The effect of 5-Hydroxytryptamine (5-HT) on neurogenic niches in brainstem and spinal cord region

Neurogenesis is the differentiation of neural stem cells into neurones, astrocytes and oligodendrocytes. There is evidence for postnatal neurogenesis in the brainstem and central canal area of the spinal cord. We therefore sought to determine the relationship between 5-HTergic fibres and neural stem cells using nestin-GFP mice and whether modulation of 5-HTergic signalling can influence neurogenesis in the spinal cord and brainstem. In nestin-GFP mice, 5-HTergic fibres formed close proximity with nestin-positive cells in brainstem and spinal cord suggesting that 5-HT may modulate the stem cells. Administration of the 5-HT uptake inhibitor, fluoxetine hydrochloride (flx, 10 mg/kg) promoted greater numbers of proliferating cells in dentate gyrus (DG) of hippocampus (used as a positive control), dorsal vagal complex, raphe nuclei and inferior olives of brainstem and gray matter in thoracic spinal cord. Nevertheless, the proportion of new cells that became astrocytes, oligodendrocytes and neurones were not significant. To determine which 5-HT receptor was involved, in vitro experiments revealed that slices treated with cisapride (5-HT4 agonist) had higher numbers of proliferating cells in central canal of spinal cord, while slices treated with another 5-HT4 partial agonist tegaserod maleate had lower numbers compared with control slices. In vivo, animals treated with tegaserod had significantly fewer proliferating cells in DG of hippocampus, NTS and ECL of brainstem and selected areas in spinal cord, compared to control. However, there were no significant differences in the proportions of proliferating cells also exhibiting markers for neurones, oligodendrocytes or astrocytes in hippocampus, brainstem and spinal cord The effects of flx on neurogenesis in animals on high-fat diet was determined, administration of 166 mg/L of flx in drinking water was not able to affect cell proliferation in the hippocampus, selected regions and thoracic spinal cord. Moreover, it did not influence cell differentiation. For metabolic changes, flx did not improve the fasting blood glucose level and did not reverse the increased bodyweight. In conclusion, this indicated the influence of endogenous 5-HT in promoting high levels of cell proliferation since flx blocks 5-HT transporters, increasing 5-HT levels in the synaptic cleft.