前额叶皮质
伏隔核
重性抑郁障碍
抗抑郁药
慢性应激
代谢组学
海马体
丙咪嗪
医学
生物
药理学
神经科学
生物信息学
中枢神经系统
扁桃形结构
病理
替代医学
认知
作者
Peter J. Hamilton,Emily Y. Chen,Vladimir Tolstikov,Catherine J. Peña,Joseph A. Picone,Punit Shah,Kiki Panagopoulos,Ana N. Strat,Deena M. Walker,Zachary S. Lorsch,Hannah L. Robinson,Nicholas L. Mervosh,Drew D. Kiraly,Rangaprasad Sarangarajan,Niven R. Narain,Michael A. Kiebish,Eric J. Nestler
标识
DOI:10.1038/s41598-020-75114-5
摘要
Major depressive disorder (MDD) is a complex condition with unclear pathophysiology. Molecular disruptions within limbic brain regions and the periphery contribute to depression symptomatology and a more complete understanding the diversity of molecular changes that occur in these tissues may guide the development of more efficacious antidepressant treatments. Here, we utilized a mouse chronic social stress model for the study of MDD and performed metabolomic, lipidomic, and proteomic profiling on serum plus several brain regions (ventral hippocampus, nucleus accumbens, and medial prefrontal cortex) of susceptible, resilient, and unstressed control mice. To identify how commonly used tricyclic antidepressants impact the molecular composition in these tissues, we treated stress-exposed mice with imipramine and repeated our multi-OMIC analyses. Proteomic analysis identified three serum proteins reduced in susceptible animals; lipidomic analysis detected differences in lipid species between resilient and susceptible animals in serum and brain; and metabolomic analysis revealed dysfunction of purine metabolism, beta oxidation, and antioxidants, which were differentially associated with stress susceptibility vs resilience by brain region. Antidepressant treatment ameliorated stress-induced behavioral abnormalities and affected key metabolites within outlined networks, most dramatically in the ventral hippocampus. This work presents a resource for chronic social stress-induced, tissue-specific changes in proteins, lipids, and metabolites and illuminates how molecular dysfunctions contribute to individual differences in stress sensitivity.
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