用暴露于氧和葡萄糖剥夺的板下神经元的免疫纯化培养来研究这一点。最后，我们假设，在体外保护板下神经元的治疗也将防止早期缺氧缺血后的板下神经元细胞死亡。

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.