Resende L S, Amaral C E, Soares R B S, Alves A S, Alves-Dos-Santos L, Britto L R G, Chiavegatto S
Department of Pharmacology, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo, Brazil.
National Institute for Developmental Psychiatry (INCT-CNPq), Department of Psychiatry, Institute of Psychiatry, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Transl Psychiatry. 2016 Oct 11;6(10):e914. doi: 10.1038/tp.2016.202.
MAX is a conserved constitutive small phosphoprotein from a network of transcription factors that are extensively studied in tumorigenesis and whose functions affect cell proliferation, differentiation and death. Inspired by its higher expression during development and in regions involved in emotional behaviors, we hypothesized its involvement in cerebral changes caused by early-life stress. We studied the effects of repeated social stress during adolescence on behaviors and on MAX and its putative partner MYC. Thirty-day-old C57BL/6 male mice underwent brief daily social defeat stress from an adult aggressor for 21 days. Following social stress episodes and housing in social groups after each defeat, adolescent mice exhibit depressive-like, but not anxiety-like behaviors and show higher MAX nuclear immunoreactivity in hippocampal (HC) but not prefrontal cortical (PFC) neurons. Conversely, MAX immunoreactivity is lower in the striatum (ST) of defeated adolescents. The positive correlation between MAX and MYC levels in the PFC revealed disruptions in both the HC and ST. The changes in MAX protein levels are not due to differential gene expression or protein degradation in those regions, suggesting that posttranscriptional modifications occurred. These findings indicate that repeated, brief social defeat in adolescent male mice, combined with group housing, is a useful protocol to study a subtype of depression that is dissociated from generalized (non-social) anxiety. To our knowledge, this is the first report of an association between dysregulation of the MAX-MYC network in the brain and a behavior, suggesting a novel approach for exploiting the neuroplasticity associated with depression.
MAX是一种保守的组成型小磷蛋白，来自一个转录因子网络，该网络在肿瘤发生中得到广泛研究，其功能影响细胞增殖、分化和死亡。受其在发育过程中以及在涉及情绪行为的区域中较高表达的启发，我们推测它参与了早期生活压力引起的大脑变化。我们研究了青春期反复社交压力对行为以及对MAX及其假定伴侣MYC的影响。30日龄的C57BL/6雄性小鼠每天遭受成年攻击者短暂的社交挫败压力，持续21天。在社交压力事件以及每次挫败后群居饲养后，青春期小鼠表现出类似抑郁的行为，但没有类似焦虑的行为，并且在海马体（HC）神经元中显示出较高的MAX核免疫反应性，但在前额叶皮质（PFC）神经元中没有。相反，在遭受挫败的青春期小鼠的纹状体（ST）中，MAX免疫反应性较低。PFC中MAX和MYC水平之间的正相关揭示了HC和ST中的破坏。MAX蛋白水平的变化不是由于这些区域中基因表达差异或蛋白质降解，这表明发生了转录后修饰。这些发现表明，青春期雄性小鼠反复、短暂的社交挫败与群居饲养相结合，是研究一种与广泛性（非社交性）焦虑分离的抑郁症亚型的有用方案。据我们所知，这是关于大脑中MAX-MYC网络失调与一种行为之间关联的首次报告，这表明了一种利用与抑郁症相关的神经可塑性的新方法。
