Graded traumatic brain injury severity differentially modulates microglial and astrocytic polarization states and response to minocycline.

Background: Traumatic brain injury (TBI) involves complex secondary injury cascades in which neuroinflammation is a prominent driver. The lack of standardized models capturing a spectrum of injury severities has hindered a systematic understanding of the associated cellular and molecular responses. This study aims to systematically characterize the dynamic responses and phenotypic shifts of neurons, microglia, and astrocytes during the acute and subacute phases following TBI of varying severities. By integrating macroscopic histopathological assessments with microscopic cellular analyses and correlating these with early peripheral biomarker changes, we seek to provide a solid experimental foundation for understanding TBI mechanisms and developing severity-stratified diagnostic and therapeutic strategies. Methods: Male mice were randomly assigned using a computer-generated randomization sequence to the following experimental groups: Sham group, mice that underwent only craniotomy ( Results: Impact depth was directly correlated with histopathological lesion volume and dictated the trajectory of functional recovery. Motor deficits and neuronal apoptosis scaled with injury severity. The neuroimmune response was severity-dependent: mild TBI triggered a transient, reparative response dominated by M2 microglia and A2 astrocytes. In contrast, severe TBI provoked an early and sustained pro-inflammatory state, characterized by persistent M1 microglial and neurotoxic A1 astrocytic activation ( Conclusion: Our findings establish that TBI severity is a critical determinant of the post-injury neuroimmune microenvironment, with severe injuries driving a maladaptive, chronic inflammatory response. This graded model provides a robust framework for identifying severity-specific biomarkers and validates the rationale for developing precision immunomodulatory therapies stratified by injury severity.