Brain Microvascular Endothelial Cell Activation and Barrier Disruption in a Mouse Model of Psychological Resilience

Abstract

Psychological resilience, as measured by the ability of an individual to overcome the development of psychological disorders following exposure to stressful or traumatic events, varies significantly from individual to individual. The mechanisms underlying this variability among individuals have not been fully elucidated. A key factor in the development and progression of psychological disorders such as depression, schizophrenia, and post‐traumatic stress disorder is disruption of the blood brain barrier, thus we hypothesized that the function of brain microvascular endothelial cells (BMECs) of resilient individuals are more resistant to disruption by endothelial cell activators (ethanol (EtOH), corticosterone (CORT), and lipopolysaccharide (LPS)), compared to non‐resilient individuals. We used Electric Cell‐substrate Impedance Signaling (ECIS) technology (Applied BioPhysics, Troy, NY) to measure transendothelial electrical resistance (TEER) of cultured BMECs of the resilient C57BL6 mouse (BMECC57BL6), and the non‐resilient BalbC mouse (BMECBalbC). BMECs were plated at a density of 4.8 × 104 cells/cm2, and allowed to establish a monolayer for 48 hours. BMECs were then treated with either EtOH (0, 1, 10, 25, 50, or 100 mM), CORT (0, 10, 100 or 1000 ng/ml), or LPS derived from E. coli (0, 1, 10, or 100 ng/ml). TEER was continuously recorded for an additional 24 hours. Barrier function (Rb), membrane capacitance (Cm), and constraint on current flow beneath the cells (α) were derived via ECIS mathematical modeling. We found that at baseline, BMECC57BL6 had significantly lower Rb (1.31±0.14 versus 2.64±0.43 Ωcm2, p = 0.009, n = 4) and α (6.13±0.33 versus 7.56±0.53 Ω0.5cm, p = 0.009, n = 4), and significantly higher Cm (2.65±1.19 versus 1.28±0.012 μF/cm2, p = 0.007, n = 4) when compared to BMECBalbC. Contrary to our hypothesis, the effect of EtOH, CORT, or LPS on these baseline parameters did not significantly differ between the two types of BMEC. These findings indicate that variability in psychological resilience among individuals may be associated with functional differences in BMECs, an important component of the blood brain barrier.Support or Funding InformationThe views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Department of the Army, the Department of Defense, or the U.S. government.