Decreased hippocampal synaptic plasticity is an important pathological change in stress-related mood disorders, including major depressive disorder. However, the underlying mechanism is unclear. PGC-1α, a transcriptional coactivator, is a key factor in synaptic plasticity. We investigated the relationships between changes in hippocampal PGC-1α expression and depressive-like and stress-coping behaviours, and whether they are related to hippocampal synapses. Adeno-associated virus was used to alter hippocampal PGC-1α expression in male C57BL/6 mice. The sucrose preference test and forced swimming test were used to assess their depressive-like and stress-coping behaviours, respectively. Immunohistochemistry and stereology were used to calculate the total number of excitatory synapses in each hippocampal subregion (the cornu ammonis (CA) 1, CA3, and dentate gyrus). Immunofluorescence was used to visualize the changes in dendritic structure. Western blotting was used to detect the expression of hippocampal PGC-1α and mitochondrial-associated proteins, such as UCP2, NRF1 and mtTFAs. Our results showed that mice with downregulated PGC-1α expression in the hippocampus exhibited depressive-like and passive stress-coping behaviours, while mice with upregulated PGC-1α in the hippocampus exhibited increased stress-coping behaviours. Moreover, the downregulation of hippocampal PGC-1α expression resulted in a decrease in the number of excitatory synapses in the DG and in the protein expression of UCP2 in the hippocampus. Alternatively, upregulation of hippocampal PGC-1α yielded the opposite results. This suggests that hippocampal PGC-1α is involved in regulating depressive-like and stress-coping behaviours and modulating the number of excitatory synapses in the DG. This provides new insight for the development of antidepressants.

中文翻译：

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海马体中的 PGC-1α 介导小鼠的抑郁样和应激应对行为并调节齿状回的兴奋性突触

海马突触可塑性降低是压力相关情绪障碍（包括重度抑郁症）的重要病理变化。然而，其根本机制尚不清楚。 PGC-1α 是一种转录共激活因子，是突触可塑性的关键因素。我们研究了海马 PGC-1α 表达的变化与抑郁样和压力应对行为之间的关系，以及它们是否与海马突触有关。使用腺相关病毒来改变雄性 C57BL/6 小鼠海马 PGC-1α 的表达。蔗糖偏好测试和强迫游泳测试分别用于评估他们的抑郁样行为和压力应对行为。使用免疫组织化学和体视学来计算每个海马亚区域（阿蒙角 (CA) 1、CA3 和齿状回）中兴奋性突触的总数。使用免疫荧光来观察树突结构的变化。 Western blotting检测海马PGC-1α和线粒体相关蛋白UCP2、NRF1、mtTFA等的表达。我们的结果表明，海马 PGC-1α 表达下调的小鼠表现出抑郁样和被动的应激应对行为，而海马 PGC-1α 表达上调的小鼠表现出增强的应激应对行为。此外，海马PGC-1α表达的下调导致DG中兴奋性突触的数量和海马UCP2蛋白表达的减少。或者，上调海马 PGC-1α 会产生相反的结果。这表明海马 PGC-1α 参与调节抑郁样和压力应对行为以及调节 DG 中兴奋性突触的数量。这为抗抑郁药的开发提供了新的见解。