Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury

Abstract

Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD resulted in neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. Following TBI, CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI. HighlightsCortical spreading depolarization after TBI causes behavioral decline in rats. Vasoconstriction and oligemia after cortical spreading depolarization is worse in TBI brains. Spreading depolarization causes impaired mitochondrial function. TBI and spreading depolarization result in constricted vessels and increased pericyte size. TBI and spreading depolarization result in mitochondrial damage in vascular cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/549872v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@176a9a6org.highwire.dtl.DTLVardef@17bfc19org.highwire.dtl.DTLVardef@e3d74dorg.highwire.dtl.DTLVardef@4c194e_HPS_FORMAT_FIGEXP M_FIG C_FIG