Postweaning iron deficiency in rats alters reelin expression in the nucleus accumbens

Background: Epidemiological research indicates that iron deficiency (ID) in infancy correlates with long-term cognitive impairment and behavioral disturbances, despite therapy. However, the mechanisms underlying these effects are unknown. Objective: We investigated how ID affected postweaning behavior and monoamine concentration in rat brains to determine whether ID during the juvenile period affected gene expression and synapse formation in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Methods: Fischer344/Jcl male rats aged 21–39 days were fed low-iron diets (0.35 mg/kg iron; ID group) or standard AIN-93 G diets (3.5 mg/kg iron; control group). The locomotor activity of male offspring was evaluated by the open field and elevated plus maze tests at ages 8 and 12 weeks. Monoamine concentrations in the PFC, NAcc, caudate-putamen, ventral midbrain, dorsal midbrain, and pons were analyzed. Comprehensive gene expression analysis was performed in the PFC and NAcc at age 13 weeks. Finally, we investigated synaptic density in the PFC and NAcc by synaptophysin immunostaining. Results: Behavioral tests revealed significant interactions between age and iron consumption for the total distance traveled and the distance traveled in the peripheral area (p < 0.05), indicating that ID during the juvenile period affected hyperactivity and that this persisted to adulthood. At age 13 weeks, the ID group had increased levels of both dopamine and the metabolites of dopamine and serotonin in the NAcc. Comprehensive gene expression analysis and immunostaining showed decreased Reelin gene expression (adjusted p < 0.01) and significantly increased spine density in the NAcc in the ID group compared with the control group (p < 0.01). Conclusions: ID during the postweaning juvenile period led to long-term hyperactivity, monoamine disturbance in the brain, and downregulation of Reelin expression in the NAcc despite complete iron repletion. Epigenetic modification of Reelin genes may be involved in synaptic plasticity in the NAcc. Overall design: Fischer344/Jcl male rats aged 21-39 days were fed low-iron diets

背景：流行病学研究表明，婴儿期铁缺乏（iron deficiency, ID）即便接受治疗，仍与长期认知损伤及行为障碍相关，但其背后的作用机制尚不明确。
目的：本研究探讨铁缺乏对大鼠断奶后行为及脑内单胺类神经递质浓度的影响，以明确幼年期铁缺乏是否会影响前额叶皮层（prefrontal cortex, PFC）与伏隔核（nucleus accumbens, NAcc）的基因表达及突触形成。
方法：选取21~39日龄的Fischer344/Jcl雄性大鼠，分别饲喂低铁饲料（铁含量0.35 mg/kg，铁缺乏组）与标准AIN-93G饲料（铁含量3.5 mg/kg，对照组）。分别在8周龄与12周龄时，通过旷场实验与高架十字迷宫实验评估雄性子代的自主运动活性。对前额叶皮层、伏隔核、尾壳核、中脑腹侧区、中脑背侧区及脑桥内的单胺类神经递质浓度进行检测分析。在13周龄时，对前额叶皮层与伏隔核开展全面基因表达分析。最后，通过突触素免疫染色检测前额叶皮层与伏隔核的突触密度。
结果：行为学实验显示，总移动距离与外周区域移动距离均存在年龄与铁摄入水平的显著交互作用（p < 0.05），表明幼年期铁缺乏会引发多动症状，且该症状可持续至成年阶段。在13周龄时，铁缺乏组伏隔核内的多巴胺及其代谢产物、血清素代谢产物水平均升高。全面基因表达分析与免疫染色结果显示，与对照组相比，铁缺乏组伏隔核内Reelin（Reelin）基因的表达量显著降低（校正后p < 0.01），且树突棘密度显著升高（p < 0.01）。
结论：断奶后幼年期的铁缺乏即便在后续实现完全补铁，仍会引发长期多动症状、脑内单胺类神经递质紊乱，以及伏隔核内Reelin基因表达下调。Reelin基因的表观遗传修饰可能参与调控伏隔核内的突触可塑性。
整体实验设计：选取21~39日龄的Fischer344/Jcl雄性大鼠，饲喂低铁饲料。