BACKGROUND Deficiency in neuronal structural plasticity is involved in the development of major depressive disorder. TWIST1, a helix-loop-helix transcription factor that is essential for morphogenesis and organogenesis, is normally expressed at low levels in mature neurons. However, it is poorly understood what role TWIST1 plays in the brain and whether it is involved in the pathophysiology of depression. METHODS Depressive-like behaviors in C57BL/6J mice were developed by chronic social defeat stress. Genetic and pharmacological approaches were used to investigate the role of the TWIST1-miR-214-PPAR-δ signaling pathway in depressive-like behaviors. Molecular biological and morphological studies were performed to define the molecular mechanisms downstream of TWIST1. RESULTS The expression of TWIST1 was positively correlated with depressive behaviors in humans and mice. Chronic stress elevated TWIST1 expression in the medial prefrontal cortex of mice, which was reversed by fluoxetine treatment. While the overexpression of TWIST1 increased susceptibility to stress, the knockdown of TWIST1 prevented the defective morphogenesis of dendrites of pyramidal neurons in layer II/III of the medial prefrontal cortex and alleviated depressive-like behaviors. Mechanistically, this prodepressant property of TWIST1 was mediated, at least in part, through the repression of miR-214-PPAR-δ signaling and mitochondrial function, which was also mimicked by genetic and pharmacological inhibition of PPAR-δ. CONCLUSIONS These results suggest that TWIST1 in the medial prefrontal cortex mediates chronic stress-induced dendritic remodeling and facilitates the occurrence of depressive-like behavior, providing new information for developing drug targets for depression therapy.

中文翻译：

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转录因子 TWIST1 整合树突状重塑和慢性压力以促进抑郁样行为

背景神经元结构可塑性的缺陷与重度抑郁症的发展有关。TWIST1 是一种螺旋-环-螺旋转录因子，对形态发生和器官发生至关重要，通常在成熟神经元中以低水平表达。然而，人们对 TWIST1 在大脑中的作用以及它是否参与抑郁症的病理生理学知之甚少。方法 C57BL/6J 小鼠的抑郁样行为是由慢性社交失败压力引起的。遗传和药理学方法用于研究 TWIST1-miR-214-PPAR-δ 信号通路在抑郁样行为中的作用。进行分子生物学和形态学研究以确定 TWIST1 下游的分子机制。结果TWIST1的表达与人和小鼠的抑郁行为呈正相关。慢性应激提高了小鼠内侧前额叶皮质中 TWIST1 的表达，而氟西汀治疗逆转了这种情况。虽然 TWIST1 的过表达增加了对压力的敏感性，但 TWIST1 的敲低阻止了内侧前额叶皮层 II/III 层锥体神经元树突的形态发生缺陷，并减轻了抑郁样行为。从机制上讲，TWIST1 的这种促抑郁特性至少部分是通过抑制 miR-214-PPAR-δ 信号传导和线粒体功能来介导的，这也被 PPAR-δ 的遗传和药理学抑制所模拟。