Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress

Abstract

During exposure to chronic stress, some individuals engage in active coping behaviors that promote resiliency to stress. Other individuals engage in passive coping that is associated with vulnerability to stress and with anxiety and depression. In an effort to identify novel molecular mechanisms that underlie vulnerability or resilience to stress, we used nonbiased analyses of microRNAs in the ventral hippocampus (vHPC) to identify those miRNAs differentially expressed in active (long-latency (LL)/resilient) or passive (short-latency (SL)/vulnerable) rats following chronic social defeat. In the vHPC of active coping rats, miR-455-3p level was increased, while miR-30e-3p level was increased in the vHPC of passive coping rats. Pathway analyses identified inflammatory and vascular remodeling pathways as enriched by genes targeted by these microRNAs. Utilizing several independent markers for blood vessels, inflammatory processes and neural activity in the vHPC, we found that SL/vulnerable rats exhibit increased neural activity, vascular remodeling and inflammatory processes that include both increased blood–brain barrier permeability and increased number of microglia in the vHPC relative to control and resilient rats. To test the relevance of these changes for the development of the vulnerable phenotype, we used pharmacological approaches to determine the contribution of inflammatory processes in mediating vulnerability and resiliency. Administration of the pro-inflammatory cytokine vascular endothelial growth factor-164 increased vulnerability to stress, while the non-steroidal anti-inflammatory drug meloxicam attenuated vulnerability. Collectively, these results show that vulnerability to stress is determined by a re-designed neurovascular unit characterized by increased neural activity, vascular remodeling and pro-inflammatory mechanisms in the vHPC. These results suggest that dampening inflammatory processes by administering anti-inflammatory agents reduces vulnerability to stress. These results have translational relevance as they suggest that administration of anti-inflammatory agents may reduce the impact of stress or trauma in vulnerable individuals.

Passive Coping Strategies During Repeated Social Defeat Are Associated With Long-Lasting Changes in Sleep in Rats

“…Many more animals were classified as passive copers than active copers. In past work, using this analysis has yielded similar segregation of groups (Chen et al, 2015;Pearson-Leary et al, 2017, 2019Grafe et al, 2018). Moreover, three additional animals had unreadable telemeter recordings (see next section).…”

“…In different individuals, or under different conditions, either active coping, characterized by the fight or flight response, or passive coping, characterized by immobility and withdrawal, can occur during exposure to stressors (Engel and Schmale, 1972;Koolhaas et al, 1999;Southwick et al, 2005;Wood and Bhatnagar, 2015). The present experiments used an animal model of repeated social defeat stress in which active and passive coping strategies dichotomize into either a resilient or vulnerable trait, respectively, as assessed post hoc by various neuroendocrine measures, behavioral tests (Wood et al, 2010;Chen et al, 2015;Wood and Bhatnagar, 2015;Finnell et al, 2017), and markers of inflammation (Pearson-Leary et al, 2017, 2019. Understanding whether such differences in coping strategy are associated with the subsequent development of sleep disturbances akin to those reported in PTSD may help to provide a basis for examining the mechanisms by which traumatic stress affects sleep in vulnerable individuals.…”

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

“…We describe here a molecular framework in which cldn5-related epigenetic modifications and transcriptional changes in the NAc lead to stress resilience or vulnerability and depression. In rodents, depression-like behaviors have been associated with increased BBB permeability (7,8) while vascular dysfunction was not observed in those displaying stress resiliency (7,24). However, the cellular and molecular mechanisms involved in this process remained elusive.…”

IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

“…The underlying immune environment alters the interaction between stress and inflammatory processes, thus contributing to the risk of depressive symptoms 36,37 . In our study we found that the levels of IL4 were decreased in the hippocampus of HS mice, but increased in LS mice.…”