Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China.
The First Clinical Medical College, Xuzhou Medical University, Xuzhou, China.
PLoS Negl Trop Dis. 2023 May 31;17(5):e0011350. doi: 10.1371/journal.pntd.0011350. eCollection 2023 May.
The neurotrophic parasite Toxoplasma gondii (T. gondii) has been implicated as a risk factor for neurodegenerative diseases. However, there is only limited information concerning its underlying mechanism and therapeutic strategy. Here, we investigated the effects of T. gondii chronic infection on the goal-directed cognitive behavior in mice. Moreover, we evaluated the preventive and therapeutic effect of dimethyl itaconate on the behavior deficits induced by the parasite.
The infection model was established by orally infecting the cysts of T. gondii. Dimethyl itaconate was intraperitoneally administered before or after the infection. Y-maze and temporal order memory (TOM) tests were used to evaluate the prefrontal cortex-dependent behavior performance. Golgi staining, transmission electron microscopy, indirect immunofluorescence, western blot, and RNA sequencing were utilized to determine the pathological changes in the prefrontal cortex of mice.
We showed that T. gondii infection impaired the prefrontal cortex-dependent goal-directed behavior. The infection significantly downregulated the expression of the genes associated with synaptic transmission, plasticity, and cognitive behavior in the prefrontal cortex of mice. On the contrary, the infection robustly upregulated the expression of activation makers of microglia and astrocytes. In addition, the metabolic phenotype of the prefrontal cortex post infection was characterized by the enhancement of glycolysis and fatty acid oxidation, the blockage of the Krebs cycle, and the disorder of aconitate decarboxylase 1 (ACOD1)-itaconate axis. Notably, the administration of dimethyl itaconate significantly prevented and treated the cognitive impairment induced by T. gondii, which was evidenced by the improvement of behavioral deficits, synaptic ultrastructure lesion and neuroinflammation.
The present study demonstrates that T. gondii infection induces the deficits of the goal-directed behavior, which is associated with neuroinflammation, the impairment of synaptic ultrastructure, and the metabolic shifts in the prefrontal cortex of mice. Moreover, we report that dimethyl itaconate has the potential to prevent and treat the behavior deficits.
神经滋养寄生虫刚地弓形虫（Toxoplasma gondii，T. gondii）已被认为是神经退行性疾病的风险因素。然而，关于其潜在机制和治疗策略的信息有限。在这里，我们研究了 T. gondii 慢性感染对小鼠目标导向认知行为的影响。此外，我们评估了二甲烯酮酸酯在寄生虫诱导的行为缺陷中的预防和治疗作用。
通过口服感染 T. gondii 的包囊建立感染模型。在感染前或感染后腹腔内给予二甲烯酮酸酯。Y 迷宫和时间顺序记忆（TOM）测试用于评估前额叶皮层依赖的行为表现。高尔基染色、透射电子显微镜、间接免疫荧光、western blot 和 RNA 测序用于确定小鼠前额叶皮层的病理变化。
我们表明 T. gondii 感染损害了前额叶皮层依赖的目标导向行为。感染显著下调了与突触传递、可塑性和认知行为相关的基因在小鼠前额叶皮层中的表达。相反，感染强烈地上调了小胶质细胞和星形胶质细胞激活标志物的表达。此外，感染后前额叶皮层的代谢表型表现为糖酵解和脂肪酸氧化增强，三羧酸循环受阻，顺乌头酸酶 1（ACOD1）-衣康酸轴紊乱。值得注意的是，二甲烯酮酸酯的给药显著预防和治疗了 T. gondii 诱导的认知障碍，这表现在行为缺陷、突触超微结构损伤和神经炎症的改善上。
本研究表明，T. gondii 感染导致小鼠前额叶皮层的目标导向行为缺陷，这与神经炎症、突触超微结构损伤和代谢变化有关。此外，我们报告二甲烯酮酸酯具有预防和治疗行为缺陷的潜力。
