PDF(Pubmed)
Abstract：
Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.
摘要：
情绪障碍是一类令人衰弱的神秘疾病，影响着全世界数百万人。虽然慢性压力明显增加了情绪障碍的发病率，包括重度抑郁症（MDD），导致这些疾病的压力介导的脑功能破坏在很大程度上仍然难以捉摸。5-羟色胺相关抗抑郁药（AD）仍然是许多抑郁症状患者的一线治疗方法。然而，低缓解率和治疗与症状缓解之间的延迟促使人们对5-羟色胺在情感障碍的沉淀和治疗中的直接作用持怀疑态度。我们小组最近证明，5-羟色胺表观遗传学修饰组蛋白（H3K4me3Q5ser）可调节大脑中的转录允许性。然而,在应激和/或AD暴露后，这种非规范现象尚未被探索。这里,我们对暴露于慢性社会失败压力的雄性和雌性小鼠的背缝核（DRN）进行了全基因组和生化分析的组合，以及人类MDD患者的DRN，为了检查压力暴露/MDD诊断对H3K4me3Q5ser动力学的影响，以及标记和抑郁相关基因表达之间的关联。我们还评估了AD暴露后H3K4me3Q5ser的应激诱导/MDD相关调节，并在小鼠中使用病毒介导的基因治疗以降低DRN中的H3K4me3Q5ser水平，并检查其对应激相关基因表达和行为的影响。我们发现H3K4me3Q5ser在应激介导的转录可塑性中起重要作用。慢性应激小鼠在DRN中表现出H3K4me3Q5ser动力学失调，AD和病毒介导的这些动力学破坏证明足以减弱应激介导的基因表达和行为。在与MDD受试者中观察到H3K4me3Q5ser调节的相应模式在他们死亡的时候关闭广告。因此，这些发现确立了5-羟色胺在应激/AD相关转录和行为可塑性中的神经传递非依赖性作用。这些观察结果可能与人类MDD及其治疗具有临床相关性。
