Understanding radiation-induced tissue modifications and cell death within the complex cellular architecture of the brain requires experimental systems that preserve tissue integrity and intercellular crosstalk. At the same time, microglial cells as primary regulators of primary and secondary inflammation in the brain are difficult to study in single cell cultures and it is crucial to investigate their behaviour in their complex tissue microenvironment. Rodent organotypic hippocampal slice cultures (OHSCs) and human patient-derived brain tumor cultures (PDTCs) offer physiologically relevant platforms for investigating the differential effects of X-ray and heavy-ion irradiation on glial as well as immune cell populations. Both models retain native cytoarchitecture, extracellular matrix composition, and functional cell-cell interactions, making them uniquely suited to study the spatial and temporal dynamics of inflammation or cell death in a multicellular context. Here, we present a standardized methodology for preparing, irradiating, and assessing PDTCs, employing multimodal readouts as cytokine measurement of the supernatant, cell death, microglia morphology and function. Novel molecular analyses are possible upon certain considerations and may alter our understanding of species differences and help to distinguish cell death pathways to attribute damage to specific cell types. Standardization of these protocols across model systems is essential for generating reproducible, comparative data while preserving the inherent complexity that underlies intercellular communication and coordinated responses to injury. This approach enables translationally relevant insight into the mechanisms of radiation-induced brain injury to develop strategies for neuroprotection and treatment in clinical settings.
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