DIABETES BIASES ACUTE AND CHRONIC NEUROVASCULAR UNIT RESPONSES TO WHOLE-BRAIN IRRADIATION

Whole-brain irradiation (WBI) induces region- and cell-type–specific alterations within the neurovascular unit (NVU), but how metabolic status influences these responses over time remains unclear. Male C57BL/6 mice were assigned to control, radiation, or diabetes + radiation groups using a streptozotocin-induced Type 1 diabetes model and exposed to single dose WBI (10 Gy; acute) or fractionated WBI (40 Gy; chronic). Cortex, hippocampus, and corpus callosum were analyzed by immunofluorescence to assess glial activity, extracellular matrix organization, vascular–pericyte relationships, and apoptotic signaling, alongside behavioral testing. In the acute phase, radiation and diabetes + radiation produced distinct NVU response profiles across brain regions. In cortex, apoptotic signaling was higher in radiation compared with diabetes + radiation. In hippocampus, diabetes + radiation showed a shift in glial balance characterized by increased astrocytic and reduced microglial and extracellular matrix signals. In white matter, radiation was associated with elevated microglial and extracellular matrix markers, whereas diabetes + radiation exhibited enhanced astrocytic signals. Vascular–pericyte relationships were modulated in a region-dependent manner following irradiation. In the chronic phase, radiation and diabetes + radiation diverged in extracellular matrix and glial trajectories. Diabetes + radiation was associated with reduced collagen levels across regions, while white matter in radiation exhibited persistent microglial elevation and altered vascular-associated signals. Cortical pericyte coverage differed between groups. Behavioral performance did not differ between groups. Together, these findings suggest that metabolic status biases the balance between glial, vascular, and extracellular matrix processes across time, potentially shaping distinct trajectories of neurovascular adaptation to irradiation.