DEVELOPMENTAL NEUROAPOPTOSIS IN NHP

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 广泛的研究表明，麻醉剂可以在发育中的啮齿动物CNS中产生广泛的凋亡（程序性细胞死亡）神经变性。 观察到的退化发生在突触发生期（神经元建立互连的时间）。 在灵长类动物中，这一时期包括子宫内生命的最后三个月和出生后生命的最初几个月。 在临床或药物滥用环境中，人类通常暴露于已发现会产生这种损害的物质。 由于啮齿动物和人类大脑结构的巨大差异，目前尚不清楚灵长类动物是否也可能对这些药物的相同神经毒性作用敏感。 确定这种损伤是否发生在灵长类动物的大脑中是非常必要的。 因此，本研究的广泛目标是检查这些不同类别的麻醉剂在非人灵长类动物中的神经毒性潜力。 重要性：每年都有数百万的胎儿和婴儿暴露在我们发现的可以引发发育中大脑神经细胞凋亡的药物中。在许多情况下，例如当危及生命的情况需要手术麻醉时，发育中的大脑暴露于致癫痫药物是必要的和不可避免的。因此，重要的是要确定发育中的灵长类动物的大脑是否容易受到麻醉诱导的神经细胞凋亡，并实现更好地理解的潜在机制，了解更多的行为后果，并制定预防神经病理学和行为后果的方法。 进展：在新生和胎儿非人灵长类动物模型方面都取得了重大进展。在临床相关条件下，胎儿和新生恒河猴暴露于异氟烷可诱导广泛的神经细胞凋亡，影响大脑皮层的所有分区。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Extensive research has shown that anesthetic agents can produce extensive apoptotic (programmed cell death) neurodegeneration in the developing rodent CNS. The observed degeneration occurs during the synaptogenesis period (the time when neurons establish interconnections). In primates the period encompasses the last trimester of in utero life and the first several months of post-natal life. Humans are commonly exposed to agents, which have been found to produce this damage, in either a clinical or drug abuse setting. Because of the large differences in rodent and human brain structure, it is unknown whether primates might also be susceptible to the same neurotoxic effects of these drugs. Determining whether the damage occurs in primate brain is critically needed. Thus, the broad goal of this research is to examine the neurotoxic potential of these various classes of anesthetic agents in non-human primates. SIGNIFICANCE: Every year millions of human fetuses and infants are exposed to the agents that we have found can trigger neuroapoptosis in the developing brain. In many cases, for example when life-threatening conditions require surgical anesthesia, exposure of the developing brain to apoptogenic drugs, is necessary and unavoidable. Therefore, it is important to determine whether the developing primate brain is susceptible to anesthesia-induced neuroapoptosis and to achieve a better understanding of the underlying mechanisms, learn more about the behavioral consequences and develop methods for preventing both the neuropathological and behavioral consequences. PROGRESS: Significant progress has been made with both the neonatal and fetal nonhuman primate models. Exposure of both the fetal and neonatal rhesus macaque to isoflurane, under clinically relevant conditions, induces widespread neuroapoptosis affecting all divisions of the cerebral cortex.