Behavioral and axonal impacts of thalamic microglial process convergence following diffuse brain injury

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Project Summary Traumatic brain injury (TBI) can lead to significant morbidities that are altered by changes in inflammatory state. Microglia, the innate immune cells of the brain, are critical mediators of neuroinflammation that can have either neurotoxic or neurotrophic effects. To date, these effects have been examined primarily in rodents, while their parallel consideration in humans has not yielded clinically translatable findings, suggesting potentially different responses in higher order mammals. The pig is an ideal pre-clinical translational animal model, due to its similarities to humans in cytoarchitecture, metabolic rates and systemic inflammatory responses, however, only a handful of TBI research centers are using pig models of brain injury and currently none are focused on the interaction between microglia and injured axons or pathology within the thalamic domain. Our preliminary data demonstrated that microglial processes converge onto injured axonal swellings (microglial process convergence; MPC) in the thalamus of micro pigs, that is not recapitulated in rats, following diffuse TBI. Increased sensitivity to sensory stimulation and anxiety are associated with TBI and inflammation, unfortunately, the limited use of behavioral assessments in pig models of TBI leaves the link between post-injury MPC and behavioral outcomes unclear. Both our preliminary data and previous studies indicate that MPC may be an ameliorative process, promoting axonal outgrowth post-injury with the caveat that aberrant axonal outgrowth is linked to heightened behavioral morbidity. Therefore, the goal of this study is to assess the role of MPC on neurite outgrowth and behavioral morbidity in a pig model of diffuse TBI and gain insight into the similarity to human pathology. Studies indicate that males have greater pro-inflammatory responses, less axonal outgrowth, and reduced sensory sensitivity and anxiety compared to females. However, there are no known studies evaluating MPC in both males and females. Accordingly, the current study will address the following specific aim 1) To elucidate the extent and role of microglial process convergence on axonal outgrowth and behavioral morbidity following diffuse TBI. To address this aim we will complete quantitative 3D assessments of multiplexed immunohistological samples for microglial-axonal interactions/MPC in pigs to determine the degree and progression of MPC in relation to sensory sensitivity and anxiety/social interaction changes, axonal outgrowth/retraction changes in both sexes within the first week post-injury. This study is significant because it will provide valuable preliminary data regarding 1) the duration and extent of MPC in a gyrencephalic pig model, 2) the behavioral dysfunction(s) associated with thalamic MPC, and 3) the sex-associated differences in MPC. These studies will serve as a springboard for future investigations into 1) the potential adaptive and/or maladaptive role of various degrees of MPC 2) the molecular mechanisms involved in and potential therapeutic modulation of MPC and 3) investigations regarding the therapeutic modulation of TBI-mediated sensory sensitivity and/or anxiety.