Acute Inflammatory Responses Are Critical for Neuronal Replacement and Improved Functional Recovery Following Cerebral Ischemia

Introduction Replacement of dead neurons following ischemia, either via enhanced endogenous neurogenesis or stem cell therapy, has been highly sought, but the low survival rate of newborn neurons has left doubt about the therapeutic potential of adult neurogenesis. However, stroke in the young injured brain reveals a greater degree of plasticity and capacity for repair, along with enhanced post‐ischemic functional outcomes compared to the adult. This may be due to neuroimmune interactions and a supportive role for inflammatory signaling in neurogenesis. Microglia are the first responders after stroke, mounting the immune response to CNS injury. While this response has been shown to be both neuroprotective and neurodegenerative following brain injury, it has been generally accepted that activation of microglia during the acute response to stroke is detrimental for neurogenesis and neuronal replacement. However, our findings indicate that early microglial responses are key to survival of newborn neurons in juveniles. Objective We utilized a juvenile stroke model to study the paracrine signaling triggered by ischemia in activated microglia and its consequence on newborn neuron survival. Methods Electrocorticography (ECoG) was recorded from cortical surface electrodes and striatal depth electrodes implanted prior to transient middle cerebral artery occlusion (MCAO). Microglia were attenuated with Ibudilast (10 mg/kg), a glial cell activation inhibitor. Neurogenesis and inflammatory markers were examined with immunohistochemistry; functional outcomes were assessed with neurobehavioral measures and ECoG recordings. Results Acute inhibition of microglial activation after stroke resulted in reduced neurogenesis and long‐lasting neurodegenerative effects, evidenced by increased astrogliosis, infiltrating macrophages and glial scarring at 30d post‐ischemia in the lateral striatum of Ibudilast‐treated compared to vehicle‐treated juvenile mice. Behavioral tests and ECoG recordings revealed deficits in affected limb use, motor functioning and total ECoG power (μV 2 ) in both Ibudilast‐treated and vehicle‐treated MCAO‐injured juveniles at 7d post‐ischemia, but only vehicle‐treated MCAO‐injured juveniles returned to near sham‐operated/baseline levels on neurobehavioral tasks and ECoG at 30d. Conclusions These surprising and striking findings provide evidence of a novel, supportive role for microglia in neuronal replacement and improved functional recovery following stroke in juveniles. That neuroimmune responses after stroke are essential for neurogenesis in the juvenile brain suggests that deliberate enhancement of anti‐inflammatory signaling could offer therapeutic benefit. This novel insight into early, anti‐inflammatory microglial responses after stroke may alter strategies for effective stroke treatment. Combining an environment supportive of neurogenesis with enhanced immunomodulation could foster substantial post‐ischemic neuronal replacement and functional recovery in both juveniles and adults. Support or Funding Information American Heart Association (16SDG30320001) and Bugher Foundation (14BFSC17690001)