AKT1基因在精神分裂症脑网络功能异常中的调控机制研究

Schizophrenia is a common severe mental disorder. Approximately one-third of patients with schizophrenia do not respond adequately to treatment and are considered treatment-resistant. The neuropathological mechanism of treatment-resistant schizophrenia remains to be elucidated. Interdisciplinary research in gene-neuroimaging has provided a vast body of evidence on intermediate phenotypes of risk genes and brain networks in schizophrenia. The interaction between the functional integration of the salience network, default mode network and central executive network, and the protein kinase B1 (AKT1) gene has been demonstrated to be closely related to occurrence and development of clinical symptoms of schizophrenia. However, there is no related research to further explore or verify these findings. Our study will conduct an in-depth exploration at a gene-brain network-behavior level to examine: ① the features of the AKT1 polymorphism and of the integration mode of salience-default mode-central executive network in treatment-resistant patients and in good responders, ② the interaction pattern between the AKT1 gene and salience-default mode-central executive network in schizophrenia, and ③ the association between the AKT1 gene, the salience-default mode-central executive network, and clinical symptoms and cognitive functions in schizophrenia. The study aims to contribute to new strategies of identifying intermediate phenotypes of treatment-resistant schizophrenia and to further understanding of the neuropathological mechanism of schizophrenia.

精神分裂症是一种常见的重性精神障碍，即使经过充分治疗仍有约1/3成为难治性患者，难治性精神分裂症的病理机制急需阐明。在寻找精神分裂症风险基因和脑网络中间表型的研究中，基因-影像学跨学科研究提供了大量研究证据。学术界推测蛋白激酶B1（AKT1）基因可能参与了突显网络、默认网络、中央执行网络之间的功能整合，与精神分裂症的发生和发展紧密相关，然而迄今为止尚无相关研究对这一假设进行深入探索和验证。本研究拟从基因-脑网络-行为三个层面深入探索：①有效精神分裂症患者与难治性患者AKT1基因多态性特征及突显-默认-中央执行网络的整合模式特征；②精神分裂症中AKT1基因影响突显-默认-中央执行网络整合模式的病理机制；③AKT1基因、突显-默认-中央执行网络整合模式与精神分裂症临床症状及认知功能的相互关系。本研究的预期成果将为寻找难治性精神分裂症的中间表型和深入理解精神分裂症的神经病理机制提供新的视角。

精神分裂症全球患病率高达1.0%，仅中国约有1000万精神分裂症患者。患者中又有高达1/3的比例是难治性精神分裂症，急需阐明难治性精神分裂症的机制。精神分裂症风险基因蛋白激酶 B1（AKT1）基因与核心脑网络如中央执行网络、默认网络和突显网络与精神分裂症的治疗效果可能存在紧密联系。本项目发现精神分裂症风险基因DISC1三个位点与诊断具有交互效应，Rs821617与诊断的交互效应脑区位于：楔前叶、基底节(壳核与苍白球)、感觉运动皮层（中央前回与中央后回）III和视觉皮层（枕中回与距状沟）；rs821616 与诊断交互效应脑区位于颞中回（延伸至颞上回）和中央后回；rs2738880与诊断的交互效应体现在颞下回。本研究首次揭示了 DISC1 基因突变对精神分裂症患者静息态下脑功能局部一致性的影响,进一步支持DISC1突变可能是精神分裂症的脑功能异常的遗传学基础。运用动态功能连接（dynamic functional connectivity, dFC）分析，首次发现和健康人相比，精神分裂症表现出一系列皮层下区域的局部dFC，丘脑-感觉运动皮层之间dFC及涉及视觉网络、注意网络、边缘系统的dFC时间变异度的显著上升,以及默认网络的dFC时间变异度的显著下降。以上发现为我们深入理解精神分裂症的病理机制和定位潜在的干预靶点提供了重要的科学依据。