Santos Lucas, Possa Luana, Fröhlich Nicole, Behrens Luiza, Barbosa Camila, Tiefensee-Ribeiro Camila, Gelain Daniel Pens, Almeida Roberto F, Moreira José Cláudio Fonseca
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Neurochem Res. 2025 Jun 12;50(3):196. doi: 10.1007/s11064-025-04455-2.
Major Depressive Disorder (MDD) is a multifactorial psychiatric condition. Evidence shows that stress plays a fundamental role in the pathophysiology of MDD. Studies have hypothesized that some changes in histone acetylation patterns and histone deacetylase (HDACs) are closely associated with the development of MDD. Histone acetylation and deacetylation are covalent modifications that influence chromatin structure, serving as key mechanisms for controlling gene expression. The aim of this study was to investigate the involvement of H2AK5ac, H2BK5ac, H3K9ac, and H4K8ac, as well as HDACs, HDAC1-7 in rats subjected to the chronic unpredictable moderate stress (CUMS) model. For this, 29 male Wistar rats were exposed to the CUMS protocol or designated as a control group. After behavioral tests the animals were classified as resilient or susceptible to the depressive-like phenotype. Subsequently, the acetylation patterns of histones and HDACs were evaluated in the hypothalamus, hippocampus, and parietal cortex. Observing sucrose consumption, open field behavior, and object recognition, it is possible to identify characteristic phenotypes of animals that are either susceptible to the depressive-like phenotype or resilient to the CUMS protocol. For the first time, it was demonstrated that the H3K9ac, H4K8ac, HDAC2, HDAC3, HDAC4, and HDAC5 patterns are associated with resilience or susceptibility to the depressive-like phenotype in a brain region-specific manner. Results from this study provide evidence that H3 and H4 acetylation's and HDACs are connected with the development of the resilient or susceptible depressive-like phenotype, hence contributing to new advances in understanding the pathophysiology of MDD and discovering mechanisms behind resilience.
重度抑郁症（MDD）是一种多因素导致的精神疾病。有证据表明，压力在MDD的病理生理学中起着重要作用。研究推测，组蛋白乙酰化模式和组蛋白去乙酰化酶（HDACs）的某些变化与MDD的发生密切相关。组蛋白乙酰化和去乙酰化是影响染色质结构的共价修饰，是控制基因表达的关键机制。本研究的目的是调查H2AK5ac、H2BK5ac、H3K9ac和H4K8ac以及HDACs、HDAC1 - 7在慢性不可预测中度应激（CUMS）模型大鼠中的作用。为此，将29只雄性Wistar大鼠暴露于CUMS方案或指定为对照组。在行为测试后，将动物分类为对抑郁样表型有抵抗力或易感性。随后，在下丘脑、海马体和顶叶皮质中评估组蛋白和HDACs的乙酰化模式。通过观察蔗糖消耗、旷场行为和物体识别，可以识别出对抑郁样表型易感或对CUMS方案有抵抗力的动物的特征性表型。首次证明，H3K9ac、H4K8ac、HDAC2、HDAC3、HDAC4和HDAC5模式以脑区特异性方式与对抑郁样表型的抵抗力或易感性相关。本研究结果提供了证据，表明H3和H4乙酰化以及HDACs与有抵抗力或易感的抑郁样表型的发展有关，从而有助于在理解MDD的病理生理学和发现抵抗力背后的机制方面取得新进展。
