Investigating the interplay between early life stress, acute secondary pathogenesis, and chronic hippocampal impairments in young mice with traumatic brain injury

Parker, Kaila N.
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While Traumatic brain injury (TBI) is the leading cause of disability in children, it is unclear how early life stress (ELS) may act as a determinant of long-term recovery in brain-injured children. A murine model of ELS preceding TBI at postnatal day (P)21 addressed the following: regionally specific acute pathogenesis of the hippocampus after ELS+TBI, are these early changes predictive of hippocampal damage and impairment at adulthood. Males and females were exposed to ELS (P2-9) with the limited bedding nestlet (LBN) model, randomized to TBI or sham, and euthanized at P22 or adulthood. At P22, ELISAs revealed an upregulation of IL1B, IL-6, TNFα, and IFNγ in both sexes after injury. ELS+TBI elevated IL-1B, IL-10, TNFα, and IFNγ in males compared to TBI. Iba-1 and caspase-3 were evaluated in hippocampal subregions. While TBI increased microglial density in both sexes, ELS+TBI increased microglial density in male CA2 and CA3 but only in the CA3 in females compared to TBI. Quantification of caspase-3 revealed apoptosis in males and females after TBI. ELS + TBI increased apoptosis in CA1 and CA3 in males and females compared to TBI. Adulthood learning and memory were assessed with the NOR and Barnes Maze. Compared to TBI, ELS+TBI reduced novelty preference in females and increased path length to target in both sexes. Hippocampal neuron loss after ELS+TBI was evaluated at adulthood. TBI significantly reduced neurons in all subregions; ELS+TBI reduced neurons in the CA1 region in females only. These findings highlight hippocampal vulnerability after ELS+TBI and ELS prior to a TBI may enhance acute pathogenesis in males. Correlation matrices determined hippocampal acute pathogenesis is predictive of neuronal loss at adulthood and is associated with learning and memory impairments. Males and females were assessed for all outcomes. Both sexes showed similar vulnerability to secondary pathogenesis following TBI and adulthood impairments in learning and memory; males showed greater vulnerability to acute pathogenesis and females showed greater vulnerability to adulthood outcomes. These findings may advocate for opportunities to tailor therapies specific to each sex. Thus, developing pre-clinical biomarkers to predict long-term recovery may continue to bolster care management.