F-15599

Perinatal hypoxic-ischemic brain damage (HIBD) is a leading cause of lifelong neurodevelopmental disability, and effective therapies remain limited. Activation of the postsynaptic serotonin-1A receptor (5-HT_1A-R) has neuroprotective potential against acute and chronic brain injuries. The present study evaluated whether activation of postsynaptic 5-HT_1A-R enhances neural regeneration and improves long-term outcomes after neonatal HIBD. Seven-day-old rats were subjected to left carotid artery ligation followed by 2 h of hypoxia (8.0 % O₂). NLX-101 (0.16 mg/kg), a selective postsynaptic 5-HT_1A-R agonist, was intraperitoneally injected at 0, 24, and 48 h after hypoxic ischemia. Brain damage in adolescent rats was quantified by magnetic resonance imaging (MRI) and hematoxylin and eosin (H&E) staining. Cognitive, social, and emotional behavioral outcomes were evaluated. Hippocampal neural regeneration was analyzed by RNA sequencing and validated by immunofluorescence. We found that the activation of 5-HT_1A-R was amplified by NLX-101 administration, which attenuated HI-induced brain tissue damage in MRI and H&E staining and improved cognitive, social, and emotional behaviors in adolescence. Gene Ontology enrichment revealed significant clustering within neural regeneration-related gene sets, corroborated by immunofluorescence, which showed 5-HT_1A-R activation enhanced neural stem/progenitor cell generation and promoted the long-term survival of regenerated neurons. Kyoto Encyclopedia of Genes and Genomes pathway enrichment indicated that 5-HT_1A-R activation was associated with the MAPK/ERK cascade, and western blotting further confirmed that it enhanced ERK phosphorylation. In conclusion, our findings demonstrate that activation of postsynaptic 5-HT_1A-R amplifies dentate gyrus neural regeneration, attenuates brain damage, and normalizes long-term cognitive, social, and affective deficits in neonatal HIBD, primarily through the MAPK/ERK pathway.