Strain-Specific Cognitive and Neurobiological Vulnerabilities to Social Isolation in Late Middle-Aged Wistar,...

Social isolation and loneliness can lead to an increased risk of cardiovascular disease, cognitive decline, and psychiatric disorders. In this study, we investigated the impact of chronic social isolation on the cognitive functions and structural-functional state of the brain in middle-aged rats. Ten-month-old male spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Wistar rats were housed individually for 15 weeks, while the control animals of respective strains were housed in groups. After 13 weeks, all the rats were trained to complete a spatial task in a Barnes maze. After the behavioral experiments, we analyzed the density of neurons, astrocytes, and microglia in the hippocampus. We also studied the expression of several genes in the hippocampus and frontal cortex, including Aqp4, Cx3cr1, Tnfa, Il1b, and Il6, using qPCR. We found that Wistar rats showed high resilience, maintaining stable physiological parameters and spatial learning abilities without significant neuroinflammatory or structural changes in the brain. In contrast, SHRs showed marked physiological vulnerability, characterized by a significant weight loss and severe memory impairments in the Barnes maze, accompanied by an elevated cytokine response in both brain regions studied. A different trajectory of neurobiological changes was observed in WKY rats. Although they had a high rate of hippocampal neurogenesis, which provided a compensatory effect on basic spatial learning and memory, they also showed decreased neuronal density and an elevated Il6 mRNA level, linked to impaired microglial Cx3cr1 mRNA expression. This study highlights the importance of genetic background in determining the outcome of brain aging in conditions of social isolation.