Novel neonatal hypoxic-ischemic model demonstrates glial activation and memory deficits without neuronal loss

BACKGROUND: Neonatal global hypoxic-ischemic cerebral injury is a leading cause of infant mortality and lifelong disability. Current rodent models do not replicate neonatal global cerebral ischemia (nGCI) and reperfusion injury. Here, we developed and characterized a rodent model of cardiac arrest and cardiopulmonary reperfusion (CA/CPR) to induce nGCI, producing acute systemic ischemia, mild neuronal injury, white matter alterations, and motor and memory deficits. METHODS: Rat pups underwent CA/CPR or sham procedure on postnatal day 9-11. CA/CPR in rat pups was performed under anesthesia while intubated. Asystole was induced with intravenous (IV) KCl and maintained for 10-14 min. Resuscitation included oxygen ventilation, chest compressions, and IV epinephrine. RESULTS: Twelve minutes of asystole provided an optimal balance between survival and systemic injury. Behavioral testing on postoperative day (POD) 7 revealed memory impairments. Despite the absence of overt neuronal death in the hippocampus or cerebellum, we observed evidence of glial activation and white matter alterations. CONCLUSION: This novel rodent model of nGCI addresses limitations in existing models while offering clinically relevant features to support future mechanistic and translational research. IMPACT: This study validates cardiac arrest and cardiopulmonary resuscitation (CA/CPR) as a novel model for neonatal global cerebral ischemia (nGCI), complementing existing rodent models of unilateral and permanent injury by enabling investigation of both global ischemia and reperfusion injury. nGCI results in memory impairment in the absence of overt neuronal cell death. Functional deficits are associated with neuroinflammatory responses in the hippocampus, white matter, and cerebellum. Neonatal CA/CPR induces global cerebral ischemia, which uniquely allows investigation of hindbrain structures, such as the cerebellum, which are typically spared in existing rodent models of neonatal hypoxia-ischemia.