Early life stress exposure worsens adult remote microglia activation, neuronal death, and functional recovery after focal brain injury.

Abstract Trauma to the central nervous system (CNS) is a devastating condition resulting in severe functional impairments that strongly vary among patients. Patients’ features, such as age, social and cultural environment, and pre-existing psychiatric conditions may be particularly relevant for determining prognosis after CNS trauma. Although several studies demonstrated the impact of adult psycho-social stress exposure on functional recovery after CNS damage, no data exist regarding the long-term effects of the exposure to such experience at an early age. Here, we assessed whether early life stress (ELS) hampers the neuroinflammatory milieu and the functional recovery after focal brain injury in adulthood by using a murine model of ELS exposure combined with hemicerebellectomy (HCb), a model of remote damage. We found that ELS permanently altered microglia responses such that, once experienced HCb, they produced an exaggerated remote inflammatory response – consistent with a primed phenotype – associated with increased cell death and worse functional recovery. Notably, prevention of microglia/macrophages activation by GW2580 treatment during ELS exposure significantly reduced microglia responses, cell death and improved functional recovery. Conversely, GW2580 treatment administered in adulthood after HCb was ineffective in reducing inflammation and cell death or improving functional recovery. Our findings highlight that ELS impacts the immune system maturation producing permanent changes, and that it is a relevant factor modulating the response to a CNS damage. Further studies are needed to clarify the mechanisms underlying the interaction between ELS and brain injury with the aim of developing targeted treatments to improve functional recovery after CNS damage.