PDF(Pubmed)
Abstract：
Stress-induced alterations in central neuron metabolism and function are crucial contributors to depression onset. However, the metabolic dysfunctions of the neurons associated with depression and specific molecular mechanisms remain unclear. This study initially analyzed the relationship between cholesterol and depression using the NHANES database. We then induced depressive-like behaviors in mice via restraint stress. Applying bioinformatics, pathology, and molecular biology, we observed the pathological characteristics of brain cholesterol homeostasis and investigated the regulatory mechanisms of brain cholesterol metabolism disorders. Through the NHANES database, we initially confirmed a significant correlation between cholesterol metabolism abnormalities and depression. Furthermore, based on successful stress mouse model establishment, we discovered the number of cholesterol-related DEGs significantly increased in the brain due to stress, and exhibited regional heterogeneity. Further investigation of the frontal cortex, a brain region closely related to depression, revealed stress caused significant disruption to key genes related to cholesterol metabolism, including HMGCR, CYP46A1, ACAT1, APOE, ABCA1, and LDLR, leading to an increase in total cholesterol content and a significant decrease in synaptic proteins PSD-95 and SYN. This indicates cholesterol metabolism affects neuronal synaptic plasticity and is associated with stress-induced depressive-like behavior in mice. Adeno-associated virus interference with NR3C1 in the prefrontal cortex of mice subjected to short-term stress resulted in reduced protein levels of NRIP1, NR1H2, ABCA1, and total cholesterol content. At the same time, it increased synaptic proteins PSD95 and SYN, effectively alleviating depressive-like behavior. Therefore, these results suggest that short-term stress may induce cholesterol metabolism disorders by activating the NR3C1/NRIP1/NR1H2 signaling pathway. This impairs neuronal synaptic plasticity and consequently participates in depressive-like behavior in mice. These findings suggest that abnormal cholesterol metabolism in the brain induced by stress is a significant contributor to depression onset.
摘要：
应激诱导的中枢神经元代谢和功能的改变是抑郁症发作的关键因素。然而,与抑郁症相关的神经元代谢功能障碍和特定的分子机制仍不清楚。这项研究最初使用NHANES数据库分析了胆固醇和抑郁症之间的关系。然后，我们通过约束应激在小鼠中诱导抑郁样行为。应用生物信息学，病理学,和分子生物学，我们观察了脑胆固醇稳态的病理特征，并探讨了脑胆固醇代谢紊乱的调节机制。通过NHANES数据库，我们初步证实了胆固醇代谢异常与抑郁症之间的显著相关性。此外，在成功建立应激小鼠模型的基础上，我们发现由于压力，大脑中与胆固醇相关的DEGs的数量显着增加，并表现出区域异质性。额叶皮层的进一步调查，与抑郁症密切相关的大脑区域，揭示的压力导致与胆固醇代谢相关的关键基因显著中断，包括HMGCR，CYP46A1,ACAT1,APOE,ABCA1和LDLR,导致总胆固醇含量增加和突触蛋白PSD-95和SYN的显着减少。这表明胆固醇代谢影响神经元突触可塑性，并与小鼠应激诱导的抑郁样行为有关。短期应激小鼠前额叶皮质中NR3C1的腺相关病毒干扰导致NRIP1，NR1H2，ABCA1和总胆固醇含量的蛋白质水平降低。同时,它增加了突触蛋白PSD95和SYN，有效缓解抑郁样行为。因此,这些结果提示短期应激可能通过激活NR3C1/NRIP1/NR1H2信号通路诱导胆固醇代谢紊乱.这会损害神经元突触可塑性，因此参与小鼠的抑郁样行为。这些发现表明，压力引起的大脑中胆固醇代谢异常是抑郁症发作的重要原因。
