Examining the central effects of chronic stressful social isolation on rats

Abstract

Stress-related disorders are extremely complex and current treatment strategies have limitations. The present study investigated alternative pathological mechanisms using a combination of multiple environmental approaches with biochemical and molecular tools. The aim of the present study was to evaluate blood-brain-barrier (BBB) integrity in socially manipulated animal housing conditions. Multiple environmentally-related models were employed in the current study. The main model proposed (chronically isolated rats) was biochemically validated using the level of peripheral corticosterone. The current study examined and compared the mRNA levels of certain inflammatory and BBB markers in the hippocampal tissue of chronically isolated rats, including claudin-5 ( cldn5 ) and tight junction protein ( tjp ). Animals were divided into four groups: i) Standard housed rats (controls); ii) chronically isolated rats; iii) control rats treated with fluoxetine, which is a standard selective serotonin reuptake inhibitor; and iv) isolated rats treated with fluoxetine. To further examine the effect of environmental conditions on BBB markers, the current study assessed BBB markers in enriched environmental (EE) housing and short-term isolation conditions. The results demonstrated a significant increase in cldn5 and tjp levels in the chronically isolated group. Despite some anomalous results, alterations in mRNA levels were further confirmed in EE housing conditions compared with chronically isolated rats. This trend was also observed in rats subjected to short-term isolation compared with paired controls. Additionally, levels of IL-6, an inflammatory marker associated with neuroinflammation, were markedly increased in the isolated group. However, treatment with fluoxetine treatment reversed these effects. The results indicated that BBB integrity may be compromised in stress-related disorders, highlighting a need for further functional studies on the kinetics of BBB in stress-related models.

Effects of early‐life stress and sex on blood–brain barrier permeability and integrity in juvenile and adult rats

“…In this respect, changes in the expression of CLDN5 are especially interesting. It has been shown that, like in our study, chronic stress in the form of prolonged social isolation increased Cldn5 levels in the HP of adult rats (Alshammari et al., 2020). On the other hand, a reduction in CLDN5 has been observed in the nucleus accumbens of depressed patients (Dudek et al., 2020).…”

The Role of PDE11A4 in Social Isolation-Induced Changes in Intracellular Signaling and Neuroinflammation

“…As noted above, we previously found that isolation-induced decreases in membrane PDE11A occur following chronic social isolation in adult mice ( Hegde et al, 2016b ). Interestingly, mice with lower levels of membrane PDE11A4 express significantly higher levels of soluble interleukin 6 (IL-6) ( Pathak et al, 2017 ), a cytokine that is upregulated in humans and rodents by social isolation ( Karelina et al, 2009 ; Alshammari et al, 2020 ) and that negatively affects social behaviors ( Wei et al, 2012a ). The fact that deletion of PDE11A increased IL-6 expression in the DHIPP ( Pathak et al, 2017 ) suggests isolation-induced decreases in membrane PDE11A signaling may drive a compartment-specific increase in IL-6 (i.e., in the soluble compartment), at least in the adult brain.…”

Barrier–environment interactions along the gut–brain axis and their influence on cognition and behaviour throughout the lifespan

“… 95 In brain endothelial cells, models of social stress, including social isolation and social defeat stress, lead to dysregulation of tight junction proteins and subsequent loss of BBB integrity in both male and female mice. 38 , 49 , 81 , 83 , 96 Interestingly, this effect is dependent on timescale; in rats, short duration of isolation stress (7 d) produces deficits in the tight junction protein claudin-5, while longer durations (6 wk) actually increase mRNA expression of claudin-5 in the male hippocampus versus the female prefrontal cortex. 81 , 83 Furthermore, targeted downregulation of claudin-5 at the BBB is sufficient to produce deficits in social interaction in male and female C57BL/6 mice.…”

“… 38 , 49 , 81 , 83 , 96 Interestingly, this effect is dependent on timescale; in rats, short duration of isolation stress (7 d) produces deficits in the tight junction protein claudin-5, while longer durations (6 wk) actually increase mRNA expression of claudin-5 in the male hippocampus versus the female prefrontal cortex. 81 , 83 Furthermore, targeted downregulation of claudin-5 at the BBB is sufficient to produce deficits in social interaction in male and female C57BL/6 mice. 38 , 49 Although these findings hint at a connection between BBB integrity and social activity, the intricacies of this relationship remain unclear.…”