持续应激重塑星形胶质细胞葡萄糖代谢促进MDD发生发展

Major depressive disorder, with high morbidity rate and occurrence rate, causes a huge economic burden to the society. Current therapeutics are largely unmet for the clinical needs; one of the important factors may be that the pathophysiology of MDD is not fully understood. Chronic stress, disrupted glucose metabolism and dysfunction of astrocytes (AS) are all risk factors for MDD. However, the causal effect between these elements has not been determined. The normal function of neural cells is closely associated with glucose homeostasis. Whether chronic stress can disrupt glucose metabolism in AS and cause pathologic changes of AS, thus contributing to the onset and progression of MDD is unknown. Our preliminary studies suggested that chronic stress-caused enhanced brain glucose metabolism preceded the onset of depression-like behaviors in mice. Furthermore, in vitro data showed high glucose can cause reduced cell viability of AS, which was consistent with the observations in clinical studies. This project will shed light on novel explanations and possible therapeutic targets for MDD. Moreover, our data may provide evidence for the possibility of measuring glucose metabolism as a biomarker for prevention and therapeutic response of MDD.

重性抑郁障碍（MDD）具有高发病率、高复发率和高医疗负担的特点，其现有治疗策略滞后于临床需求的原因之一可能是病理机制未被充分阐明。研究发现持续应激（CS）、葡萄糖代谢异常以及星形胶质细胞（AS）的病变都不同程度参与了MDD的病理进展，但相互之间的关系并不清楚。AS的正常生理功能与葡萄糖代谢稳态密切相关，而CS作为MDD的确证风险因子，是否可扰乱AS的葡萄糖代谢从而促进其病变有待证明。前期工作发现给予小鼠7天CS即可诱导大脑葡萄糖代谢增加；同时体外实验证实高糖环境可抑制AS细胞存活率，这与临床MDD患者脑内存在AS数目减少的现象吻合。本项目拟进一步阐明CS可重塑AS内葡萄糖代谢从而促进其病变参与MDD病理进程。项目的实施将为MDD提供新的病理解释和可能治疗靶点，同时也可为临床预防MDD提供早期干预指标和治疗反应性指标。

抑郁症是精神疾病危害之首。现有抗抑郁药物多基于神经元病理，存在起效慢和疗效个体差异大等问题，限制了抑郁症的精准治疗进展。申请人针对抑郁症脑内白质病变这一临床现象，深入探索这一病理表型与抑郁的相关性及其潜在神经机制。前期工作中，申请人利用单细胞测序、谱系示踪等技术，结合抑郁患者尸脑样本与动物模型，发现少突胶质细胞（负责髓鞘形成）在慢性应激致抑郁过程中相较于神经元更早期出现损伤，提示少突胶质谱系细胞（OLC）功能异常是抑郁症形成与发展的新型细胞机制。且申请人发现多种促髓鞘化策略能有效改善抑郁症状，进一步证实 OLC障碍是促进抑郁病理进展的重要因素。通过进一步机制分析，申请人发现慢性应激可诱导兴奋性神经元中EphA4的上调表达，其通过抑制少突胶质细胞髓鞘化进程促进抑郁病理进展，同时以上研究也在临床样本中得到了进一步证实。本研究的发现有望拓展抑郁症的神经病理机制，为以逆转髓鞘病变为策略的新型抗抑郁药物开发提供重要理论依据。

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