Direct energy consumption by inhibitory GABA (A) receptors: from synaptic mechanisms to network activity.

Annually, over 50 million individuals worldwide are affected by TBI, which is associated with high rates of mortality and disability (). Increases in life expectancy and motor vehicle use have contributed to the rising incidence and prevalence of TBI (). Current management primarily focuses on supportive measures to reduce acute mortality by stabilizing hemodynamics and controlling intracranial pressure (). Nonetheless, TBI frequently leads to persistent cognitive deficits (), profoundly affecting patients’ quality of life and social functioning. However, effective management of post-TBI cognitive impairment remains a major challenge. A growing body of clinical evidence indicates that cognitive impairment following TBI commonly arises from disruption of cognition-related neural networks (; ; ). However, the pathophysiological processes underpinning damage to these critical brain connectomes remain poorly understood. Neuroinflammation, particularly diffuse neuroinflammatory responses extending beyond the primary injury site, may represent a pivotal driving factor. Increasing clinical research suggests that neuroinflammatory changes may be widely distributed within key hub regions of cognition-related networks (; ). As the major immune cells within the central nervous system, microglia can disrupt white matter connections between brain regions by affecting myelin and axonal integrity and can also directly regulate synaptic plasticity and neuronal activity (; ). Preclinical evidence indicates that post-traumatic neuroinflammatory responses involving microglia are closely associated with the severity of cognitive deficits (). This suggests that widespread neuroinflammatory responses within critical nodes of cognitive networks may ultimately disrupt circuit function by impairing the integrity of both network connectivity (white matter) and information-processing units (gray matter synapses). However, most previous basic studies have focused on post-TBI neuroinflammation within the perilesional area or the hippocampus, with inadequate attention given to the more clinically relevant diffuse, network-level inflammatory response. Therefore, further research is required to deepen our understanding of and intervention in this diffuse neuroinflammatory response. This may offer novel therapeutic strategies and targets for restoring impaired neural network function and improving cognitive outcomes following TBI. Pharmacological or genetic elimination of microglia has been demonstrated to suppress early neuroinflammation and improve outcomes following TBI (). However, the inflammatory response is a “double-edged sword” (), as it also plays a crucial role in clearing necrotic tissue and cells during injury repair. Therefore, precise modulation, rather than complete elimination, of the diffuse inflammatory response following injury may represent a potential therapeutic strategy for TBI. Beyond their characterization as mesoderm-derived multipotent stem cells, MSCs are primarily distinguished by their potent immunomodulatory and paracrine functions, which underpin their significant therapeutic potential in complex inflammatory environments (). Consequently, they have gradually emerged as a highly promising therapeutic approach for TBI (). Compared with conventional adherent-cultured MSCs, 3D-MSCs exhibit superior engraftment and homing capacity, immunomodulatory function, and amplified paracrine effects (; ). In this study, “3D-MSCs” refers to MSCs preconditioned by 3D spheroid culture and administered as a dissociated single-cell suspension rather than as intact spheroids. In addition, our previous research demonstrated that intrathecal administration of 3D spheroid culture-preconditioned MSCs results in fewer complications, such as obstructive hydrocephalus and ventricular dilation, than 2D-MSCs, indicating a superior safety profile (). Nevertheless, to our knowledge, the therapeutic potential of 3D-MSCs for TBI has not yet been investigated.