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

Early-life stress (ELS) is considered a relevant etiological factor for neurodegenerative and mental disorders. In the present study, we hypothesized that ELS may persistently and sex dependently influence blood–brain barrier (BBB) integrity and function during critical periods of brain development and consequently determine susceptibility to and sex-related prevalence of chronic diseases in adult life. We used the maternal separation (MS) procedure in rats to model ELS and evaluated BBB permeability and gene expression of selected tight junction (TJ) proteins, glucose transporter type 1 (Slc2a1) and aquaporin 4 (Aqp4) in the medial prefrontal cortex (mPFC), dorsal striatum (dSTR) and hippocampus of juvenile and adult rats. Serum concentrations of a peripheral marker of BBB function (S100β) and proinflammatory cytokines were also assessed. We observed developmental sealing of the BBB and sex differences in the permeability of the BBB and the mRNA expression of TJ proteins and Slc2a1. Adult females showed lower BBB permeability and higher levels of Cldn3, Cldn5, Ocln, and Slc2a1 in the mPFC and dSTR than males. MS temporarily increased BBB permeability in the dSTR of juvenile males and affected mRNA expression of the majority of studied proteins related to BBB function in age-, region- and sex-dependent manners. Additionally, MS sex dependently decreased serum S100β levels and did not affect proinflammatory cytokine concentrations. In general, our study did not reveal a clear or strong negative effect of MS on BBB integrity. However, the results suggest that ELS may induce adaptive/maladaptive changes or compensatory mechanisms within the BBB of unknown yet consequences.