Background: Neurodevelopmental abnormalities in experimental fetal alcohol spectrum disorder (FASD) are associated with impaired signaling through complex pathways that mediate neuronal survival, growth, migration, en...Background: Neurodevelopmental abnormalities in experimental fetal alcohol spectrum disorder (FASD) are associated with impaired signaling through complex pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Gestational dietary soy prevents alcohol-related impairments in placentation and FASD-associated fetal anomalies. Objective: This study was designed to determine if gestational dietary soy would be sufficient to normalize cognitive function in young adolescent offspring after chronic in utero exposure to alcohol. In addition, efforts were made to characterize the mechanisms of FASD prevention by maternal dietary soy. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source from gestation day 6 through delivery/postnatal day 0 (P0). From P24 - P28, the offspring were subjected to Morris water maze (MWM) testing, and on P35, they were sacrificed to harvest temporal lobes for histopathologic and molecular studies. Results: The in-utero ethanol-exposed offspring exhibited significant performance impairments on the MWM test, and they had a significantly reduced mean brain weight with neuronal loss in the CA1 hippocampal region and evidence of white matter myelin loss. Gestational dietary soy nearly normalized MWM performance and preserved brain weight, hippocampal CA1 architecture, and white matter myelin staining in alcohol-exposed offspring. Mechanistically, the main positive effects of soy included increased temporal lobe expression of HES-1 and HIF-1α, reflecting enhanced Notch signaling, and broadly increased expression of GnRH network molecules, including Erb1, Gper1, GnRH, GnRH-R, KiSS, and KiSS-R, irrespective of gestational ethanol exposure. Conclusions: Dietary soy intervention early in pregnancy may reduce FASD-associated cognitive deficits. The findings suggest that targeting Notch and GnRH-related networks may help reduce long-term disability with FASD. Additional mechanistic and experimental research is needed to determine if longer-duration, postnatal dietary soy could prevent the adverse neurobehavioral effects of FASD.展开更多
酒精使用障碍(alcohol use disorder,AUD)是一种复杂的慢性复发性脑部疾病,对个体健康和公共卫生构成重大影响。痛觉过敏是导致AUD治疗失败的关键因素。现有药物不能有效缓解AUD患者的疼痛,因而亟需研发新的干预措施。本文系统综述了AU...酒精使用障碍(alcohol use disorder,AUD)是一种复杂的慢性复发性脑部疾病,对个体健康和公共卫生构成重大影响。痛觉过敏是导致AUD治疗失败的关键因素。现有药物不能有效缓解AUD患者的疼痛,因而亟需研发新的干预措施。本文系统综述了AUD导致痛觉过敏的多系统神经生物学机制,从分子到环路,再从中枢到外周,揭示了神经递质失衡[如谷氨酸能兴奋增强/γ-氨基丁酸(γ-aminobutyric acid,GABA)能抑制]、神经胶质细胞介导的神经炎症等经典通路,并深入分析了表观遗传调控(DNA甲基化、组蛋白修饰和microRNA对关键基因的表达调控)和肠-脑轴(肠道菌群通过代谢物影响中枢神经系统)等新型机制,同时强调了性激素介导的性别差异性。基于这些见解,本文提出靶向神经环路、表观遗传修饰酶、肠道菌群等新型干预策略,为临床治疗AUD引起的痛觉过敏提供新视角,这对降低复饮率、改善患者预后具有重要意义。展开更多
文摘Background: Neurodevelopmental abnormalities in experimental fetal alcohol spectrum disorder (FASD) are associated with impaired signaling through complex pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Gestational dietary soy prevents alcohol-related impairments in placentation and FASD-associated fetal anomalies. Objective: This study was designed to determine if gestational dietary soy would be sufficient to normalize cognitive function in young adolescent offspring after chronic in utero exposure to alcohol. In addition, efforts were made to characterize the mechanisms of FASD prevention by maternal dietary soy. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source from gestation day 6 through delivery/postnatal day 0 (P0). From P24 - P28, the offspring were subjected to Morris water maze (MWM) testing, and on P35, they were sacrificed to harvest temporal lobes for histopathologic and molecular studies. Results: The in-utero ethanol-exposed offspring exhibited significant performance impairments on the MWM test, and they had a significantly reduced mean brain weight with neuronal loss in the CA1 hippocampal region and evidence of white matter myelin loss. Gestational dietary soy nearly normalized MWM performance and preserved brain weight, hippocampal CA1 architecture, and white matter myelin staining in alcohol-exposed offspring. Mechanistically, the main positive effects of soy included increased temporal lobe expression of HES-1 and HIF-1α, reflecting enhanced Notch signaling, and broadly increased expression of GnRH network molecules, including Erb1, Gper1, GnRH, GnRH-R, KiSS, and KiSS-R, irrespective of gestational ethanol exposure. Conclusions: Dietary soy intervention early in pregnancy may reduce FASD-associated cognitive deficits. The findings suggest that targeting Notch and GnRH-related networks may help reduce long-term disability with FASD. Additional mechanistic and experimental research is needed to determine if longer-duration, postnatal dietary soy could prevent the adverse neurobehavioral effects of FASD.
基金supported by the National Natural Science Foundation of China(No.82271256 and 32200817)General Program from Nantong Commission of Health(No.MS2024049)Guided Research Program of Nantong Municipal Bureau of Science and Technology(No.JCZ2023023)。
文摘酒精使用障碍(alcohol use disorder,AUD)是一种复杂的慢性复发性脑部疾病,对个体健康和公共卫生构成重大影响。痛觉过敏是导致AUD治疗失败的关键因素。现有药物不能有效缓解AUD患者的疼痛,因而亟需研发新的干预措施。本文系统综述了AUD导致痛觉过敏的多系统神经生物学机制,从分子到环路,再从中枢到外周,揭示了神经递质失衡[如谷氨酸能兴奋增强/γ-氨基丁酸(γ-aminobutyric acid,GABA)能抑制]、神经胶质细胞介导的神经炎症等经典通路,并深入分析了表观遗传调控(DNA甲基化、组蛋白修饰和microRNA对关键基因的表达调控)和肠-脑轴(肠道菌群通过代谢物影响中枢神经系统)等新型机制,同时强调了性激素介导的性别差异性。基于这些见解,本文提出靶向神经环路、表观遗传修饰酶、肠道菌群等新型干预策略,为临床治疗AUD引起的痛觉过敏提供新视角,这对降低复饮率、改善患者预后具有重要意义。
