不同比例n-6/n-3多不饱和脂肪酸对丙戊酸诱导孤独症模型大鼠行为学的影响及其作用机制

The ratio of n-6/n-3 polyunsaturated fatty acids (PUFA) is reported to associate with the pathogenesis and abnormal behavior of autism spectrum disorders (ASD). ASD are a heterogeneous group of neurodevelopmental disorders characterized by impaired social interactions and communication, and by restricted and repetitive behavior. However, therapies for treating core symptoms of ASD are limited. PUFA is a potential choice for treating autistic behavior, but the suitable ratio and time of n-6/n-3 PUFA and its mechanism of action have not yet known. On basis of the aforementioned evidences, we hypothesize that autistic behaviors are influenced by different ratios n-6/n-3 PUFA in different stages of life. A murine model of ASD induced by prenatal exposure to Valproic acid is utilized in the present study. Different ratios n-6/n-3 PUFA will be given to the murine model of ASD. The core symptoms, developmental behavior tests, and neuropathological indicators will be assessed in order to determine the suitable ratio and time of n-6/n-3 PUFA for ASD treatment. PUFA might affect the intestinal microbiota, while the connections between intestinal microbes and ASD has aroused a widespread concern around the world. The PCR-DGGE analysis and high-throughput sequencing analysis will be used to assess the intestinal microbiota for the most effective group before and after the PUFA treatment, respectively. Meanwhile, the neuropathological features and gut barrier integrity will be described. This study of the role of different ratios of n-6/n-3 PUFA in the therapy of ASD will provide theoretical basis for further research on the aspect of nutritional treatment for ASD and potential therapy targets.

n-6、n-3多不饱和脂肪酸(PUFA)的比例失调与孤独症谱系障碍(ASD)的发病及行为学表现有关。ASD是一组严重的神经发育障碍性疾病，对其异常行为尚无特效疗法；PUFA有望用于ASD的行为干预，但n-6/n-3 PUFA作用的适宜比例、时点有待研究。本研究以丙戊酸诱导的ASD模型大鼠为研究对象，探讨在模型鼠不同生命时期给予不同比例n-6/n-3 PUFA干预对其行为学的影响，从发育行为学、神经生物学等指标探讨n-6、n-3 PUFA改善ASD异常行为的适宜比例和时点。PUFA可影响肠道微生态，而肠道微生态与ASD的关联已引起了关注。本研究采用PCR-DGGE技术、高通量测序技术检测行为学改善最显著组大鼠肠道菌群变化，寻找相关联及共变化的菌群，结合神经生物学、肠道黏膜屏障功能等关联研究，阐明适宜构成的PUFA改善ASD行为学的可行性及其机理，为ASD的营养治疗提供科学依据和潜在靶标。

n-6、n-3多不饱和脂肪酸(PUFA)的比例失调与孤独症谱系障碍(ASD)的发病及行为学表现有关，PUFA可影响肠道微生态；而肠道微生态与ASD的关联已引起了广泛的关注。ASD是一组严重的神经发育障碍性疾病，对ASD的异常行为尚无特效疗法。本研究构建了ASD研究中应用最广泛的孕期注射丙戊酸诱导ASD大鼠模型，证明其具备儿童ASD的社会交往障碍、言语和非言语交流障碍、兴趣狭窄和重复、刻板行为等行为学核心症状。本研究通过在不同生命时期给予不同比例的n-6/n-3 PUFA干预，明确行为学改善最显著组的n-6/n-3 PUFA构成比例为5:1和生后21天；研究揭示了与之相关联及共变化的肠道菌群、神经生物学变化。本研究为适宜比例的n-6/n-3 PUFA用于ASD异常行为的临床营养干预提供实验基础和科学依据，为更深入探讨ASD的肠道微生态相关发生、发展机制提供实验依据，而且还为筛选、发现ASD相关联菌群和治疗的潜在靶标提供平台，具有良好的临床意义和应用前景。但是，该研究结论仍需要未来通过临床研究来证实。目前已经发表论文4篇，其中SCI收录论文2篇，核心期刊论文2篇，待投稿SCI论文2篇，培养青年骨干2名，硕士研究生1名。