Restraint Stress-Induced Morphological Changes at the Blood-Brain Barrier in Adult Rats

Abstract

Stress is well-known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognized in the development of neurodegenerative disorders, such as Alzheimer's disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3, and 21 days) were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occluding, and glucose transporter-1) and astroglia (GFAP). Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, 1-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5, and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes, cognitive and behavioral dysfunctions.

Hippocampal and amygdalar cell‐specific translation is similar soon after stress but diverge over time

“…Many of the structural and physiological changes in neural adaptation are facilitated by glia (Sofroniew & Vinters, ), which likely also regulate their translation over similar timescales. In some cases, acute stress has been compared to an ischemic insult wherein there is significant inflammatory response (Sántha et al, ; Walker, Nilsson, & Jones, ). We tested several antibodies against astrocytes and microglia proteins, of which only GFAP was consistently compatible with the FUNCAT slice processing workflow.…”

“…Finally, the overwhelming majority of translation literature in the brain is neuron‐centric though there is evidence of altered expression of glial proteins in the pathology of diseases (Sántha et al, ). This is the first time that the astrocytic proteomic response has been recorded simultaneously with neuronal translation within a tissue.…”

Blood-brain barrier regulation in psychiatric disorders

“…Animal models of depression have provided insight on the role of the BBB in depression. In a stress-induced model of depression, stress was associated with reduced expression of claudin-5 and occludin and neurovascular dysfunction [202]. Similarly, stress induced increases in the permeability of the BBB to intravenously injected tracers [200] and to Evans blue [203].…”

In vivo profiling of four centrally administered opioids for antinociception, constipation and respiratory depression: Between‐colony differences in Sprague Dawley rats

“…There are also considerable concerns on the reproducibility of major findings reported in published papers . Factors potentially contributing to between‐laboratory differences in pharmacological phenotypes observed in animal studies using the same experimental paradigm are, the species, strain/stock, gender, hormonal status, aging, stress, developmental stage, genetics, environment and gastrointestinal microbiome . As University‐based researchers source their experimental animals from either commercial or institutional breeding facilities, they are dependent upon their breeding settings and are often unaware of changes in the source of breeding pairs/colonies.…”