Rinaudo Marco, Natale Francesca, La Greca Francesco, Spinelli Matteo, Farsetti Antonella, Paciello Fabiola, Fusco Salvatore, Grassi Claudio
Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy.
Biomedicines. 2022 Jun 11;10(6):1387. doi: 10.3390/biomedicines10061387.
Despite being a crucial physiological function of the brain, the mechanisms underlying forgetting are still poorly understood. Estrogens play a critical role in different brain functions, including memory. However, the effects of sex hormones on forgetting vulnerabilitymediated by retroactive interference (RI), a phenomenon in which newly acquired information interferes with the retrieval of already stored information, are still poorly understood. The aim of our study was to characterize the sex differences in interference-mediated forgetting and identify the underlying molecular mechanisms. We found that adult male C57bl/6 mice showed a higher susceptibility to RI-dependent memory loss than females. The preference index (PI) in the NOR paradigm was 52.7 ± 5.9% in males and 62.3 ± 13.0% in females. The resistance to RI in female mice was mediated by estrogen signaling involving estrogen receptor α activation in the dorsal hippocampus. Accordingly, following RI, females showed higher phosphorylation levels (+30%) of extracellular signal-regulated kinase1/2 (ERK1/2) in the hippocampus. Pharmacological inhibition of ERK1/2 made female mice prone to RI. The PI was 70.6 ± 11.0% in vehicle-injected mice and 47.4 ± 10.8% following PD98059 administration. Collectively, our data suggest that hippocampal estrogen α receptor-ERK1/2 signaling is critically involved in a pattern separation mechanism that inhibits object-related RI in female mice.
尽管遗忘是大脑的一项关键生理功能，但其潜在机制仍未得到充分理解。雌激素在包括记忆在内的不同脑功能中发挥着关键作用。然而，性激素对由逆向干扰（RI）介导的遗忘易感性的影响仍知之甚少，逆向干扰是一种新获取的信息干扰已存储信息检索的现象。我们研究的目的是描述干扰介导的遗忘中的性别差异，并确定其潜在的分子机制。我们发现成年雄性C57bl/6小鼠比雌性小鼠对RI依赖性记忆丧失更敏感。在新奇物体识别范式中，雄性小鼠的偏好指数（PI）为52.7±5.9%，雌性小鼠为62.3±13.0%。雌性小鼠对RI的抗性是由雌激素信号介导的，涉及背侧海马中雌激素受体α的激活。因此，在RI后，雌性小鼠海马中细胞外信号调节激酶1/2（ERK1/2）的磷酸化水平更高（+30%）。ERK1/2的药理学抑制使雌性小鼠易于发生RI。注射溶剂的小鼠PI为70.6±11.0%，给予PD98059后为47.4±10.8%。总体而言，我们的数据表明海马雌激素α受体-ERK1/2信号通路关键参与了一种模式分离机制，该机制抑制雌性小鼠中与物体相关的RI。
