Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA.
Cereb Cortex. 2019 Dec 17;29(12):5061-5071. doi: 10.1093/cercor/bhz046.
We previously observed an association between mode of delivery and brain mitochondrial mechanisms in pups. We also showed that mitochondrial processes impact adult behavior. However, no experimental data is available to causally connect mode of delivery with cellular processes of neurons in the cerebral cortex and adult behavior. Here we show that surgical delivery of pups alters mitochondrial dynamics and spine synapses of layer 3 pyramidal neurons of the prefrontal cortex compared to the values of mice delivered vaginally. These alterations in ultrastructure seen in adult mice delivered surgically were associated with the development of behavioral phenotypes resembling those characteristic of animal models of psychiatric illness. This included impaired performance in prepulse inhibition as well as hyperlocomotion in the open field and elevated plus maze tests. Knocking out a mitochondria-related gene, UCP-2, blocked cellular and behavioral adaptations induced by surgical delivery. These results highlight a crucial role for brain mitochondrial adaptations in the process of birth to affect neuronal circuitry in support of normal and altered adult behaviors. Further, these findings were supported with neuroimaging data from human neonates delivered vaginally and surgically, suggesting that the murine findings have human clinical relevance.
我们之前观察到分娩方式与幼崽大脑线粒体机制之间存在关联。我们还表明，线粒体过程会影响成年行为。然而，尚无实验数据可以将分娩方式与大脑皮层神经元的细胞过程和成年行为联系起来。在这里，我们表明与阴道分娩的小鼠相比，通过手术分娩的幼崽会改变前额叶皮层第 3 层锥体神经元的线粒体动力学和棘突触。在成年接受手术分娩的小鼠中观察到的这些超微结构变化与发展出类似于精神病动物模型特征的行为表型有关。这包括在预脉冲抑制测试中表现受损以及在旷场和高架十字迷宫测试中过度活跃。敲除与线粒体相关的基因 UCP-2 可以阻止手术分娩引起的细胞和行为适应。这些结果强调了大脑线粒体适应在分娩过程中的关键作用，以影响支持正常和改变的成年行为的神经元回路。此外，这些发现得到了来自阴道分娩和手术分娩的人类新生儿的神经影像学数据的支持，这表明小鼠的发现与人类临床相关。
