The impact of repetitive neonatal procedural pain on cognitive behavioral development in male Mice: A microglial Perspective.

Early life experiences, such as repetitive neonatal procedural pain (RNP), may result in alterations in the function of the nervous and immune systems. In this study, we investigated the effect of RNP (postnatal day 0-7, 4 times/day) in male juvenile mice. Specifically, we evaluated (1) the spatial learning and memory, (2) the hippocampal microglia change, and (3) the regulatory role of microglial SIRP in hippocampal neuroinflammatory response. Our results show that RNP led to cognitive-behavioral changes. In addition, RNP activated hippocampal microglia in mice, promoting a proinflammatory phenotype and increasing the expression of relevant markers. Both in vivo and in vitro experiments revealed abnormal hippocampal microglia-mediated synaptic pruning in the pain model. Hippocampus-specific knockout model of microglial SIRPα, as well as microglial SIRPα overexpression/knockdown in vitro, was performed to demonstrate the regulatory role of SIRPα in microglia-mediated synaptic pruning and its contribution to RNP-induced brain function abnormalities and behavioral development abnormalities. Taken together, our results suggest that RNP causes spatial learning and memory impairment in juveniles. SIRPα as a "don't eat me" signaling molecule regulates engulfment of spines by activated microglia, potentially contributing to pain-related cognitive-behavioral development deficits, as well as impairment of microglia-mediated synaptic pruning.