Neuronal ensemble reactivation in stress sensitization: a focus on dopaminergic neurons in the ventral tegmental area

Abstract

Research has established a strong relationship between childhood adversity and sus- ceptibility to neuropsychiatric disorders, suggesting that early-life stress (ELS) sen- sitizes individuals to stress that occurs later in life. The connection between child- hood adversity and vulnerability to neuropsychiatric disorders is mimicked in animals through the “two-hit” stress model. However, the underlying neural mechanisms by which ELS sensitizes the brain to subsequent stressors is poorly understood. In this thesis, I investigate whether cell ensembles triggered by ELS are preferentially reacti- vated by adult stress in the ventral tegmental area (VTA), with a particular focus on dopaminergic cells. In order to determine the underlying mechanisms of stress sen- sitization, we used double transgenic mice to tag experience-specific cellular activity, and analyzed how recent stress reactivates these cells. Furthermore, the literature suggests that inhibitory interneurons may have different markers of recent cellular activity. Thus, the question is raised as to whether NPAS4- an inhibitory interneu- ron marker- overlaps with cells activated during ELS. I employ various experimental methods, such as immunostaining, microscopy, cell counting, and quantification of brain slices from double-transgenic mice exposed to different stress across the lifes- pan. Contrary to the initial hypothesis, mice that experienced ELS did not exhibit a greater proportion of reactivated cells in the VTA than the standard-reared mice. Additionally, expression of NPAS4 was not clearly observed in the VTA. These find- ings suggest that cellular reactivation of dopamine neurons in the VTA may not be responsible for animal sensitization to adult stress, and I suggest future experimen- tation and avenues of inquiry to enhance our understanding of stress vulnerability.