Department of Anatomy and Neuroscience, College of Medicine, Eulji University, Daejeon, 34824, Republic of Korea.
Department of Nuclear Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
Int J Biol Sci. 2024 Oct 7;20(14):5450-5473. doi: 10.7150/ijbs.97723. eCollection 2024.
Exposure to adverse experiences during early life is associated with an increased risk of psychopathology during adolescence. In a previous study, we demonstrated that neonatal maternal separation (NMS) combined with social isolation led to impulsive and depressive-like behaviors in male adolescents. Additionally, it significantly reduced the expression of excitatory amino acid carrier 1 (EAAC1) in the hippocampus. Building upon this work, we investigated the effects of N-acetylcysteine (NAC), a precursor to glutathione, in early-life stress (ELS) model rats and in EAAC1 mice. EAAC1 plays a dual role in transporting both glutamate and cysteine into neurons. Our findings revealed that female adolescents subjected to in the ELS model also exhibited behavioral defects similar to those of males. NAC injection rescued depressive-like behaviors in both male and female NMS models, but it improved impulsive behavior only in males. Furthermore, we observed increased reactive oxidative stress (ROS) and neuroinflammation in the ventral hippocampus (vHPC) and prefrontal cortex of NMS model rats, which were mitigated by NAC treatment. Notably, NAC reversed the reduced expression of EAAC1 in the vHPC of NMS model rats. In EAAC1 mice, severe impulsive and depressive-like behaviors were evident, and the NAC intervention improved only depressive-like behaviors. Collectively, our results suggest that ELS contributes to depression and impulsive behaviors during adolescence. Moreover, the cysteine uptake function of EAAC1 in neurons may be specifically related to depression rather than impulsive behavior.
早期生活中遭受不良经历与青少年时期精神病理学风险增加有关。在之前的一项研究中，我们证明了新生期母体分离（NMS）结合社会隔离会导致雄性青少年出现冲动和抑郁样行为。此外，它还显著降低了海马中的兴奋性氨基酸载体 1（EAAC1）的表达。在此基础上，我们研究了 N-乙酰半胱氨酸（NAC），即谷胱甘肽的前体，对早期生活应激（ELS）模型大鼠和 EAAC1 小鼠的影响。EAAC1 在将谷氨酸和半胱氨酸转运到神经元中具有双重作用。我们的研究结果表明，雌性青少年在 ELS 模型中也表现出与雄性相似的行为缺陷。NAC 注射可挽救雄性和雌性 NMS 模型中的抑郁样行为，但仅改善雄性的冲动行为。此外，我们观察到 NMS 模型大鼠腹侧海马（vHPC）和前额叶皮质中的反应性氧化应激（ROS）和神经炎症增加，NAC 处理可减轻这种情况。值得注意的是，NAC 逆转了 NMS 模型大鼠 vHPC 中 EAAC1 的表达减少。在 EAAC1 小鼠中，明显表现出严重的冲动和抑郁样行为，而 NAC 干预仅改善了抑郁样行为。总之，我们的研究结果表明，ELS 导致青少年时期的抑郁和冲动行为。此外，神经元中 EAAC1 的半胱氨酸摄取功能可能与抑郁而不是冲动行为特别相关。
