Investigating the Existence of Ensembles of Early Life Stress in Reward and Stress-associated Regions

Abstract

Experience of early life stress (ELS) is known to increase the risk of developing mental health disorders such as anxiety and depression. One potential mechanism mediating this increased susceptibility is through a sensitization of responses to future experiences of stress. However, little is known about the level at which this sensitization might be occurring in the brain. We hypothesized that ELS-induced stress sensitization may be evident at the level of neuronal ensembles, such that cells activated by ELS might be more reactive to adult stress. To test this, we used a mouse model of ELS and a transgenic mouse line to tag and track experience-activated cell populations. We used a 2x2 design of ELS and mild unpredictable adult stress, and fixed brains one hour after the last adult stress to be able to quantify immediate early gene activity. Brains were then sliced, stained with immunohistochemistry, and imaged on a slide-scanning microscope. We focused on four brain regions known to be integral to stress response and depression-like behavior, including the ventral tegmental area (VTA), prefrontal cortex (PFC), nucleus accumbens (NAc), and the amygdala. We first asked whether ELS changed levels of cellular activity in any of these regions by quantifying cells labeled with our experience- activated tag. We observed increased activation of the NAc in response to ELS. We next tested the hypothesis that a history of ELS alters cellular activation in response to adult stress. This was done by counting cells showing immediate early gene expression in response to the final adult stress. Finally, we compared cellular responses to ELS and adult stress, and quantified the number and percent of reactivated cells. Contrary to our hypothesis, we found decreased reactivation of the VTA in mice with an ELS history. Finally, we examined potential sex differences in the effects of ELS and adult stress on these measures. Differential activation of the amygdala in early life was found between males and females. The results of the present study highlight the need to develop interventions and policies to prevent the adverse long-term impacts of ELS experiences.