基于精准影像学导航对抑郁症海马损伤的启动及正反馈机制研究

Hippocampal injury is the core event of depressive disorder, and its mechanism is still not clear. Our previous studies had found that: ① the possibility of progressive hippocampal injury in depressive disorder; ② the initiation area of progressive hippocampal injury; ③ the positive feedback effects triggered by the high inflammatory state after the initiation of injury. Therefore, the research hypothesis was established: the hippocampal injury of depressive disorder might be not entirely attributable to the traditional theoretical definition of stimulus - effect linear event. It was more likely that the high inflammatory state created by the first CA1 injury would trigger the whole area injury in hippocampus and then progressive progressing, and it was strongly echoed with the progressive clinical manifestations and behaviourology of depressive disorder. In this study, we intended to follow up the clinical data of large samples and dynamic test of the depressive animal model to tamp the progressive injury of the hippocampus using 3.0T and 7.0T magnetic resonance (MRI); dynamically monitor hippocampal subregions and verify the CA1 area as a starting area for progressive injury using precise imaging; explore the downstream events and positive feedback effects triggered by the high inflammatory state after the CA1 injury.This project, combined in two ways in vivo and in vitro, revealed the hippocampal injury mechanism of the initiation and evolution in depression through clinical, animal and cell levels, also provided a theoretical basis for exploring the mechanism of depression, establishing the target of prevention and treatment, and promoting the benign return.

海马损伤是抑郁疾病的核心事件，其机制仍未明晰。我们前期研究发现：①抑郁疾病海马进行性损伤的可能；②海马进行性损伤的启动区域；③启动区损伤后的高炎状态可能触发的正反馈效应。由此建立假说：抑郁海马损伤可能并非传统理论定义的刺激-效应的线性事件，更可能为海马CA1区率先损伤后缔造的高炎性状态触发海马全区域损伤并进行性进展，且与抑郁疾病进行性进展的临床表现及行为学异常强烈呼应。本研究拟以3.0T和7.0T磁共振实施大样本临床数据随访及抑郁动物模型动态检测夯实海马进行性损伤；以精准影像学动态监测海马各亚区并验证CA1区为进行性损伤的启动区域；以动物和细胞实验探究CA1区损伤后缔造的高炎状态及其触发的下游事件和正反馈效应。项目以在体、离体两种方式结合，通过临床、动物、细胞三个层面揭示抑郁疾病海马损伤的启动与演变机制，为探索抑郁疾病机制、建立防治靶点、促进良性转归提供理论依据。

海马损伤是抑郁疾病的核心事件。尽管既往丰富的研究由浅至深对抑郁海马损伤进行了详尽探讨，从不同角度形成诸多机制学说（应激、神经递质、神经营养、凋亡再生、炎性等），但传统理论昭示的“海马线性损伤”未能诠释近年引发临床工作高度注意、且日益凸显的棘手问题—抑郁疾病的进行性进展，而后者是抑郁患者自残、自杀及预后的决定因素。本项目研究从如下5个科学问题对海马损伤进行解析：①获得抑郁疾病海马进行性损伤的证据；②CA1区为海马进行性损伤启动区域的证据；③验证CA1区损伤后的高炎性状态及其在海马进行性损伤的启动作用；④高炎性状态通过抑制TrkB调控BDNF-TrkB/STAT3通路；⑤BDNF-TrkB/STAT3/miR-211正反馈环路对抑郁海马进行性损伤的调控。我们的结果和关键数据显示：①结构磁共振数据揭示了抑郁患者海马的时间跨度萎缩率，证实海马结构萎缩呈现递增方式。抑郁大鼠模型的海马结构萎缩率由伊始的约7%进展升至19%。②以PET-CT、DTI为手段对其海马代谢进行做动态分析，证实抑郁患者以及模型大鼠海马代谢障碍呈现明显渐增趋势。③基于临床样本及动物模型数据证实抑郁疾病下海马CA1区损伤的首现性及纵向随访研究中海马全区域损伤的进行性。④给予正常大鼠海马CA1定点注射炎症因子，大鼠产生抑郁样行为异常及海马结构能障碍。⑤在原代培养的大鼠海马神经元细胞中，滴加高炎症因子配液，TrkB表达水平显著降低。⑥抑郁大鼠模型建立过程中海马miR-211与BDNF水平随周龄呈递增及递减趋势，两者在海马中表达呈明显负相关。⑦在原代培养大鼠海马细胞中，miR-211的模拟物呈剂量依赖性下调BDNF mRNA及蛋白水平。本项目成果详细解析了抑郁疾病海马损伤及其相关研究的系列问题，对探索抑郁疾病机制，建立防治靶点、促进良性转归具有重要的意义。