Department of Research Administration, Children Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri, USA.
Department of Neurology, Hainan Provincial People's Hospital, Haikou, Hainan, China.
Anat Rec (Hoboken). 2023 Jan;306(1):162-175. doi: 10.1002/ar.25056. Epub 2022 Aug 19.
An adverse maternal environment (AME) and Western diet (WD) in early life predispose offspring toward cognitive impairment in humans and mice. Cognitive impairment associates with hippocampal dysfunction. An important regulator of hippocampal function is the hippocampal Nociceptin/Orphanin FQ (N/OFQ) system. Previous studies find links between dysregulation of hippocampal N/OFQ receptor (NOP) expression and impaired cognitive function. NOP is encoded by the opioid receptor-like 1 (Oprl1) gene that contains multiple mRNA variants and isoforms. Regulation of Oprl1 expression includes histone modifications within the promoter. We tested the hypothesis that an AME and a postweaning WD increase the expression of hippocampal Oprl1 and select variants concurrent with altered histone code in the promoter. We created an AME-WD model combining maternal WD and prenatal environmental stress plus postweaning WD in the mouse. We analyzed the hippocampal expression of Oprl1, Oprl1 variants, and histone modifications in the Oprl1 promoter in offspring at postnatal day (P) 21 and P100. An AME and an AME-WD significantly increased the total hippocampal expression of Oprl1 and variant V4 concurrently with an increased accumulation of active histone marks in the promoter of male offspring. We concluded that an AME and an AME-WD alter hippocampal Oprl1 expression in offspring through an epigenetic mechanism in a variant-specific and sex-specific manner. Altered hippocampal Oprl1 expression may contribute to cognitive impairment seen in adult males in this model. Epigenetic regulation of Oprl1 is a potential mechanism by which an AME and a WD may contribute to neurocognitive impairment in male offspring.
不良的母体环境（AME）和西方饮食（WD）在生命早期使后代易患人类和小鼠的认知障碍。认知障碍与海马功能障碍有关。海马的孤啡肽/孤啡肽 FQ（N/OFQ）系统是海马功能的重要调节因子。先前的研究发现海马 N/OFQ 受体（NOP）表达失调与认知功能受损之间存在联系。NOP 由阿片受体样 1（Oprl1）基因编码，该基因包含多个 mRNA 变体和同工型。Oprl1 表达的调节包括启动子内的组蛋白修饰。我们假设 AME 和断奶后 WD 会增加海马 Oprl1 的表达，并伴有启动子中组蛋白密码的改变，从而选择特定的变体。我们在小鼠中创建了一个 AME-WD 模型，该模型结合了母体 WD 和产前环境应激以及断奶后 WD。我们分析了后代在出生后第 21 天（P）和第 100 天（P）时海马中 Oprl1、Oprl1 变体和启动子中组蛋白修饰的表达。AME 和 AME-WD 显著增加了雄性后代海马中 Oprl1 的总表达和变体 V4 的表达，同时启动子中活性组蛋白标记的积累增加。我们得出结论，AME 和 AME-WD 通过特定变体和性别特异性的表观遗传机制改变后代海马中 Oprl1 的表达。改变的海马 Oprl1 表达可能导致该模型中成年雄性的认知障碍。Oprl1 的表观遗传调节是 AME 和 WD 可能导致雄性后代神经认知障碍的潜在机制。
