Abstract
Intense or prolonged exposure to stress can damage various brain structures, including the amygdala and hippocampus, which are associated with emotional-cognitive functions. Furthermore, this deterioration has been linked to a myriad of neurodegenerative and psychiatric disorders, in particular through disruption of the blood-brain barrier (BBB). However, insights remain scarce concerning the effects and mechanisms associated with stress on the BBB in the amygdala. This study explored the effects of restraint stress on the permeability and integrity of the BBB in the amygdala of male adult SD rats. Serum levels of corticosterone (CORT) and S100B were determined through ELISA. The permeability of the BBB was assessed by measuring Evans Blue (EB) leakage in tissue samples from the rats’ amygdala. These samples were immunostained for markers of tight junctions (Claudin-5, Occludin, ZO-1) and adherens junctions (VE-cadherin), as well as GLUT-1 and AQP-4. Staining was evaluated through confocal microscopy, and the level of expression of these proteins was quantified using the Western Blot (WB) technique. The ultrastructure of brain microvascular endothelial cells was assessed with transmission electron microscopy. Moreover, interleukin-1 beta (IL-1β) content in serum and amygdalar tissues were determined by employing ELISA. Exposure to restraint stress was associated with higher serum levels of S100B and EB leakage in amygdala tissues, especially in days 14 and 21 of the experiment, indicating increased permeability of the BBB. After restraint stress, significant decreases in protein expression were detected for tight junctions, adherens junctions and GLUT-1, while a significant increase was observed for AQP-4. The variation trends of fluorescence intensity generally paralleled these results. Following restraint stress, transmission electron microscopy ascertained enlarged gaps in tight junctions and thickened basal membranes in amygdalar capillaries. In addition, increased IL-1β contents in serum and amygdalar tissues were observed in the restraint-stressed groups. These findings suggest that restraint stress mediates time-dependent alterations in the permeability of the BBB, with modifications in the expression of proteins from tight junctions and adherens junctions, as well as ultrastructural changes in brain microvascular endothelial cells. And it was associated with the inflammation. These alterations may be associated with behavioral and cognitive dysfunctions and neurodegenerative disorders.
Highlights
Stress is a non-specific psychobiological and neuroendocrine response experienced on encountering a threat
3 rats were used for ELISA (IL-1β) analysis, 3 rats were used for Evans Blue (EB) BBB permeability analysis and 3 rats were used for Electron Microscope analysis. 9 rats were used for Elevated Plus Maze (EPM) test analysis, 3 of which were used for Immunohistochemistry analysis and 6 of which were used for Western Blot, ELISA (CORT and S100B) analysis
Our results showed there was a significant elevation of EB [F(5,12) = 11.702, p < 0.001] leakage in rats subjected to restraint stress for 14 (5.58 ± 1.85, p = 0.037) and 21 (8.23 ± 1.76, p = 0.001) days, compared with the control (1.84 ± 0.92) rats (Figure 2A)
Summary
Stress is a non-specific psychobiological and neuroendocrine response experienced on encountering a threat. Moderate stress plays an adaptive role and is necessary for survival, intense or prolonged exposure to stress can damage brain areas associated with emotional-cognitive functions—such as fear memory and anxiety–, including the amygdala and hippocampus (Sathyanesan et al, 2017; Lowery-Gionta et al, 2018). These changes may be involved in a variety of neurodegenerative and psychiatric disorders (Mcewen and Gianaros, 2010).
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