基于脑网络组图谱的精神分裂症工作记忆障碍研究

Characteristic brain magnetic resonance imaging (MRI) abnormalities in schizophrenic patients with working memory impairment are largely unknown, and genetic and molecular mechanisms of their impaired neural circuits are not well understood as well. The plan of current project is based on the previous research work supported by the Key Program of Major Research Plan from the National Natural Science Foundation (NSFC). We will take advantage of multidisciplinary strategy, by combining technology and methods from psychopathology, molecular genetics, brain imaging, animal modeling, behavioral assessment, optical imaging, neural circuit tracing, optogenetics, electrophysiology, cell and molecular biology etc. Focusing on the mechanism of abnormal neural circuits involved in impaired working memory in patients with schizophrenia, we will carry out a comprehensive study on the scientific issue - “Disorder of working memory, Dysfunction of brain region, Impairment of neural plasticity are the neurobiological features for schizophrenia”. The research work will include investigating the characteristic MRI abnormalities of bran networks related to working memory disorders based on the latest Brainnetome atlas, the regulation effects of repeated transcranial magnetic stimulation (rTMS) on the brain networks of working memory; further determining the susceptibility genes/variations associated with the impaired working memory in schizophrenic patients; mapping the abnormal neural circuits in animal models qualitatively and quantitatively; uncovering the molecular mechanism of abnormal changes of memorial neural circuits caused by the susceptibility genes/variations. The project will establish brain network models of working memory impairment in schizophrenia including abnormalities in brain regions and circuits; preliminarily determine the molecular mechanism of working memory impairment. The expected results will provide important experimental evidence for developing new biomarkers for clinical diagnosis and efficacy prediction of schizophrenia.

精神分裂症(分裂症)患者工作记忆损害脑影像异常特征尚不清楚，其神经环路受损的遗传及分子机理也不明确。本项目拟在前期重大研究计划重点支持项目的基础上，采用精神病理、分子遗传、脑影像、动物建模、行为评定、光学成像、环路示踪、光遗传调控、电生理、细胞与分子生物等多学科技术方法，围绕“分裂症患者工作记忆障碍的神经环路机制”这一科学问题展开综合性研究，探讨基于“新一代脑网络组图谱”的分裂症工作记忆障碍相关脑网络的影像学异常表征以及非药物治疗(rTMS)对记忆网络的调控、进一步确定与该病工作记忆障碍关联的易感基因/变异、对动物模型记忆神经环路功能异常进行定量定性描述、探讨易感基因/变异所致记忆神经环路异常改变的分子机制。本项目预期结果将建立分裂症工作记忆障碍脑区以及神经环路异常的脑网络模型，初步明确分裂症记忆环路受损的分子机制，并为发展可用于临床诊断和疗效预测的影像遗传生物标志提供重要的实验依据。

工作记忆障碍是精神分裂症的核心认知损害之一，然而其脑影像异常特征尚不清楚，相关神经环路受损的遗传及分子机理也不明确。本项目在前期重大研究计划重点支持项目的基础上，采用精神病理、分子遗传、脑影像、动物建模、行为评定、光学成像、环路示踪、光遗传调控、电生理、细胞与分子生物等多学科技术方法，围绕“分裂症患者工作记忆障碍的神经环路机制”这一科学问题展开综合性研究。超额完成精神分裂症患者及正常对照者的样本收集工作，并完成工作记忆的评定和多模态MRI数据采集，在此基础上，探讨精神分裂症工作记忆障碍相关脑网络的影像学异常表征，发现背外侧前额叶的效率下降和腹外侧前额叶的弥补机制可能是精神分裂症工作记忆损害的特征性脑功能异常模式，额叶功能和白质结构网络效率受损可能是疾病的生物学中间表型。进一步确定ALDH2、ZNF804A参与工作记忆相关海马-前额叶静息态功能网络的分子遗传机制。基于前期工作基础，进一步开展疾病全基因组数据的Meta分析，确定疾病易感基因/变异，建立完成OPCML, NKAPL和TSPAN18条件性敲除小鼠模型，尝试从行为、形态、分子信号通路等多个层次水平观察精神分裂症易感基因修饰小鼠的表型，利用光遗传学等手段对环路缺陷进行探索，利用干扰RNA/ CRISPR/Cas9等病毒脑内立体定位注射的方法，观察在非人灵长类动物模型中敲低OPCML是否导致与啮齿类动物中相似的发育及行为学表型。完成STON2 307P-851A和307S-851S基因敲入小鼠行为学评定、小鼠脑片的电生理学特征和神经元突触前递质释放和回收等分子机理研究。同时开展了探索性研究，发现社会应激环境因素及疾病遗传风险因素对工作记忆神经环路的影响存在遗传-环境交互效应。本项目初步明确精神分裂症记忆环路受损的分子机制，为发展可用于临床诊疗的影像遗传生物标志提供重要的实验依据。