Hippocampal Activated Microglia May Contribute to Blood–Brain Barrier Impairment and Cognitive Dysfunction in Post-Traumatic Stress Disorder-Like Rats

Abstract

Post-traumatic stress disorder (PTSD)-associated cognitive dysfunction significantly disturbs patients' quality of life and will to live. However, its underlying mechanism is as yet unknown. Recent researches indicate that blood-brain barrier (BBB) breakdown is responsible for early cognitive dysfunction. Microglia might participate in remodeling of BBB-associated tight junction and regulating BBB integrity. Nevertheless, it is unclear whether microglia activation and BBB injury involve in PTSD-associated cognitive dysfunction. Hence, we established an animal model of PTSD, single prolonged stress (SPS), and investigated permeability changes in the hippocampus and further explored the effects of microglia on BBB remodeling. The Y maze was used to assess the changes of cognitive function. The sodium fluorescein (NaFlu) assay and western blotting analysis were employed to detect BBB integrity changes. Minocycline was administered to inhibit microglial activation. Immunofluorescence stains were used to assess the activation states in microglia. The results showed that SPS-exposed rats exhibited poorer cognitive performance, higher passage of NaFlu, and lower expression of tight junction proteins (occludin and claudin 5) in the hippocampus on the day after SPS, but no difference on the 7th day. Inhibition of microglial activation by minocycline attenuated poor cognitive performance and BBB impairment including the extravasation of NaFlu and protein levels of the tight junction. Taken together, the present study indicates that BBB impairment may underlie the shared pathological basis of PTSD and cognitive dysfunction. Microglial activation may involve in BBB remodeling at the early stage of SPS.

The Relationship between Post-Traumatic Stress Disorder Due to Brain Injury and Glutamate Intake: A Systematic Review

“…The association between PTSD with BBB permeability has been a subject of growing interest. BBB disruption seems to significantly influence the pathophysiology of PTSD, and PTSD is associated with increased BBB permeability, possibly contributing to the development of cognitive dysfunction and other symptoms associated with the disorder [ 51 , 52 , 53 ]. Multiple mechanisms clarifying the link between PTSD and BBB permeability have been advanced.…”

“…For instance, molecular mechanisms and inflammatory signaling pathways are potentially responsible for stress-induced BBB disruption, with evidence pointing to increased BBB permeability as a crucial factor in the development of PTSD-related behavioral abnormalities [ 53 , 54 ]. Additionally, the role of microglia in BBB impairment and cognitive dysfunction in a PTSD-like rodent model has been highlighted, further emphasizing the potential impact of BBB integrity on the pathogenesis of PTSD [ 52 ].…”

“…Furthermore, the association between PTSD and dysfunctional endothelia has been implicated, implying that increased BBB permeability likely predisposes individuals to the development of PTSD, potentially linking the disorder to vascular and cerebrovascular conditions [ 51 ]. Moreover, the breakdown of the BBB may be involved in the early cognitive dysfunction associated with PTSD, suggesting that BBB impairment underlies the common pathological foundation of PTSD and cognitive dysfunction [ 52 ].…”

Vulnerability of the Hippocampus to Insults: Links to Blood–Brain Barrier Dysfunction

“…This finding suggests that the harmful effects of SPS on the BBB and hippocampal-dependent cognition are mediated by microglia activation. Another study [179] found rats that were especially sensitive to stress produced by the SPS procedure also exhibited a significant reduction in claudin 5, but not occludin.…”