Musillo Chiara, Samà Marianna, Creutzberg Kerstin Camile, Begni Veronica, Collacchi Barbara, Bitraj Jonida, Collo Ginetta, Riva Marco Andrea, Berry Alessandra, Cirulli Francesca
Center for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
Transl Psychiatry. 2025 Aug 22;15(1):306. doi: 10.1038/s41398-025-03530-0.
While a clear association between maternal obesity and an increased risk for neuropsychiatric disorders in the offspring has been described, the underlying mechanisms remain poorly understood. We hypothesised that a maternal high-fat diet (mHFD) would act as a stressor, increasing glucocorticoids, resulting in an altered redox balance and disrupted neuronal plasticity of the limbic system. Such enduring effects would impair the emotional and cognitive profile, neuroendocrine responses, and metabolic and redox homeostasis in the adult offspring. We utilised a mouse model and a translational cellular model employing human neurons derived from inducible Pluripotent Stem Cells (iPSCs) to evaluate the impact of mHFD on neurodevelopment and to test the protection afforded by the antioxidant N-acetyl-cysteine (NAC). Our approach combined behavioural and metabolic phenotyping, biochemical assays, morphological assessment, and targeted gene expression analysis. Results indicate that prenatal administration of NAC prevented anxiety-like and risk-taking behaviours, cognitive impairments and metabolic alterations in mHFD adult mouse offspring, particularly in females. These changes were accompanied by hippocampal downregulation of genes involved in neuronal plasticity, such as BDNF. Using human neurons in vitro, pre-treatment with NAC rescued the negative effects of glucocorticoids on neuronal plasticity via a BDNF-mediated mechanism. The protective effects of NAC over mHFD in females suggest that rebalancing the redox status could be exploited as an overall strategy to buffer the negative effects of early adversities on neurodevelopment.
虽然已有研究表明母亲肥胖与后代患神经精神疾病的风险增加之间存在明确关联，但其潜在机制仍知之甚少。我们推测，母亲高脂饮食（mHFD）会作为一种应激源，增加糖皮质激素，导致氧化还原平衡改变，破坏边缘系统的神经元可塑性。这种持久影响会损害成年后代的情绪和认知状况、神经内分泌反应以及代谢和氧化还原稳态。我们利用小鼠模型和一个采用源自诱导多能干细胞（iPSC）的人类神经元的转化细胞模型，来评估mHFD对神经发育的影响，并测试抗氧化剂N-乙酰半胱氨酸（NAC）提供的保护作用。我们的方法结合了行为和代谢表型分析、生化检测、形态学评估以及靶向基因表达分析。结果表明，产前给予NAC可预防mHFD成年小鼠后代出现焦虑样和冒险行为、认知障碍及代谢改变，尤其是在雌性后代中。这些变化伴随着海马体中参与神经元可塑性的基因（如脑源性神经营养因子，BDNF）的下调。在体外使用人类神经元时，NAC预处理通过BDNF介导的机制挽救了糖皮质激素对神经元可塑性的负面影响。NAC对雌性mHFD小鼠的保护作用表明，重新平衡氧化还原状态可作为一种总体策略，以缓冲早期逆境对神经发育的负面影响。
