Childhood social isolation causes anxiety-like behaviors via the damage of blood-brain barrier in amygdala in female mice

Abstract

Social interaction plays an essential role in species survival for socialized animals. Previous studies have shown that a lack of social interaction such as social isolation, especially in the early-life phase, increases the risk of developing mental diseases in adulthood. Chronic social stress alters blood-brain barrier (BBB) integrity and increases peripheral cytokines to infiltrate the brain, which is linked to the development of depressive-like behaviors in mice, suggesting that BBB function is crucial in environmental stimuli-driven mood disorders via increased neuroinflammation in the brain. However, the precise mechanisms of inflammation and BBB integrity underlying the behavioral profiles induced by social isolation remain poorly understood. Here we showed that chronic childhood social isolation from post-weaning for consecutive 8 weeks in female but not male C57BL/6J mice induces anxiety-like behaviors. The levels of peripheral inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the plasma of socially isolated female mice were increased. Importantly, we found decreased expression of the endothelial cell tight junction protein Claudin-5, increased BBB breakdown and microglial activation in the amygdala of isolated but not group-housed female mice. Moreover, the neuronal activity in the amygdala was increased as evidenced by c-fos positive cells, and the levels of IL-1β in the amygdala, a critical brain region for regulating social processing and interaction, were also higher in female mice exposed to social isolation. Finally, down-regulation of Claudin-5 induced anxiety-like behaviors in group-housed females and overexpression of Claudin-5 with adeno-associated virus in the amygdala to restore BBB integrity decreased subsequent anxiety-like behaviors. Together, these findings suggest that chronic childhood social isolation impaired BBB permeability and caused neuroinflammation in the amygdala by recruiting peripheral cytokines into the brain and activating microglia, consequently triggering the development of anxiety-like behaviors in female mice.

The Impact of Social Isolation and Environmental Deprivation on Blood Pressure and Depression-Like Behavior in Young Male and Female Mice

“… 64 On the contrary, 6 weeks of SI in young male rats 24 and mice 20 as well as 4 weeks of SI in adult mice 65 and prairie voles 66 induced depression-like behavior. However, these results were not replicated either in our study or the study by Wu et al 63 Differences in species, strain, age, cage enrichment, housing conditions, and duration of SI may account for the lack of substantial depression-like behavior in socially isolated animals in this study.…”

“…Our results corroborate to some extent with those of a recent study that used the same strain and age of animals of both sexes and chronic SI as in our study and found no depression-like behavior in either males or females. 63 However, the FST by Wu et al, was conducted during the dark cycle, included the adaptation stage (pre-test one day before the actual test), and all mice were able to smell one another. Based on additional evidence from this study, neither male nor female mice developed depression-like symptoms after 8 weeks of SI.…”

Chemical analysis of calabash chalk and its effect on locomotor activities and behavior in Swiss albino mice

“…The most established indicators of emotional behavior in the open field test are ambulation [ 37 , 38 ]. It has been proposed that the fear or anxiety response of the animal exposed to a new environment is accompanied by low ambulation, especially in the central zone [ 37 , 38 , 39 , 40 , 41 ]. This study showed a decreased effect on both the central square entry and duration, which may happen due to the consumption of calabash chalk [ 3 , 37 ].…”

Neurovascular unit adjustments following chronic distress explain motivational deficits in mice

“…A down-regulation of TJ protein Claudin-5 has been observed in the nucleus accumbens (NAc) and in the medial prefrontal cortex (mPFC) of mice exposed to social defeat stress (2,32). Furthermore, the work of Wu and colleagues (2022) demonstrated a link between Claudin-5 down-regulation and the emergence of anxious-like behaviour in female mice, as well as a decrease of these behaviours in mice under social isolation by overexpressing Claudin-5 in the amygdala (33). Similarly, in the chronic social defeat murine model of depression, the expression of endothelial Claudin-5 is reduced along with abnormal blood vessel morphology in the NAc of stress-susceptible but not resilient mice (32).…”