Although neuroinflammation has been studied extensively in animal models of cerebral ischemia, their contrasting functions are still not completely understood. A major participant in neuroinflammation is microglia and microglial activation usually regulated by the chemokine CX3CL1 (fractalkine) and its receptor, CX3CR1. Here, we examined the involvement of CX3CR1 on ischemia-induced chronic neuroinflammation and cognitive function using small interfering RNA (siRNA). Forty adult male Wistar rats were included in the study and received either ischemia or sham surgery then were randomized to receive either CX3CR1 siRNA or scrambled RNA as control starting at 7 days after reperfusion. Behavioral testing commenced 28 days after siRNA delivery and all rats were euthanized after behavioral testing. Our data showed that: (i) transient global cerebral ischemia significantly decreased fractalkine/CX3CR1 signaling in the hippocampus; (ii) inhibition of CX3CR1 function exacerbated the ischemia-induced chronic increase in microglial activation and pro-inflammatory cytokine levels; (iii) inhibition of CX3CR1 function worsened ischemia-induced chronic cognitive impairment; (iv) inhibition of CX3CR1 function in sham rats resulted in increased IL-1β expression and impaired behavioral performance. However, no significant effect of CX3CR1 on ischemia-induced neurodegeneration was seen. The present study provides important insight to understanding the involvement of CX3CR1 in chronic neuroinflammation and cognitive impairment.

Neurogenesis in the mammalian brain continues throughout adulthood. Several factors have been shown to influence neurogenesis, including experience in a complex environment (EC), exercise (EX), and ischemic insult. The authors investigated the effects of behavioral rehabilitation training following transient global cerebral ischemia on the number of new cells in the dentate gyrus that incorporated bromodeoxyuridine (BrdU), a thymidine analog that labels cells undergoing DNA replication. Seventy-two animals were included in the study, and 4-vessel occlusion was used to induce cerebral ischemia while control animals were subjected to anesthesia and sham surgery alone. Within 3 days of surgery, rats were randomly assigned to either EC, EX, or control (paired housing in standard laboratory conditions) groups. All animals were sacrificed 2 weeks after behavioral training. Immunohistochemistry results showed an increased number of BrdU-labeled cells in the subgranular zone of the dentate gyrus in all ischemic groups and in the EC and EX sham groups, although no significant group differences were seen. Examination of cell phenotype showed that almost all BrdU-positive cells colabeled with TuJ1, an immature neuron marker, in all animals whereas only a few BrdU-positive cells colabeled with NeuN, a mature neuron marker. BrdU/NeuN-labeled cells were seen only in the sham and ischemia EC groups. No new cells showed glial fibrillary acidic protein, astrocyte marker, colabeling. These results suggest that the adult brain has an inherent regenerative capacity after insult and that behavioral training following injury does not have an additive effect on neurogenesis. Finally, the enhanced maturation of BrdU-positive cells seen in the EC rats is probably modulated by environmental cues.

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