Adolescent adversity persistently induces proinflammatory HMGB1 signaling and disrupts the basal forebrain...

Adolescence is a critical period of neurodevelopment characterized by heightened neuroplasticity and refinement of executive functioning and cognition. Basal forebrain cholinergic neurons mature during this period, coinciding with development of adult cognitive function. Exposure to adolescent adversity has been linked to long-lasting neurobiological and cognitive consequences, yet the mechanisms underlying these outcomes remain poorly understood. Using a preclinical model of adolescent intermittent restraint stress (AIRS), we tested the hypothesis that adolescent adversity induces lasting proinflammatory innate immune signaling, loss of basal forebrain cholinergic neurons, and cognitive deficits in adult female rats. We report that AIRS elevated plasma levels of corticosterone and proinflammatory high mobility group box 1 (HMGB1), consistent with HPA axis activation and systemic inflammation. In the late adolescent (P55) basal forebrain, AIRS caused an increase of the proinflammatory signaling molecule HMGB1, the HMGB1 receptors TLR4 and RAGE, the downstream proinflammatory transcription activation marker pNF-κB p65, and proinflammatory cytokines that persisted into adulthood (P95). This was accompanied by persistent adult increases of microglial activation markers, Iba-1 and CD11b. Importantly, AIRS caused a reduction of ChAT+ and TrkA + basal forebrain cholinergic neurons that persisted into adulthood, paralleling significant impairments in recognition memory on the novel object recognition memory test. Together, these findings suggest that adolescent adversity induces persistent proinflammatory HMGB1-TLR4/RAGE-pNF-κB signaling, microglial priming, and reductions of basal forebrain cholinergic neurons as well as enduring cognitive impairment. The HMGB1 proinflammatory pathway may represent a promising therapeutic target for mitigating the long-term neurobiological and behavioral consequences of adolescent adversity.