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

Chronic hypertension in mid-life is a leading cause of vascular cognitive impairment (VCI), the second leading cause of age-related cognitive decline. Further, social isolation is another risk factor for dementia, and disproportionately impacts middle-aged adults. However, mechanisms by which social isolation may compound chronic hypertension to damage the cerebrovasculature and contribute to VCI remain unclear. The current study used male and female adult Wistar rats and spontaneously hypertensive rats (SHR) to investigate how social isolation during chronic hypertension disrupted blood-brain barrier (BBB) and memory function. Half of the SHR were housed individually for three months, with remaining SHR and Wistar rats housed in groups and routinely handled (n = 8/group). At six months old, long-term and spatial working memory were assessed using object recognition and continuous y maze tasks, respectively. BBB permeability was measured in-vivo in dorsal hippocampus and prefrontal cortex and serum markers of inflammation assessed. Long-term memory function was impaired only in isolated male SHR, as recognition index was lower compared to socialized male Wistar and SHR (0.59 ± 0.07 vs. 0.70 ± 0.02 and 0.77 ± 0.03; p < 0.05 by 2way ANOVA), which was associated with increased BBB permeability in the hippocampus. In contrast, spatial working memory was only impaired in isolated female SHR that had a decreased alternation index compared to socialized female Wistar rats (0.59 ± 0.04 vs. 0.74 ± 0.02; p < 0.05 by 2way ANOVA). This sex-specific deficit was associated with greater BBB disruption in prefrontal cortex that correlated with elevated levels of circulating oxidative stress marker 8-isoprostane. These findings suggest that social isolation during chronic hypertension differentially impairs memory function in a sex-dependent manner. Overall, this study advances our understanding of cerebrovascular consequences of social isolation in adulthood and indicate brain region/memory domain dysfunction differ by sex during chronic hypertension.