Sex differences in neuroimmune function and developmental vulnerability to early life traumatic brain injury

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Project summary: Traumatic brain injury (TBI) in childhood is the leading cause of pediatric emergency room visits, with over 800,000 children visiting the ER each year according to the CDC. Pediatric TBI can have lifelong consequences for behavioral health, increases rates of ADHD, drug and alcohol abuse, long-term cognitive and social deficits, depression and anxiety. This suggests that early childhood is a period of particular vulnerability to long-term, deleterious neurological outcomes after TBI. Despite the clear evidence of a significant public health problem, the proximal mechanisms leading up to those long term TBI-related outcomes are poorly understood. TBI induces robust neuroinflammation and brain-resident innate immune cells, such as microglia, regulate normal brain development, including synaptic patterning. The impact of TBI on microglia-synaptic interactions is poorly understood. We have demonstrated dramatic developmental biases in activation and sex differences in the profile of neuroimmune cells in the immature rat brain, both microglia and the less studied mast cells. Mast cells are abundant in the developing brain and sparse in adults, suggesting that mast cells could contribute uniquely to the neuroimmune milieu after pediatric TBI. Mast cells are ‘first responders’ to immune insults and coordinate subsequent immune cell (microglia and astrocyte) activation as well as vascular permeability but their role in TBI has not been well studied. In our project, we will use lateral fluid percussion injury on juvenile rats to model pediatric TBI, which our preliminary data suggest elicits robust mast cell activation in the hippocampus, acute gliosis, and long-term, sex-dependent shifts in social behavior and stress hormones. Because so little is known about the unique pediatric response to injury, we will compare the pediatric versus adult injury response of male and female rats via RNAseq and Nanostring profiling of isolated immune cells in a comprehensive time course study (Aim 1). To test for a contribution of mast cells to pediatric TBI, we will use an acute mast cell inhibition using an FDA-approved pharmacological agent and comprehensively profile neuroinflammatory responses, alterations in blood brain barrier (BBB) permeability to narrow in on a potential mechanism through which mast cells are acting after TBI, and correlate BBB changes with social and stress-related behavior outcomes (Aim 2). To determine whether microglia are important for long-term neurodevelopmental programming of behavioral outcomes and sculpting neural circuits after pediatric TBI, we will perform microglia depletion/forced turnover experiments post-TBI (Aim 3). We will compare sexes in all studies, and we predict that males more robust basal neuroimmune tone in the developing brain may render them more vulnerable to TBI-related outcomes. Our studies have the potential to improving long-term outcomes following pediatric traumatic brain injury and uncover potential new therapeutic options targeted to the unique neuroimmune environment of the developing brain.