Mancini Giulia Federica, Di Cesare Benedetta, Bove Maria, Sikora Vladyslav, Virgilio Anna, Morena Maria, Caraci Filippo, Trabace Luigia, Riva Marco Andrea, Campolongo Patrizia, Schiavone Stefania
Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy; Neuropharmacology Unit, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy.
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Aug 30;141:111447. doi: 10.1016/j.pnpbp.2025.111447. Epub 2025 Jul 13.
Redox imbalance can affect several processes within the brain (e.g., synaptic plasticity, neurotransmitters release and their related pathways), leading to altered emotional and cognitive states. These effects can be particularly detrimental during adolescence, a critical period for brain development when some of the brain areas regulating emotional and cognitive functions, such as prefrontal cortex (PFC) and hippocampus (HIPP), are not fully matured yet. Nonetheless, the role of redox markers in the modulation of emotional and cognitive states in adolescent rodents remains under-investigated. Here, we performed correlation analyses between behavior and biomolecular data of redox markers measured in PFC and HIPP of male and female adolescent naïve rats, together with the evaluation of possible sex differences. Our results reveal sex differences in anxiety-like behavior as well as exploratory activity in the open field test, and in fear memory in the auditory fear conditioning task. Moreover, female rats showed decreased NADPH oxidase 2 (NOX-2) and catalase protein levels in PFC, alongside reduced nuclear factor erythroid 2-related factor 2 (NRF-2) and increased lipid peroxidation content in HIPP, thus highlighting sex differences in these redox markers. When considering both sexes together, NRF-2 and NOX-2 expression in PFC and HIPP correlated with several emotional- and cognitive-related behavioral parameters, suggesting that redox status might affect brain maturation, and thus behavior, during adolescence. Collectively, these findings point towards a possible role of redox-related markers in the occurrence of emotional and cognitive behaviors, providing new insights into their potential as pharmacological targets for the treatment of psychiatric disorders.
氧化还原失衡会影响大脑内的多个过程（如突触可塑性、神经递质释放及其相关通路），导致情绪和认知状态改变。在青春期，这些影响可能尤其有害，青春期是大脑发育的关键时期，此时一些调节情绪和认知功能的脑区，如前额叶皮质（PFC）和海马体（HIPP），尚未完全成熟。尽管如此，氧化还原标志物在调节青春期啮齿动物情绪和认知状态中的作用仍未得到充分研究。在此，我们对雄性和雌性青春期未处理大鼠的PFC和HIPP中测量的氧化还原标志物的行为和生物分子数据进行了相关性分析，并评估了可能存在的性别差异。我们的结果揭示了在旷场试验中的焦虑样行为、探索活动以及听觉恐惧条件反射任务中的恐惧记忆存在性别差异。此外，雌性大鼠PFC中的NADPH氧化酶2（NOX - 2）和过氧化氢酶蛋白水平降低，同时HIPP中的核因子红细胞2相关因子2（NRF - 2）减少，脂质过氧化含量增加，从而突出了这些氧化还原标志物的性别差异。当综合考虑两性时，PFC和HIPP中NRF - 2和NOX - 2的表达与几个情绪和认知相关的行为参数相关，这表明氧化还原状态可能在青春期影响大脑成熟，进而影响行为。总体而言，这些发现表明氧化还原相关标志物在情绪和认知行为的发生中可能发挥作用，为其作为治疗精神疾病的药理学靶点的潜力提供了新的见解。
