Injury and Recovery in Developing Brain

多达50%的低出生体重婴儿由于慢性缺氧和循环系统疾病而患有认知缺陷。 并发症纵向研究表明，早期脑容量和认知功能恢复 然而，这种恢复是可变的，其神经生物学基础是 改进是不被理解。我们的慢性亚致死性缺氧损伤小鼠模型再现了最初的 皮质容量不足和脑室扩大，以及随后的恢复，虽然一些神经元损失 并且认知异常在这些小鼠中长期存在。识别细胞和分子事件， 神经元恢复的基础和寻找方法来加强这一进程是该计划的共同目标 项目我们假设缺氧性脑损伤的恢复是由于神经源性/血管生成性的耦合作用。 反应这包括（1）神经干细胞和祖细胞的增殖，这需要特异性生长 神经干细胞和血管内皮细胞因子;（2）新生神经元和神经胶质细胞的存活 种群，这需要在新产生的细胞和营养改善能量代谢 神经和血管的影响。本计划中的具体项目将测试这些 通过生成组织特异性和时间依赖性功能丧失或获得遗传模型来测试假设 神经干细胞、少突胶质细胞、神经胶质细胞和神经胶质细胞中的增殖、存活和分化因子的作用 祖细胞和血管内皮。正在研究的因素包括成纤维细胞生长因子2 （FGF 2）、表皮生长因子受体（EGFR）、TrkB及其配体脑源性向神经生长 脑源性神经营养因子（BDNF）、线粒体解偶联蛋白2（UCP 2）和肠激素生长激素释放肽。阐明 这些基因在特定细胞类型中的作用将揭示它们之间的相互作用和动态相互作用。 血管、神经和代谢成分，因为动物从标准或富集的损伤中恢复。 环境一种多学科方法，包括形态测量和免疫细胞化学分析， 电子显微镜和电生理学，用于评估是否正在研究的信号系统， 有助于缺氧动物的丰富环境引发的适应性变化。而且 增强这些信号传导系统的特定组分的有益效果将在细胞内进行测试。 行为层面。这些研究的长期目标是确定新的治疗干预手段 减少早产的发育障碍和神经行为后遗症。

As many as 50% of low-birth-weight infants suffer cognitive deficits due to chronic hypoxia and circulatory complications. Longitudinal studies suggest recovery in both brain volume and cognitive functions by early adulthood in some children, however this recovery is variable and the neurobiological basis of this improvement are not understood. Our mouse model of chronic sublethal hypoxic injury reproduces the initial cortical volume deficit and ventriculomegaly, as well as the subsequent recovery, although some neuron loss and cognitive abnormalities persist long-term in these mice. Identifying tlie cellular and molecular events that underlie neuronal recovery and finding ways to enhance this process are the common goals of this program project. We hypothesize that recovery from hypoxic brain injury is due to a coupled neurogenic/angiogenic response. This includes (1) proliferation of neural stem cells and progenitors, which requires specific growth factors in neural stem cells and vascular endothelium; (2) survival of newly-born neuronal and glial populations, which requires improved energetic metabolism in the newly-generated cells and trophic influences from neural and vascular compartments. Specific projects in this program will test these hypotheses by generating tissue-specific and time-dependent loss- or gain-of function genetic models to test the function of several proliferative, survival and differentiation factors in neural stem cells, oligodendrocyte progenitors, and vascular endothelium. The factors under investigation include Fibroblast growth factor 2 (FGF2), the Epidermal growth factor receptor (EGFR), TrkB and its ligand Brain derived neurotropic growth factor (BDNF), the mitochondrial uncoupling protein 2 (UCP2) and the gut hormone ghrelin. Elucidating the role of these genes in specific cell types will reveal the reciprocal and dynamic interactions between vascular, neural and metabolic components as the animals recover from injury in standard or enriched environment. A multidisciplinary approach, which includes morphometric and immunocytochemical analyses, electron microscopy and electrophysiology, is used to assess whether the signaling systems under study contribute adaptive changes triggered by the enriched environment in hypoxic animals. Furthermore, the beneficial effect of enhancing specific components of these signaling systems will be tested at the cellular and behaviorallevel. The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth.