Aging potentiates glioma-driven remodeling of cortico-hippocampal neuron-astrocyte dynamics

Age is the strongest determinant of glioblastoma incidence and outcome, yet how aging shapes the functional consequences of tumor burden across the brain remains unclear. Glioblastoma is accompanied by cognitive and affective dysfunction that implicates disruption of neural networks beyond the tumor core, particularly in the aged state. Here, we show that aging modifies how glioma burden progressively reshapes extratumoral brain circuit dynamics. Neurons largely retained behaviorally-aligned activity early in disease, with neuronal alterations such as diminished neuronal event magnitudes emerging with tumor progression in a region- and age-dependent manner. In contrast, astrocytic activity was disproportionately affected by aging and tumor burden, with age amplifying astrocytic engagement under control conditions and glioma burden selectively weakening astrocytic responsiveness, coordination, and long-range synchrony, most prominently in aged hosts and at earlier stages of tumor progression. These functional disruptions were accompanied by transcriptional remodeling in extratumoral regions, with astrocytes exhibiting inflammatory activation and suppression of circuit-supportive programs, and neurons showing complementary, region- and age-dependent alterations in genes related to synaptic function and activity. Together, these findings position astrocytic dysfunction as a dominant feature of age-associated extratumoral circuit vulnerability in glioblastoma and highlight glial mechanisms as key contributors to progressive functional decline in the aging brain.