Chronic hypertension and social isolation disrupt the blood-brain barrier and memory in a sex-dependent manner

Figures

• 

  Fig. 1.. Body weights of male and female rats. Socialized normotensive Wistar rats and spontaneously hypertensive rats (SHR) that were either socially housed or housed in isolation (+Isol.) had body weights measured prior to terminal blood-brain barrier permeability experiments. **p < 0.01; n = 8/group. Data are mean ± SEM and analyzed by two-way ANOVA with a post-hoc Šídák's test for multiple comparisons.

• 

  Fig. 2.. Locomotion and exploratory behavior. A. Average speed and B. total distance traveled in an open field arena during the habituation phase of the novel object recognition task. Socialized male and female normotensive Wistar rats and spontaneously hypertension rats (SHR) that were either socialized or socially isolated (SHR + Isol.) freely explored the arena for five minutes. *p < 0.05, **p < 0.01; n = 8/group. Data are mean ± SEM and analyzed by two-way ANOVA with a post-hoc Šídák's test for multiple comparisons.

• 

  Fig. 3.. The combination of social isolation during chronic hypertension selectively disrupted memory function in a sex- and domain-dependent manner. A. Schematic of the novel object recognition paradigm used to calculate a recognition index and assess long-term memory function in socialized male and female normotensive Wistar rats and spontaneously hypertensive rats (SHR) that were either socialized or isolated (SHR + Isol.). B. Recognition index was decreased in male SHR that were socially isolated compared to socialized SHR. Recognition index was unaffected in females. C. Schematic of continuous 8 min y-maze task used to calculate alternation index as a measure of spatial working memory function. D. Alternation index was unaffected by chronic hypertension without and with social isolation in males, but decreased in female SHR that were socially isolated compared to Wistar rats. *p < 0.05; n = 8/group. Data are mean ± SEM and analyzed by two-way ANOVA with a post-hoc Šídák's test for multiple comparisons.

• 

  Fig. 4.. Chronic hypertension and social isolation differentially increased blood-brain barrier (BBB) permeability in the dorsal hippocampus based upon sex. BBB permeability to A. small solute sodium fluorescein (NaFl) and B. 3 kDa Texas red dextran was increased in socially isolated male spontaneously hypertensive rats (SHR + Isol.) compared to socialized Wistar and SHR. Permeability was higher in female SHR compared to normotensive Wistar rats and was unaffected by social isolation. *p < 0.05, **p < 0.01; n = 6–8/group. Data are mean ± SEM and analyzed by two-way ANOVA with a post-hoc Šídák's test for multiple comparisons.

• 

  Fig. 5.. Increased blood-brain barrier (BBB) permeability occurred in prefrontal cortex during chronic hypertension to a greater extent in females than males. A. BBB permeability to small solute sodium fluorescein (NaFl) was increased in socialized spontaneously hypertensive rats (SHR) of both sexes compared to socialized Wistar rats and unaffected by social isolation (SHR + Isol.). B. In males, there were no differences in BBB permeability to 3 kDa Texas red dextran. Permeability was increased in female SHR and SHR + Isol. compared to female Wistar rats. *p < 0.05, **p < 0.01; n = 6–8/group. Data are mean ± SEM and analyzed by two-way ANOVA with a post-hoc Šídák's test for multiple comparisons.

• 

  Fig. 6.. Serum levels of markers of oxidative stress, endothelial dysfunction and inflammation and the relationship with blood-brain barrier (BBB) permeability. A-C. 8-isoprostane; D-F. intercellular adhesion molecule-1 (ICAM-1); G-I. tumor necrosis factor-alpha (TNFα) serum levels and correlations with BBB permeability to sodium fluorescein (NaFl) and 3 kDa Texas red dextran (TxR) in dorsal hippocampus and prefrontal cortex of male and female normotensive Wistar rats and spontaneously hypertensive rats (SHR) that were either socialized or isolated (SHR + Isol.). Data are mean ± SEM; n = 4–8/group. Panels A, D and G *p < 0.05, **p < 0.01 by two-way ANOVA with a post-hoc Šídák's test for multiple comparisons. Panels B-C, E-F, and H-I *p < 0.05, **p < 0.01 by linear regression analyses to detect if the slope is significantly non-zero.