Investigating The Effects of a Double-Hit Developmental Stress Model on Behavioral, Physiological, and Microglial Outcomes

Project Overview

We investigated the behavioral effects of a double-hit developmental stress model consisting of maternal separation (MatSep) and chronic unpredictable stress (CUS) in a preclinical model. We hypothesized that MatSep and CUS would cause more pronounced depressive-like phenotypes and greater stress susceptibility than either stressor alone. Behavioral tests were conducted to compare anxiety-like behaviors across all groups and we aimed to identify cellular changes related to stress. 

Specifically, we planned to examine the neurobiological effects of MatSep and CUS by analyzing the expression of a glucocorticoid receptor mediator in microglia of the hippocampus. We hypothesized the expression would be elevated in groups exposed to both MatSep and CUS, suggesting an impaired stress regulatory system. 

Working with microglia proved to be more difficult than anticipated, so while troubleshooting took place, we shifted the project’s focus to examine how stress impacts the meninges. The meninges are a protective layer of the central nervous system (CNS). At this time, data from only the MatSep group was collected for the meninges. We examined two proteins, ERK1/2 and Occludin, via Western Blot. ERK1/2 is important in responding to stress and inflammation in meningeal cells. Occludin’s importance is based more heavily on regulating the integrity of the meninges and their tight junctions. 

Our primary finding was a sex difference in occludin expression, which appears to be influenced by hormonal factors, particularly estrogen. Together, our work provides insight into how early-life and chronic stress influence both behavioral and cellular responses.