The Developing Brain Under Stress: Long-Term Consequences of Early Life Adversity on Behavior and Neuroplasticity in the Hippocampus

Abstract

Individuals exposed to early life stress (ELS), such as neglect, abuse, or trauma, have an increased risk for developing persisting psychiatric problems, including depression, anxiety, and attention deficit hyperactivity disorder (ADHD). These conditions are associated with neurobiological changes during development in many areas of the brain, including the hippocampus (HIP), which persist into adulthood. Animal models of early life stress have been extensively used to further understand the mechanisms underlying the effects of ELS and its long-term implications. A modification of the classical maternal separation model (MS), the Maternal Separation Stress with Early Weaning (MSEW) model of ELS has been specially adapted for mice, as it produces consistent and long-lasting anxiety-like behaviors. Previous findings using the MS paradigm in rats show an increase in anxiety-like behavior and a decrease in adult neurogenesis in the HIP in adulthood. We used the MSEW model in C57BL/6J mice to characterize anxiety-like behavior and neuroplasticity changes within the HIP in mice. The rodent ventral HIP has been linked to anxiety-like behavior, as lesions of this region have been shown to increase anxiety-like behavior. Rodent studies have shown an increase in theta frequency neuronal oscillations in the ventral HIP, especially during anxious behavioral states(Adhikari, Topiwala, & Gordon, 2010). Parvalbumin (PV+) and somatostatin (SST+) interneurons have been implicated as the primary drivers of theta neuronal oscillations in the brain. In this work, we have investigated the effects of ELS on changes in neuroplasticity, including examining adult neurogenesis, inhibitory interneuron populations, perineuronal nets, and OTX2 levels in the HIP. Our results showed that MSEW mice display increased anxiety-like behavior and hyperactivity. Additionally, MSEW mice showed reduced densities of PV+ and SST+ interneurons, but not calretinin interneurons, doublecortin positive immature neurons, or Ki67 positive proliferating cells in the hippocampus. We also observed increased perineuronal nets surrounding PV cells, which modulate PV+ cell plasticity. PV+ cells showed an increase in expression of OTX2, a transcription factor involved in the regulation of the critical period of plasticity in the visual cortex of developing mice. Understanding the various components of the mechanisms underlying the behavioral and neurobiological changes associated with MSEW provides clues for future clinical studies that can help guide the improvement and development of therapies for individuals subjected to ELS.