Understanding alterations in serotonin connectivity in a rat model of depression within the monoamine-deficiency and the hippocampal-neurogenesis frameworks

• Stress-induced changes in Raphe connectivity are connection-specific.
• Raphe connectivity with the basal ganglia and hippocampus is reduced in CMS rats.
• Raphe connectivity with the septum increases in CMS rats.
• Alterations in connectivity are asymmetrical and predominant in the right hemisphere.
• Direct and indirect mechanisms for raphe–hippocampus modulation are hypothesized.

The monoamine-deficiency and the hippocampal-neurogenesis hypotheses of depression propose that alterations in the serotonin system and of hippocampal functionality are critical in the pathogenesis of depression. We measured the alterations in the connectivity level of the raphe nucleus in the chronic mild stress (CMS) rat model of depression using the manganese enhanced MRI method (MEMRI). Manganese ions were injected into the median raphe and their anterograde intracellular propagation was followed. Depression-like behavior was demonstrated using the sucrose preference tests.We show that the raphe’s connectivity is differentially altered through chronic stress. In line with the monoamine-deficiency hypothesis, the connectivity of the raphe with the basal ganglia (BG) output nuclei, the hippocampus, the habenula and the entorhinal and insular cortices was reduced in CMS rats, suggesting an overall reduction in raphe excitability. Connectivity reductions were predominantly found in the right hemisphere, strengthening previous evidence pointing at a-symmetric hemispheric involvement in depression. Despite the general reduction in raphe connectivity, enhanced connectivity was found between the raphe and the septum, suggesting that alterations are connection-specific.On the basis of our results – while yet equivocal – we further discuss the possible coupling between the serotonergic and dopaminergic systems and two distinct mechanisms (direct and indirect) in which alterations in raphe connectivity may affect hippocampal dysfunction in chronic stress, thus linking the monoamine-deficiency and the hippocampal-neurogenesis hypotheses.