Microglia ameliorate delirium-like phenotypes in a murine model of acute ventilator-induced lung injury
- J Neuroinflammation. 2024 Oct 21;21(1):270. doi: 10.1186/s12974-024-03260-y.
- 1. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- 2. Biostatistics Shared Resources, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- 3. Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- 4. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- 5. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- 6. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- 7. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
- 8. Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
- 9. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
- # Contributed equally.
Background: Delirium affects 50-85% of patients on mechanical ventilation and is associated with increased mortality, prolonged hospitalization, and a three-fold higher risk of dementia. Microglia, the resident immune cells of the brain, exhibit both neuroprotective and neurotoxic functions; however, their effects in mechanical ventilation-induced acute lung injury (VILI) are unknown. We hypothesize that in a model of short-term VILI, microglia play a neuroprotective role to ameliorate delirium-like phenotypes.
Methods: Microglia depletion (n = 18) was accomplished using an orally administered colony stimulating factor 1 receptor inhibitor, while controls received a vehicle diet (n = 18). We then compared extent of neuronal injury in the frontal cortex and hippocampus using cleaved Caspase-3 (CC3) and multiple delirium-like behaviors in microglia depleted and non-microglia depleted male mice (C57BL/6 J aged 4-9 months) following VILI. Delirium-like behaviors were evaluated using the Open Field, Elevated Plus Maze, and Y-maze assays. We subsequently evaluated whether repopulation of microglia (n = 14 repopulation, 14 vehicle) restored the phenotypes.
Results: Frontal/hippocampal neuronal CC3 levels were significantly higher in microglia depleted VILI mice compared to vehicle-treated VILI controls (p < 0.01, p < 0.01, respectively). These structural changes were accompanied by worse delirium-like behaviors in microglia depleted VILI mice compared to vehicle controls. Specifically, microglia depleted VILI mice demonstrated: (1) significantly increased time in the periphery of the Open Field (p = 0.01), (2) significantly increased coefficient of variation (p = 0.02), (3) trend towards reduced time in the open arms of the Elevated Plus Maze (p = 0.09), and (4) significantly decreased spontaneous alternations on Y-maze (p < 0.01). There was a significant inverse correlation between frontal CC3 and percent spontaneous alternations (R2 = 0.51, p < 0.01). Microglia repopulation showed a near-complete return to vehicle levels of delirium like-behaviors.
Conclusions: This study demonstrates that microglia depletion exacerbates structural and functional delirium-like phenotypes after VILI, while subsequent repopulation of microglia restores these phenotypes. These findings suggest a neuroprotective role for microglia in ameliorating neuronal and functional delirium-like phenotypes and call for consideration of interventions that leverage endogenous microglia physiology to mitigate delirium.