Repetitive Mild TBI and Physiological Stress as Catalysts for Chronic Neurovascular Dysfunction - Project Summary: Traumatic brain injury (TBI) causes acute neurovascular dysfunction and is associated with long-term behavioral, cognitive, and neurodegenerative changes that can emerge after initial recovery, yet the mechanisms underlying this variable latent period remain poorly understood. During this period, secondary physiological stressors may trigger the transition from subclinical pathology to overt disease. We hypothesize that repetitive mild blast TBI (rmTBI) leads to chronic neurovascular remodeling, creating a vulnerable state where latent pathology is unmasked by secondary stressors. We propose that these effects are mediated by neuroinflammation, characterized by excessive CNS cytokine production, and that pharmacological targeting of inflammation can prevent stressor-induced neurovascular unit (NVU) dysfunction. To test this, we will use a well-established mouse model of rmTBI induced by the McMillan Blast Device, followed 30 days post-injury by sleep fragmentation (SF), a common and translationally relevant physiological stressor. While blast TBI is directly relevant to military-associated injuries, the selection of this model was driven by its ability to reproduce widespread vascular injury. This pattern of injury is a key pathological feature of human TBI, including those resulting from rotational forces, which are challenging to replicate in rodent models. Unlike impact-based models, which predominantly produce focal axonal injury with limited vascular involvement, the blast model offers a more comprehensive tool to investigate neurovascular dysfunction, making it well-suited for testing our hypothesis. Mice will undergo SF for eight weeks, with the final three weeks including treatment with MW151, a CNS-targeted anti-inflammatory compound with a defined therapeutic window. We will assess NVU dysfunction across three aims, incorporating multiple levels of analysis to examine how SF interacts with rmTBI to drive disease progression. Aim 1 will assess NVU function by measuring cerebral perfusion and BBB permeability. Aim 2 will characterize vascular inflammation and glial activation, providing insight into tissue- level interactions shaping neurovascular remodeling. Aim 3 will focus on the cellular and molecular changes within the NVU, evaluating tight junction integrity and capillary transcriptional responses. By identifying inflammation-driven NVU dysfunction as a mechanism by which latent pathology transitions to disease, this study will establish the latent phase as a window for intervention. Findings will inform strategies to mitigate the long-term impact of TBI and redefine the role of vascular dysfunction in post-traumatic neurodegeneration.
