Background Germinal Matrix Hemorrhage(GMH) induced debilitating cognitive deficits in preterm.Neurogenesis in the hippocampus play a key role in spatial learning and cognitive repairment.We have reported the neuroprotective effects of Cannabinoid receptor 2(CB2R) on GMH by inhibiting microglial activation but the relationship of which and neurogenesis and the underlined mechanism remain poorly understand.Here,we report CX3CR1 as a novel therapeutic target of CB2R activation on microglia,which maintain microglia in a neuroprotective phenotype(M2) and prompting proliferation of hippocampus neural progenitor cells(NPCs).Methods 108 rat pups neonatal day seven(P7)were involved in the study and the GMH model was induced by intracerebral injection of collagenase Ⅶ.As a long-term therapeutic strategy,JWH133(1.5mg/kg,for seven days)was used to stimulate CB2R.siRNA-CX3CR1 was intraventricular injected in pup of P3.28 days following surgery,neurological experiments were performed to test the motor and memory ability in each group and the brain were weighted immediately after decapitation.At indicated day 1,3 and 7 following surgery,the brain were used to study CX3CR1 expression in microglia and its correlation with hippocampal neurogenesis by western blot and q-PCR assay and immunofluorescence staining.Results We found that long term-administration of JWH133 significantly protected neurological deficit at day-28 and enhanced the expression of CX3CR1 in microglia at day 1、3 and 7 after GMH.In-Vitro IVIS image and proliferation assay of BrdU demonstrated a increasing tendency of SOX2 and β3-tubulin positive cells in hippocampus of pups in JWH133 group.Moreover,detection of brain in each group reported a increasing weight of JWH133 treated pups 28 days after surgery.Additional cerabral-ventricular administration of CX3CR1-Sh RNA attenuated the proliferation of NPCs in hippocampal induced by CB2R activation,leading no significant difference in neurological deficit compared with vehicle-treated group.Conclusion We propose that administration of CB2R agonist activated CX3CR1 expression after GMH and transferred microglia into CX3CR1 positive that secret neurotrophic factors,which prompting neurogenesis in hippocampus.The data give a novel therapeutic target for the treatment of GMH in clinic.