Neuroscience and Behaviour Laboratory, Department of Physiology, Institute of Biosciences, Universidade de São Paulo, São Paulo, SP, Brazil; Neuroscience Laboratory, Department of Anatomy, Institute of Biomedical Sciences, Universidade de São Paulo, São Paulo, SP, Brazil.
Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands; Experimental Neuropathology Laboratory, Institute of Cellular Biology and Neuroscience "Prof. E. De Robertis" (IBCN), Faculty of Medicine, University of Buenos Aires, CONICET, Buenos Aires, Argentina; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands; Biomedical Sciences Institute, Faculty of Medical Sciences, Catholic University of Cuyo, San Juan, Argentina; Neurogenetics Laboratory, Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil.
Exp Neurol. 2021 Jun;340:113691. doi: 10.1016/j.expneurol.2021.113691. Epub 2021 Mar 11.
Therapeutic hypothermia (TH) is well established as a standard treatment for term and near-term infants. However, therapeutic effects of hypothermia following neonatal anoxia in very premature babies remains inconclusive. The present rodent model of preterm neonatal anoxia has been shown to alter developmental milestones and hippocampal neurogenesis, and to disrupt spatial learning and memory in adulthood. These effects seem to be reduced by post-insult hypothermia. Epigenetic-related mechanisms have been postulated as valuable tools for developing new therapies. Dentate gyrus neurogenesis is regulated by epigenetic factors. This study evaluated whether TH effects in a rodent model of preterm oxygen deprivation are based on epigenetic alterations. The effects of TH on both developmental features (somatic growth, maturation of physical characteristics and early neurological reflexes) and performance of behavioral tasks at adulthood (spatial reference and working memory, and fear conditioning) were investigated in association with the possible involvement of the epigenetic operator Enhancer of zeste homolog 2 (Ezh2), possibly related to long-lasting effects on hippocampal neurogenesis. Results showed that TH reduced both anoxia-induced hippocampal neurodegeneration and anoxia-induced impairments on risk assessment behavior, acquisition of spatial memory, and extinction of auditory and contextual fear conditioning. In contrast, TH did not prevent developmental alterations caused by neonatal anoxia and did not restore hippocampal neurogenesis or cause changes in EZH2 levels. In conclusion, despite the beneficial effects of TH in hippocampal neurodegeneration and in reversing disruption of performance of behavioral tasks following oxygen deprivation in prematurity, these effects seem not related to developmental alterations and hippocampal neurogenesis and, apparently, is not caused by Ezh2-mediated epigenetic alteration.
治疗性低温（TH）已被确立为足月和近足月婴儿的标准治疗方法。然而，极低早产儿新生儿缺氧后低温治疗的疗效仍不确定。目前的早产新生儿缺氧啮齿动物模型已被证明会改变发育里程碑和海马神经发生，并破坏成年后的空间学习和记忆。这些影响似乎可以通过损伤后低温来减轻。表观遗传相关机制已被推测为开发新疗法的有用工具。齿状回神经发生受表观遗传因素调节。本研究评估了早产儿缺氧模型中 TH 的作用是否基于表观遗传改变。研究了 TH 对成年后行为任务表现（空间参考和工作记忆以及恐惧条件反射）的发育特征（躯体生长、身体特征成熟和早期神经反射）的影响，以及表观遗传操作增强子的可能参与Zeste 同源物 2（Ezh2），可能与海马神经发生的长期影响有关。结果表明，TH 降低了缺氧诱导的海马神经退行性变和缺氧诱导的风险评估行为、空间记忆获得以及听觉和情境恐惧条件反射的消退障碍。相比之下，TH 不能预防新生儿缺氧引起的发育改变，也不能恢复海马神经发生或引起 EZH2 水平的变化。总之，尽管 TH 在缺氧后海马神经退行性变和逆转行为任务表现障碍方面有有益的作用，但这些作用似乎与发育改变和海马神经发生无关，显然也不是由 Ezh2 介导的表观遗传改变引起的。
