Cognitive and socioemotional development after postnatal anesthesia

描述（由申请方提供）：在哺乳动物发育早期给予全身麻醉剂时，全身麻醉剂可能作为神经毒素。啮齿类动物的实验表明，在生命早期给予全身麻醉药后，认知和社会行为会出现长期损害。全身麻醉剂对非人类灵长类动物的婴儿也有神经毒性，但其对认知和社会行为的长期影响尚不清楚。人类回顾性研究表明，在4岁之前接受一种以上全身麻醉的儿童患学习障碍的风险更大。因此，全身麻醉的早期神经毒性损伤可能会对人类认知发育产生长期影响，但不可能直接在人类中解决这个问题，因为随机前瞻性研究是不可能的，回顾性（观察性）研究受到严重的混淆：例如，在生命早期需要多种全身麻醉剂的儿童可能在许多方面与不需要的儿童不同。全身麻醉是否对婴儿和儿童具有神经毒性，并可能导致长期的认知障碍，是当今麻醉学中最关键的问题之一。 早期暴露于麻醉后认知发育的非人灵长类动物模型将解决两个关键问题，以确定生命早期给予全身麻醉的神经毒性是否值得关注。首先，非人类灵长类动物和人类的神经解剖学和认知发育之间的密切联系增加了动物模型中的发现可以转化为人类的程度。其次，早期麻醉剂暴露的认知效应的非人灵长类动物模型将提供一种方法来比较不同的麻醉方案，或可能在麻醉剂暴露期间或之后给予的潜在治疗，以减轻或逆转神经毒性效应和随后的认知障碍。 我们将测试在出生后第6周之前接受三种全身麻醉剂和七氟烷（一种常用于儿科麻醉的吸入麻醉剂）的恒河猴在出生后前三年的认知和社会情绪任务，以跟踪重复出生后麻醉对认知和社会情绪发育的影响。这将提供麻醉对神经认知发育的影响以及对年龄大致对应于儿童开始接受正规教育的幼年猴的认知和社会情感行为的影响的数据。 这项工作将为研究出生后麻醉对非人灵长类动物认知和社会行为的长期影响提供一个关键的转化模型，这对于评估儿科人群麻醉的潜在风险以及测试可能减轻或消除这种风险的潜在药物至关重要。

DESCRIPTION (provided by applicant): General anesthetics may act as neurotoxins when given early in mammalian development. Experiments in rodents have demonstrated long-term impairments in cognition and social behavior after administration of general anesthetics early in life. General anesthetics are also neurotoxic to infant nonhuman primates, but their long-term effects on cognition and social behavior are not known. Retrospective studies in humans have shown that children who received more than one general anesthetic before the age of 4 are at a greater risk of learning disability. Thus, early neurotoxic insults from general anesthesia may result in long-term impacts on human cognitive development, but it is not possible to address this question directly in humans because randomized prospective studies are not possible and retrospective (observational) studies are subject to serious confounds: for example, children who need multiple general anesthetics early in life may differ in many ways from children who do not. Whether general anesthesia is neurotoxic to infants and children, and may result in long-term cognitive impairments, is one of the most critical questions in anesthesiology today. A nonhuman primate model of cognitive development after early exposure to anesthesia will address two key issues in establishing whether neurotoxicity of general anesthesia given early in life is cause for concern. First, the closer correspondence between neuroanatomy and cognitive development in nonhuman primates and humans increases the extent to which findings in the animal model can be translated to humans. Second, a nonhuman primate model of cognitive effects of early anesthetic exposure would provide a means to compare different anesthetic regimens, or potential treatments that could be given during or after anesthetic exposure to mitigate or reverse neurotoxic effects and subsequent cognitive impairments. We will test rhesus monkeys that have received three general anesthetics with sevoflurane (an inhalation anesthetic commonly used in pediatric anesthesiology) before their 6th week of life on cognitive and socioemotional tasks throughout their first three years of life, to track the effects of repeated postnatal anesthesia on cognitive and socioemotional development. This will provide data both on the effect of anesthesia on neurocognitive development, and on cognition and socioemotional behavior in juvenile monkeys at an age roughly corresponding to the onset of formal schooling in children. This work will provide a critical translational model for studying long-term effects of postnatal anesthesia on cognition and social behavior in nonhuman primates, which will be vital for assessing potential risks of anesthesia in pediatric populations, as well as for testing potential agents that may mitigate or eliminate this risk.