Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Key Laboratory of Forensic Medicine, Department of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China.
Int J Mol Sci. 2024 Jul 24;25(15):8075. doi: 10.3390/ijms25158075.
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.
应激导致中枢神经元代谢和功能改变是抑郁症发病的重要原因。然而，与抑郁症相关的神经元代谢功能障碍及其特定的分子机制仍不清楚。本研究首先使用 NHANES 数据库分析了胆固醇与抑郁症之间的关系。然后，我们通过束缚应激诱导小鼠产生抑郁样行为。应用生物信息学、病理学和分子生物学，观察脑胆固醇稳态的病理特征，研究脑胆固醇代谢紊乱的调节机制。通过 NHANES 数据库，我们初步证实胆固醇代谢异常与抑郁症之间存在显著相关性。此外，基于成功建立应激小鼠模型，我们发现应激导致大脑中与胆固醇相关的 DEGs 数量显著增加，且具有区域性异质性。进一步研究与抑郁症密切相关的额皮质发现，应激导致胆固醇代谢关键基因显著失调，包括 HMGCR、CYP46A1、ACAT1、APOE、ABCA1 和 LDLR，导致总胆固醇含量增加，突触蛋白 PSD-95 和 SYN 显著减少。这表明胆固醇代谢影响神经元突触可塑性，并与应激诱导的小鼠抑郁样行为有关。腺相关病毒干扰短期应激小鼠前额皮质中的 NR3C1，导致 NRIP1、NR1H2、ABCA1 和总胆固醇含量的蛋白水平降低。同时，增加了突触蛋白 PSD95 和 SYN，有效缓解了抑郁样行为。因此，这些结果表明，短期应激可能通过激活 NR3C1/NRIP1/NR1H2 信号通路引起胆固醇代谢紊乱。这损害了神经元突触可塑性，并参与了小鼠的抑郁样行为。这些发现表明，应激引起的大脑中异常胆固醇代谢是抑郁症发病的重要原因。
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