Wen Wen, Li Hui, Lauffer Marisol, Hu Di, Zhang Zuohui, Lin Hong, Wang Yongchao, Leidinger Mariah, Luo Jia
Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
Neural Circuits and Behavior Core, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
Front Pharmacol. 2024 Jul 26;15:1407576. doi: 10.3389/fphar.2024.1407576. eCollection 2024.
Excessive alcohol exposure can cause neurobehavioral deficits and structural alterations in the brain. Emerging research evidence suggests that endoplasmic reticulum (ER) stress plays an important role in alcohol-induced neurotoxicity. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress inducible protein and is responsible to maintain ER homeostasis. MANF is highly expressed in both the developing and mature brain. We have previously shown that MANF deficiency exacerbated alcohol induced neurodegeneration and ER stress in the developing brain. However, little is known regarding the role of MANF in alcohol induced neuronal damage in the adult brain. In this study, we used a neuron-specific MANF knockout (KO) mouse model to investigate the effect of MANF deficiency on acute binge alcohol exposure-induced neurobehavioral deficits and ER stress. Adult male and female MANF KO mice and littermate controls received daily alcohol gavage (5 g/kg) for 10 days and then subjected to a battery of neurobehavioral tests including rotarods, balance beam, DigiGait, open field, elevated plus maze, Barnes maze, and three-chamber sociability task. Female MANF KO animals were more susceptible to alcohol-induced body weight loss. Alcohol exposure did not affect motor function, however female but not male MANF KO mice exhibited an increased locomotor activity in open field test. Learning and memory was not significantly impaired, but it was altered by MANF deficiency in females while it was affected by alcohol treatment in males. Both alcohol-exposed male and female MANF KO mice displayed increased sociability. Alcohol induced the expression of ER chaperones GRP78 and GRP94 and altered the levels of several unfolded protein response (UPR) and neuroinflammation markers in MANF KO mice in a sex-specific manner. The expression of MANF interacting proteins neuroplastin, PDIA1, and PDIA6 was increased in MANF KO mice, and was further induced by alcohol. In conclusion, alcohol exposure and neuronal MANF deficiency interacted to alter neurobehavioral outcomes, ER homeostasis and neuroinflammation in a sex-specific manner.
过量饮酒会导致神经行为缺陷和大脑结构改变。新出现的研究证据表明，内质网（ER）应激在酒精诱导的神经毒性中起重要作用。中脑星形胶质细胞衍生的神经营养因子（MANF）是一种内质网应激诱导蛋白，负责维持内质网稳态。MANF在发育中的大脑和成熟大脑中均高度表达。我们之前已经表明，MANF缺乏会加剧发育中大脑酒精诱导的神经退行性变和内质网应激。然而，关于MANF在成人大脑酒精诱导的神经元损伤中的作用知之甚少。在本研究中，我们使用神经元特异性MANF基因敲除（KO）小鼠模型来研究MANF缺乏对急性暴饮酒精暴露诱导的神经行为缺陷和内质网应激的影响。成年雄性和雌性MANF KO小鼠及其同窝对照每天接受酒精灌胃（5 g/kg），持续10天，然后进行一系列神经行为测试，包括转棒试验、平衡木试验、DigiGait试验、旷场试验、高架十字迷宫试验、巴恩斯迷宫试验和三室社交任务试验。雌性MANF KO动物更容易受到酒精诱导的体重减轻影响。酒精暴露不影响运动功能，然而，雌性而非雄性MANF KO小鼠在旷场试验中表现出运动活动增加。学习和记忆没有明显受损，但在雌性中MANF缺乏会改变学习和记忆，而在雄性中酒精处理会影响学习和记忆。酒精暴露的雄性和雌性MANF KO小鼠均表现出社交能力增强。酒精以性别特异性方式诱导内质网伴侣蛋白GRP78和GRP94的表达，并改变了MANF KO小鼠中几种未折叠蛋白反应（UPR）和神经炎症标志物的水平。MANF相互作用蛋白神经纤连蛋白、PDIA1和PDIA6的表达在MANF KO小鼠中增加，并进一步被酒精诱导。总之，酒精暴露和神经元MANF缺乏相互作用，以性别特异性方式改变神经行为结果、内质网稳态和神经炎症。
