Novel mechanisms of epigenetic regulation in stress and depression: toward a precision medicine model

项目总结/摘要 抑郁症是全世界疾病和残疾的主要原因，女性的发病率是男性的两倍。压力是抑郁症的一个公认的危险因素。迄今为止的研究表明，压力导致基因表达的表观遗传重编程，这对大脑回路（如腹侧海马）的神经元可塑性至关重要，腹侧海马与抑郁症有关。我们之前报道过：1）乙酰-L-肉碱（LAC）的施用通过增加慢性应激诱导的H3 K27 ac抑制和vDG谷氨酸能神经元中谷氨酸释放mGlu 2受体的关键抑制剂的相关表达而导致快速和持续的抗抑郁样应答;和2）在患有抑郁症的受试者中LAC水平降低。本申请的目的是了解LAC相关的线粒体代谢在应激反应调节中的作用。这一贡献将促进我们对线粒体代谢应激反应的细胞和分子机制的理解，并确定这些机制的性别差异。

PROJECT SUMMARY/ABSTRACT Depression is a leading cause of illness and disability worldwide, with a two-fold higher incidence in women than men. Stress is a well-established risk factor for depression. Studies to date showed that stress leads to epigenetic reprogramming of gene expression key for neuronal plasticity of brain circuits such as the ventral hippocampus, which has been implicated in depression. We previously reported that: 1) administration of acetyl-L-carnitine (LAC), leads to a rapid and persistent antidepressant-like response by increasing a chronic stress-induced suppression of H3K27ac and the related expression of a key inhibitor of glutamate release mGlu2 receptor in vDG glutamatergic neurons; and 2) LAC levels are decreased in subjects suffering from depression. The objective of this application is to understand the role of LAC-related mitochondrial metabolism in the regulation of stress responses. This contribution will advance our understanding of cellular and molecular mechanisms of mitochondrial metabolism for stress responses, and identify sex-differences in these mechanisms.