Environmental Exposure Perturbs Mitochondrial Mechanisms during Neurodevelopment

描述（由申请人提供）：美国近五分之一的儿童继续在家中暴露于环境烟草烟雾（ETS）。流行病学数据表明，儿童时期接触ETS会增加与产前接触无关的行为和认知问题以及相关神经行为障碍的风险。然而，尚不清楚是否产后暴露于ETS对高度可塑性的幼小大脑有直接的神经生物学影响，从而导致所报道的神经功能缺陷和精神疾病。这些知识是支持长期机制研究的基础，有可能影响个人的决定和政策，并开发有益于人类健康的新型预测诊断方法。因此，在现有奖励机制的推动下，我们提出探索性研究，利用新开发的出生后ETS暴露动物模型，证明其会诱发注意力、活动和冲动控制方面的相关行为缺陷。初步研究结果表明，ETS会引起线粒体能量的显著扰动，这意味着在青少年小脑发育的关键时期出现异常的短暂高代谢状态，随后出现低代谢，表明青春期成熟后功能下降。小脑在皮质介导的功能中提供纠正和灵活性；因此，我们的初步研究结果为一种创新假设提供了理论基础，即在动物的发育易感性和高阶行为缺陷的关键皮质回路功能障碍中，ets诱导的能量失调是潜在的。我们将通过两个具体目标来验证我们的中心假设：目标1将测试产后ETS暴露对青春期高阶回路发育中线粒体能量学和随后的功能性抑郁的影响。目标2将开发创新的方法来选择性地解决与高阶电路中ets诱导的线粒体扰动相关的新型生化网络。预期的研究结果将为ETS在关键时期高阶电路发育和随后的青少年功能障碍期间引起的能量扰动提供解剖学和生化机制的见解。这些结果将通过显示负责回路的功能障碍，为ets诱导的异常行为之间的联系提供突破性的线索，从而推进我们目前对神经发育缺陷和疾病的生物学原因的理解。我们进一步预期，这些研究的结果将支持未来的研究意图，将这些发现转化为美国和国外高危儿童对ETS易感性的预后生物标志物，用于有针对性的干预。

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.