Circuit-wide proteomics profiling reveals brain region-specific protein signatures in the male WKY rats with endogenous depression

Background: Although the Wistar Kyoto (WKY) rat has been consistently recognized as an animal model with endogenous depression, the exact molecular mechanisms underlying its genetic susceptibility to depression remain undetermined.Methods: Compared with the Wistar rats, the depression-like behaviors of the male WKY ones were evaluated by both the sucrose preference test and forced swimming test. Golgi staining analysis was conducted to access the dendritic morphology. TMT-labelled quantitative proteomics analyses were respectively performed in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and hippocampus (Hip), followed by KEGG enrichment -based clustering analysis, Venn diagram analysis, and Pearson correlation analysis.Results: The WKY strain showed significant differences in both the depression-like behaviors and synaptic plasticity. Moreover, the WKY model displayed markedly distinct differentially-expressed protein (DEP) profiles, with minor differences between the WKY subgroups. A cerebral regional commonality and specificity were evident in the signaling pathways enriched in the WKY model, and a total of 15 brain region-specific DEPs were identified to closely correlate with the depression-like phenotypes (in the mPFC: Lrrc8d, Dcun1d2, and Mtnd5; in the NAc: Ccdc154, Sec14l2, Kif2a, LOC680322, Me1, Mknk1, and Ret7; in the Hip: Sec14l2, Serpinf2, LOC103694855, Fam13c, and Loxl1). Data were available via ProteomeXchange with identifier PXD029079.Limitations: Female WKY rats are not included, and the roles of these candidate DEPs in depression remain further elucidation.Conclusion: The present study further evidences the brain region-specific protein signatures in the male WKY model with endogenous depression, providing novel insights into the pathogenesis of depression in males.

背景：尽管Wistar Kyoto（WKY）大鼠一直被认为是具有内源性抑郁症的动物模型，但其遗传易感性抑郁症的确切分子机制仍未确定。方法：与Wistar大鼠相比，与WISTAR大鼠相比，男性WKY的抑郁症行为通过两种抑郁症的行为进行了评估。进行了高尔基染色分析以获取树突形态。 TMT标记的定量蛋白质组学分析分别在内侧前额叶皮层（MPFC）中进行可塑性。此外，WKY模型显示出明显不同的差异表达的蛋白（DEP）曲线，WKY亚组之间的差异很小。在富含WKY模型的信号传导途径中明显存在脑区域通用性和特异性，总共确定了15个大脑区域特异性DEP与抑郁型表型紧密相关（在MPFC：LRRC8D中LOC680322，ME1，MKNK1和RET7；可以通过蛋白酶换识别剂PXD029079。限制：不包括女性WKY大鼠，这些候选dep在抑郁症中的作用仍然进一步阐明。结论：本研究进一步证明了雄性WKY抑郁症的大脑区域特异性蛋白质的脑部特异性蛋白质，可抑郁症状，可抑制抑郁症，使抑郁症患有抑郁症，使其具有抑郁症的病原体，并具有抑郁症。