Injury and Recovery in Developing Brain

多达50%的低出生体重儿因慢性缺氧和循环而患有认知障碍 并发症。纵向研究表明，脑容量和认知功能在早期恢复 然而，在一些儿童成年后，这种恢复是可变的，其神经生物学基础 改进是不被理解的。我们的慢性亚致死性缺氧损伤小鼠模型复制了最初的 皮质容量不足和脑室增大，以及随后的恢复，尽管一些神经元丢失 而认知异常在这些小鼠身上长期存在。识别细胞和分子事件 这项计划的共同目标是进行潜在的神经元恢复，并找到加强这一过程的方法 项目。我们假设缺氧性脑损伤的恢复是由于神经源性/血管源性的耦合作用。 回应。这包括(1)神经干细胞和祖细胞的增殖，这需要特定的生长。 神经干细胞和血管内皮细胞中的因素；(2)新生神经元和神经胶质细胞的存活 种群，这需要改善新生成的细胞和营养物质中的能量代谢 来自神经和血管隔间的影响。该计划中的特定项目将测试这些 通过生成特定于组织的、与时间相关的功能丧失或获得的遗传模型来检验假设 几种增殖、存活和分化因子在神经干细胞、少突胶质细胞中的作用 祖细胞和血管内皮细胞。正在调查的因素包括成纤维细胞生长因子2 表皮生长因子受体(EGFR)、TrkB及其配体脑源性神经营养生长 BDNF、线粒体解偶联蛋白2(UCP2)和胃肠激素Ghrelin。澄清 这些基因在特定细胞类型中的作用将揭示 当动物从标准或强化的损伤中恢复时，血管、神经和代谢成分 环境。一种多学科的方法，包括形态计量和免疫细胞化学分析， 电子显微镜和电生理学被用来评估正在研究的信号系统 对低氧动物丰富的环境所引发的适应性变化做出贡献。此外， 增强这些信号系统的特定组件的有益效果将在细胞 和行为层面。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 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.