Abstract Background Emerging evidence points at a central role of mitochondria in psychiatric disorders. However, little is known about the molecular players that regulate mitochondria in neural circuits regulating anxiety and depression, and how they impact on neuronal structure and function. Here, we investigate the role of molecules involved in mitochondrial dynamics in medium spiny neurons (MSNs) from the nucleus accumbens (NAc), a hub of the brain’s motivation system. Methods We assess how individual differences in anxiety (elevated plus maze and open field tests) and depression-like (forced swim and saccharin preference tests) behaviors in outbred rats relate to mitochondrial morphology (electron microscopy and 3D reconstructions) and function (mitochondrial respirometry). Mitochondrial molecules are measured for protein (Western blot) and mRNA (qRT-PCR, RNAscope) content. Dendritic arborization (Golgi sholl analyses), spine morphology, and MSNs excitatory inputs (path-clamp electrophysiology) are characterized. Mitofusin 2 (Mfn2) overexpression in the NAc is induced through an AAV9-syn1-MFN2. Results High anxious animals show increased depression-like behaviors, as well as reduced expression of the mitochondrial GTPase Mfn2 in the NAc. They also show alterations in mitochondria (i.e., respiration, volume, interactions with the endoplasmic reticulum) and MSNs (i.e., dendritic complexity, spine density and typology, excitatory inputs). Viral Mfn2 overexpression in the NAc reverses all these behavioral, mitochondrial and neuronal phenotypes. Conclusions Our results implicate a causal role for accumbal Mfn2 on the regulation of anxiety and depression-like behaviors through actions on mitochondrial and MSN structure and function. Mfn2 is posited as a promising therapeutic target to treat anxiety and associated behavioral disturbances.

中文翻译：

---

伏隔核中的 Mitofusin-2 通过线粒体和神经元活动调节焦虑和抑郁样行为

摘要 背景 新出现的证据指出线粒体在精神疾病中的核心作用。然而，关于在调节焦虑和抑郁的神经回路中调节线粒体的分子参与者，以及它们如何影响神经元结构和功能，我们知之甚少。在这里，我们研究了参与来自伏隔核 (NAc) 的中等多刺神经元 (MSN) 中线粒体动力学的分子的作用，伏隔核是大脑动机系统的中枢。方法 我们评估远交大鼠的焦虑（高架十字迷宫和野外测试）和抑郁样（强迫游泳和糖精偏好测试）行为的个体差异如何与线粒体形态（电子显微镜和 3D 重建）和功能（线粒体呼吸测量）相关. 测量线粒体分子的蛋白质（蛋白质印迹）和 mRNA（qRT-PCR、RNAscope）含量。树突状树枝化（高尔基体分析）、脊柱形态和 MSNs 兴奋性输入（路径钳电生理学）的特征。NAc 中的丝裂融合素 2 (Mfn2) 过表达是通过 AAV9-syn1-MFN2 诱导的。结果 高度焦虑的动物表现出更多的抑郁样行为，以及 NAc 中线粒体 GTPase Mfn2 的表达降低。它们还显示线粒体（即呼吸、体积、与内质网的相互作用）和 MSN（即树突复杂性、脊柱密度和类型学、兴奋性输入）的改变。NAc 中的病毒 Mfn2 过表达逆转了所有这些行为、线粒体和神经元表型。结论 我们的结果表明，accumbal Mfn2 通过对线粒体和 MSN 结构和功能的作用对焦虑和抑郁样行为的调节具有因果作用。Mfn2 被认为是治疗焦虑和相关行为障碍的有希望的治疗靶点。