Xinxiang Key Laboratory of Forensic Toxicology, School of Forensic Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
Henan Key Laboratory of Biological Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China.
Neurochem Int. 2024 Oct;179:105834. doi: 10.1016/j.neuint.2024.105834. Epub 2024 Aug 12.
Alcohol exposure in adolescence is considered a major cause of cognitive impairments later in life including spatial learning and memory. Integrated stress response (ISR), a program of conservative translation and transcription, is crucial in synaptic plasticity and memory. Although previous studies have elucidated ISR in different brain areas involved in learning and memory disorders, the impact of ISR on learning and memory following adolescent alcohol exposure remains unclear. Here, we demonstrated that adolescent intermittent ethanol (AIE) exposure caused spatial learning and memory impairment, combined with neuronal damage in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and hippocampus (HIP) in adult rats. Moreover, integrated stress response inhibitor (ISRIB) administration not only improved spatial learning and memory impairment and neuronal damage but also inhibited the endoplasmic reticulum stress (ER) and reversed changes in synaptic proteins. These findings suggested that ISRIB ameliorates AIE exposure-induced spatial learning and memory deficits by improving neural morphology and synaptic function through inhibiting ER stress signaling pathway in the mPFC, NAc and HIP in adulthood. Our findings may enhance comprehension of cognitive function and neuronal effects of adolescent ethanol exposure and ISRIB treatment may be an underlying potential option for addressing alcohol-induced learning and memory deficits.
酒精暴露在青春期被认为是导致认知障碍的主要原因，包括空间学习和记忆。综合应激反应（ISR），一种保守的翻译和转录方案，对突触可塑性和记忆至关重要。尽管先前的研究已经阐明了 ISR 在学习和记忆障碍相关的不同脑区中的作用，但 ISR 对青春期酒精暴露后学习和记忆的影响仍不清楚。在这里，我们证明了青少年间歇性乙醇（AIE）暴露会导致成年大鼠的空间学习和记忆障碍，同时伴有内侧前额叶皮质（mPFC）、伏隔核（NAc）和海马（HIP）神经元损伤。此外，综合应激反应抑制剂（ISRIB）的给药不仅改善了空间学习和记忆障碍以及神经元损伤，还抑制了内质网应激（ER），并逆转了突触蛋白的变化。这些发现表明，ISRIB 通过抑制成年 mPFC、NAc 和 HIP 中的 ER 应激信号通路，改善神经形态和突触功能，从而改善 AIE 暴露引起的空间学习和记忆缺陷。我们的发现可能会增强对青少年乙醇暴露和 ISRIB 治疗认知功能和神经元影响的理解，ISRIB 可能是解决酒精引起的学习和记忆缺陷的潜在选择。
