Injury and Recovery in Developing Brain

由于慢性缺氧和循环并发症，多达50%的低出生体重婴儿患有认知障碍。纵向研究表明，一些儿童在成年早期大脑体积和认知功能都会恢复，但这种恢复是可变的，这种改善的神经生物学基础尚不清楚。我们的慢性亚致死性缺氧损伤的小鼠模型复制了最初的皮质体积缺陷和脑室增大，以及随后的恢复，尽管一些神经元丢失和认知异常在这些小鼠中长期存在。确定神经元恢复背后的细胞和分子事件并找到加强这一过程的方法是该计划项目的共同目标。我们假设缺氧性脑损伤的恢复是由于耦合的神经源性/血管生成反应。这包括(1)神经干细胞和前体细胞的增殖，这需要神经干细胞和血管内皮细胞中特定的生长因子；(2)新生神经元和神经胶质细胞的生存，这需要改善新生细胞的能量代谢，以及神经和血管隔区的营养影响。该计划中的特定项目将通过生成特定组织和时间相关的功能丧失或获得的功能遗传模型来测试神经干细胞、少突胶质前体细胞和血管内皮细胞中几种增殖、存活和分化因子的功能。研究中的因子包括成纤维细胞生长因子2(FGF2)、表皮生长因子受体(EGFR)、TrkB及其配体脑源性神经生长因子(BDNF)、线粒体解偶联蛋白2(UCP2)和胃肠激素Ghrelin。阐明这些基因在特定细胞类型中的作用，将揭示在标准或丰富的环境中动物从损伤中恢复时，血管、神经和代谢成分之间的相互作用和动态作用。多学科的方法，包括形态计量学和免疫细胞化学分析，电子显微镜和电生理学，被用来评估所研究的信号系统是否有助于在丰富的低氧环境中触发的适应性变化。此外，将在细胞和行为水平上测试增强这些信号系统的特定组件的有益效果。这些研究的长期目标是确定新的治疗干预手段，以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 the 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 behavioral level. 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.