Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. Further, blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure.

中文翻译：

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可卡因通过 Egr3 转录调控诱导神经元亚型线粒体动力学


线粒体功能是大脑能量稳态和神经适应所必需的。最近的研究表明，可卡因影响伏隔核 (NAc) 内的线粒体动力学和形态特征。此外，在含有多巴胺受体 1 的中型多棘神经元 (D1-MSN) 和多巴胺受体 2 (D2)-MSN 中，线粒体受到可卡因的差异调节。然而，人们对可卡因诱导的转录机制及其在调节线粒体过程中的作用知之甚少。在这里，我们证明可卡因增强了转录因子早期生长反应因子 3 (Egr3) 与参与线粒体功能和动力学的核基因的结合。此外，在偶然或非偶然的可卡因给药以及啮齿动物模型和人类死后组织中，可卡因暴露调节这些线粒体相关核基因的mRNA。有趣的是，几个线粒体核基因在 D1-MSN 和 D2-MSN 中表现出不同的表达谱，接触可卡因通常会增加 D1-MSN 中线粒体相关核基因的表达，而在 D2-MSN 中则受到抑制。此外，削弱 D1-MSN 中 Egr3 的表达会阻断可卡因对线粒体相关转录共激活因子、过氧化物酶体增殖物激活受体 γ 共激活因子 (PGC1α) 和线粒体裂变分子动力相关蛋白 1 (Drp1) 的增强作用。最后，D1-MSN Egr3 表达的减少减弱了可卡因诱导的小线粒体的增强，从而证明 Egr3 调节线粒体形态适应。 总的来说，这些研究表明，可卡因暴露通过线粒体相关核基因转录本的 Egr3 转录调控影响线粒体动力学和形态；表明这些分子机制在可卡因暴露引起的神经元功能和可塑性中的作用。