Prefrontal Cortical and Behavioral Adaptations to Surgical Delivery Mediated by Metabolic Principles

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.