Early life stress in mice disrupts blood–brain barrier function and reduces claudin-5 expression in the lateral septum and striatum, with linked behavioral impairments

• Early life stress disrupt blood brain barrier function specifically in the lateral septum and striatum. • Claudin 5 expression is diminished in response to early life stress in the lateral septum and striatum. • Bodyweight early after stress predict striatal claudin-5 loss. • Long term behavioral impairments are seen with operant conditioning and in the social interaction test. • The observed long term behavioral impairments are associated with the affected brain regions. Early life stress (ELS) has been implicated in blood–brain barrier (BBB) dysfunction, yet its long-term behavioral consequences remain poorly understood. Here, we found that limited bedding and nesting (LBN) in mice from postnatal day (P) 2–9, to induce ELS, increases BBB permeability, demonstrated by enhanced sodium fluorescein (NaF) extravasation in the lateral septum and striatum at P9. In parallel, we observed that levels of the major tight junction protein claudin-5 were reduced in the lateral septum and striatum of LBN-exposed mice. Notably, lower P9 bodyweights in LBN-exposed mouse pups correlated with reduced claudin-5 levels in the striatum, identifying body weight as a correlate of stress susceptibility at this stage. Furthermore, stress-susceptible LBN-exposed pups (≤6.5 g bodyweight at P9) exhibited elevated peripheral levels of the key pro-inflammatory cytokine IL-6, compared to stress-resilient (>6.5 g bodyweight at P9) and non-stressed control groups. In adulthood, LBN-exposed mice displayed deficits in social behavior and effort-based reward learning, functions associated with the lateral septum and striatum, respectively. We hypothesize that the BBB disruptions at P9 may have led to intracerebral leakage of inflammatory mediators, such as IL-6, thereby contributing to the observed behavioral impairments in adulthood. Our findings underscore the importance of BBB integrity during early development and highlight P9 bodyweight as a correlate for stress susceptibility, with relevance to understanding how early adversity may impact long term brain function and behavior.