The blood brain barrier as target for mental resilience and susceptibility

• Applicants: Professorin Dr. Susann Schweiger; Dr. Marta Segarra
• Subject Area: Biological Psychiatry ; Cognitive, Systems and Behavioural Neurobiology ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 462506723

Exposure to chronic psychosocial stress can lead to posttraumatic stress disorder and major depressive disorder (MDD). It is however not every individual developing pathology in response to such stress. In an animal model around 20 % of mice exposed to a chronic social defeat paradigm do not show aversities following the stress but show resilient behavior instead. The blood brain barrier (BBB) keeps vasculature and brain parenchyma apart and guarantees that toxins cannot enter the brain. Among possible mechanisms underlying resilient behavior, integrity of the BBB seems to play an important role. Increased permeability of the BBB has been found in animal models for depression and also in non-resilient animals after CSD exposure. The mTOR (mechanistic target of rapamycin) kinase and its target molecules VEGF-A (vascular endothelial growth factor-A) and matrix-metalloproteinase 9 (MMP-9) are key players in the regulation of tight junctions that connect endothelial cells in the neurovascular unit thereby sealing the BBB. We had shown previously that resilient behavior is not a static measure at a certain time-point after CSD exposure but is rather a highly dynamic trajectory over a longer time period during which phases of recovery take turns with phases of susceptibility. In preliminary work we identified a substantial up-regulation of VEGF-A in chronically stressed animals and we found that inhibition of mTOR by rapamycin leads to a significant increase of the number of resilient animals after CSD exposure (17 % to 50 %). We hypothesize that by inhibiting mTOR, VEGF-A and MMP-9 the behavior trajectory after CSD can substantially be influenced, and speed of recovery of animals can significantly be increased. We furthermore hypothesize that this change in animal behavior is caused by a protection of BBB integrity. In this proposal we will systematically inhibit mTOR, VEGF-A and MMP-9 using small molecule inhibitors. In MRI and tracer experiments we will look at the effects on BBB integrity and will link these with behavior readouts in social interaction after CSD exposure. This work will lead to an understanding of the molecular mechanisms underlying recovery processes after chronic social defeat stress and its connection to BBB integrity. Furthermore, our data will pave the way for the development of interventions in animals and humans that positively influence resilient behavior after chronic stress.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Amparo Acker-Palmer