精神分裂症是一种致残性的重性精神障碍，病因机制不清。抗精神病药物的使用、脑组织取样的侵入性及动物实验中使用麻醉剂对脑功能的改变等都是研究中面临的极大挑战。李涛教授的研究团队收集了大量首发未治疗精神分裂症患者的脑影像学数据，初步揭示了精神分裂症患者全脑网络的失连接模式，发现不同脑网络之间的失连接可能与精神分裂症相关核心症状相关，并发现患者进行性灰质缺损的神经退行性证据。 合作申请人张南鄞博士的研究团队建立了在无麻醉剂的影响下直接比较清醒动物与人影像学数据的方法。合作双方在过去几年里已开展了卓有成效的合作，本项目将充分利用双方在该研究领域技术、资源等优势，通过多模态的方式来建立“人－动物”转化模式，这种模式的建立将有助于在精神分裂症病人和动物模型中的同步研究，多层次地从分子（如：基因和表观遗传）到系统（如：脑结构、功能和神经网络连接）水平进行分析以揭示精神分裂症发病机制。

Schizophrenia is a devastating mental disorder that still lacks effective treatment. Major obstacles to effectively treating the disease include insufficient knowledge of core brain regions and circuitries of pathological change as well as still elusive molecular mechanisms. There are several challenges in schizophrenia research. For instance, medications used by patients in many studies can be an important confound because antipsychotic drugs by themselves have significant impact on the brain. In addition, to gain insight into neurochemical alterations in pathological brain regions, a great deal of vital information can only be obtained in animal studies due to invasive procedures involved. However, translating findings from animal studies to human applications is nontrivial because anesthesia used in most animal experiments can profoundly change the brain function. To overcome these challenges, Dr. Tao Li and Dr. Nanyin Zhang have established an outstanding collaborative partnership to investigate schizophrenia with translational approaches. Dr. Li’s lab has already collected data of structural and functional magnetic resonance imaging (MRI) in a large sample of first-episode, treatment naive schizophrenia patients. By ruling out the effects of treatment and the chronicity of the illness, this extremely valuable dataset has great potential to reveal core brain regions and circuitries of pathological changes in schizophrenia. Indeed, preliminary analysis of this dataset has revealed the patterns of disconnectivity across whole-brain networks in patients, and disconnections between separate brain networks might be associated with different primary symptoms of schizophrenia. We also found that progressive gray matter loss was faster in first-episode schizophrenia patients relative to age-matched controls, suggesting significant neurodegenerative processes in schizophrenia that cannot be attributed to medications. Equally importantly, Dr. Zhang’s lab has established an awake animal imaging paradigm, making it possible to directly compare human and animal imaging data without the influence of anesthesia, and thus has paved the way for establishing a new translational approach for evaluating animal models of schizophrenia. Based on these preliminary results, the primary objective of this collaborative application is to establish a translational model that allows schizophrenia to be studied from the molecular to systematic level in both human patients and animal models by utilizing multi-modal approaches. Successful completion of the proposed research will significantly improve our understanding of the neural and molecular mechanisms underpinning schizophrenia. In addition, it has the potential to reveal the relationships between neurobiological measurements and symptomatology.

精神分裂症是一种严重的慢性致残性精神障碍，目前对该病的病因以及病理生理过程仍缺乏深入理解。本研究以 “人类和动物研究的转化模式”为基础，针对精神分裂症基因敲除小鼠模型样本，采用行为学检测、超高场多模态磁共振成像（脑结构MRI和DTI）等技术手段，结合遗传分子表达定量分析技术分析精神分裂症的核心脑结构网络特征及分子表达转录水平指标，探索精神分裂症异常核心脑环路的分子通路异常；并同步针对高质量、大样本的、未治疗的首发精神分裂症患者样本采用高场磁共振成像（脑结构MRI和DTI）和全基因组测序技术，发现精神分裂症核心脑网络异常的潜在分子通路遗传风险。本研究发现ErbB4敲除精神分裂小鼠存在核心躯体感觉皮层-背侧纹状体脑结构环路异常。此外，采用经典评价精神分裂症前脉冲抑制行为指标，分析发现ErbB4敲除精神分裂小鼠存在感知门控缺陷。前脉冲抑制指标和躯体感觉区域、体感皮层上唇区域及次生体感皮层的灰质体积呈明显正相关。在脑神经结构网络异常多模态生物学指标基础上，进一步研究发现GAD1 mRNA表达水平和躯体感觉区域、体感皮层上唇区域及次生体感皮层的灰质体积呈明显呈正相关。此外，同步研究发现首发未用药精神分裂症患者出现左、右侧躯体感觉皮层及尾状核灰质的体积减少及右侧尾状核白质纤维的完整性下降；GABAergic通路遗传风险得分与患者躯体感觉皮层存在明显负相关。本研究发现ErbB4基因敲除导致精神分裂症核心表型前脉冲抑制下降，表明ErbB4对调节精神分裂症大脑感知门控功能具有重要意义，并可能受到（系统水平）皮层-纹状体结构异常和（分子水平）GABA能分子通路异常的影响，该研究排除药物等混杂因素影响，为精神分裂症人类和动物研究的转化模式研究提供了范式，对探讨精神分裂症的发生发展机制具有重要价值，为探索潜在新药物靶标提供新依据。