The immediate and long term effects of microglial cell activation on stress response in fetal alcohol exposure model

Fetal alcohol exposure has many detrimental effects on the developing fetus that can result in fetal alcohol spectrum disorder (FASD). The developing CNS is particularly sensitive to ethanol neurotoxic effects and exposure during the fetal period results in increased neuronal damage and cell death. Furthermore, many of FASD patients display lifelong stress response abnormalities involving alterations in hypothalamic-pituitary-adrenal (HPA) response. Microglia, which are long lived self-replenishing CNS immune cells, have been shown to contribute to ethanol induced neurotoxicity through the release of pro-inflammatory cytokines and reactive oxygen species. We found that ethanol exposure during the early postnatal period, which is equivalent to the third trimester in humans, significantly increases microglial activation and expression of pro-inflammatory cytokines and chemokines in the mediobasal hypothalamus of neonates. Minocycline, an inhibitor of microglial activation, prevented ethanol induced microglial activation and production of pro-inflammatory cytokines in neonates. Moreover, microglial activation during the neonatal period permanently reduced the number of hypothalamic β-endorphin (BEP) expressing neurons, an endogenous opioid involved in immune and stress regulation. We provide supporting evidence that the microglia mediated reduction of BEP neurons may contribute to HPA hyper response to acute restraint stress in ethanol exposed animals. Microglia can initiate and perpetuate stress activation by releasing pro-inflammatory cytokine. It has been shown that microglial stimulation and activation can alter their responses to subsequent stimuli. We found that neonatal ethanol exposure activates hypothalamic microglia and programs them to become more sensitize to subsequent stimuli in adulthood. We demonstrate that neonatal ethanol exposed adult males are hyper-responsive to acute restraint stress and LPS exposure as quantified by the increase in plasma CORT and ACTH levels. This change correlated with an increase expression of the pro-inflammatory cytokine TNF-α in the PVN. Minocycline pre-treatment during neonatal ethanol exposure prevented the increased expression of TNF-α and the hyper response to immune challenge in alcohol fed adult males. This study demonstrates that ethanol exposure during development results in long term alterations in stress response partially due to over sensitized microglia.Ph. D.Includes bibliographical referencesby Tina Carla Frankli