Environmental Exposure Perturbs Mitochondrial Mechanisms during Neurodevelopment

描述(由申请人提供)：在美国，近五分之一的儿童继续在家中暴露在环境烟草烟雾(ETS)中。流行病学数据表明，儿童暴露于ETS会增加行为和认知问题以及相关神经行为障碍的风险，而不受产前暴露的影响。然而，目前尚不清楚长期接触ETS是否会对高度可塑性的年轻大脑产生直接的神经生物学影响，从而导致报告的神经缺陷和精神障碍。这些知识是支持长期机械性研究的基础，有可能影响个人的决策和政策，并开发有利于人类健康的新的预测性诊断方法。因此，在目前奖励机制的推动下，我们在这里提出了探索性研究，使用一种新开发的出生后ETS暴露的动物模型，证明可以导致注意、活动和冲动控制方面的相关行为缺陷。初步研究结果表明，在幼年小脑发育关键期，ETS对线粒体能量学产生显著的扰动，表现为短暂的高代谢异常状态，随后表现为青春期功能低下和成熟。小脑在皮质调节的功能中提供了校正和灵活性；因此，我们的初步发现为创新假说提供了理论基础，即后足月ETS诱导的扰乱的能量学是动物发育易感性和关键皮质回路内调节高阶行为缺陷的功能障碍的基础。我们将通过两个具体目标用现代基于系统的方法来测试我们的中心假设：目标1将测试后长期ETS暴露对青春期高阶电路发育和随后的功能性抑郁中线粒体能量学的影响。目的2将开发创新的方法来选择性地解决与ETS诱导的高阶回路中的线粒体扰动相关的新的生化网络。预期的发现将提供解剖学和生化机制方面的洞察，以了解ETS在关键时期诱导的能量扰动、更高阶回路的发育以及随后的青少年功能障碍。这些结果将通过显示负责回路的功能障碍，在ETS诱导的异常行为之间提供一个突破性的联系，促进我们目前对神经发育缺陷和障碍的生物学原因的理解。我们还预计，这些研究的结果将支持未来的研究意图，即将这些发现转化为ETS易感性的预后生物标记物，用于在美国和国外对高危儿童进行有针对性的干预。

DESCRIPTION (provided by applicant): Nearly one-in-five children in the U.S. continue to be exposed to environmental tobacco smoke (ETS) in the home. Epidemiological data suggest that childhood ETS exposure increases risk for behavioral and cognitive problems and related neurobehavioral disorders independent of prenatal exposure. Yet, it remains unknown whether post-term ETS exposure has a direct neurobiological effect on the highly-plastic young brain to cause reported neurological deficits and psychiatric disorders. Such knowledge is fundamental to support long-term mechanistic research, with potential to influence individual decisions and policy, and to develop novel predictive diagnostics that are of benefit to human health. Thus, here we propose exploratory research, promoted by the present award mechanism, using a newly developed animal model of postnatal ETS exposure demonstrated to induce relevant behavioral deficits in attention, activity and impulse control. Preliminary findings show that ETS induces significant perturbation to mitochondrial energetics signifying an abnormal transient hypermetabolic state during critical period development in the juvenile cerebellum, followed by hypometabolism indicative of depressed function with maturation in adolescence. The cerebellum provides correction and flexibility in cortical-mediated functions; thus, our preliminar findings provide rationale for the innovative hypothesis that post-term ETS-induced perturbed energetics underlies developmental susceptibility and dysfunction within key cortical circuitry mediating higher-order behavioral deficits in animals. We will test our central hypothesis with a modern systems-based approach across two Specific Aims: Aim 1 will test an effect of post-term ETS exposure on mitochondrial energetics within developing higher-order circuitry and subsequent functional depression in adolescence. Aim 2 will develop innovative methodology to selectively resolve novel biochemical networks correlated with ETS-induced mitochondrial perturbation in higher-order circuitry. Expected findings will provide anatomical and biochemical mechanistic insight into ETS- induced energetic perturbation during critical period higher-order circuit development and subsequent adolescent dysfunction. These results would provide a breakthrough link between ETS-induced aberrant behavior by showing dysfunction in responsible circuitry, advancing our current understanding on biological causation of neurodevelopmental deficits and disorders. We further anticipate that results from these studies will support future research intent on translating these findings into prognostic biomarkers of susceptibility to ETS for targeted intervention of at-risk children in the U.S. and abroad.