Neural Mechanisms in Primates Underlying Short- and Long-Term SSRI Effects

Selective Serotonin Reuptake Inhibitors (SSRIs) are used to treat several neuropsychiatric disorders including depression and anxiety. Despite their extensive use, the mechanisms behind SSRIs initial anxiogenic and delayed anxiolytic responses remain unclear. The amygdala and dorsal anterior cingulate cortex (dACC) are key interconnected regions implicated in these disorders and are targeted by SSRIs. Notably, maladaptive alpha-band oscillatory activity in these regions has been linked to neuropsychiatric pathophysiology, yet the relationship between neural activity in this network and the SSRI effects over the course of administration is still not fully understood.In this longitudinal electrophysiology study, we conducted simultaneous extracellular recordings from the amygdala and dACC of non-human primates. The subjects performed a classical tone-odor fear conditioning task involving aversive learning and discrimination, before and during continuous SSRI administration across acute , chronic , and after discontinuation phases.Behavioral conditioned responses and discrimination were elevated during the acute phase and subsequently reduced during the chronic phase. At the neural level, alpha band oscillatory power and synchrony within and across amygdala and dACC were significantly reduced following SSRI administration, demonstrating a profound transient overall effect. Conversely, the transition from acute to chronic SSRI phase was accompanied by more subtle and selective alterations in neural measures. Interestingly, conditioned stimulus (CS) related synchrony across the two areas, measured by CS phase coherence relative to the intertrial interval (ITI), showed distinct dynamics, selectively elevated during the acute and subsiding during the chronic phase. A key finding is that the observed behavioral changes across SSRI phases were best accounted for by the combined influence of local and global neural dynamics, rather than by either measure individually.Our results reveal a network-level mechanism within the dACC-amygdala circuitry that underlies the temporal dynamics of SSRI-induced behavioral modulation. By delineating distinct neural effects of acute and chronic SSRI administration, this work provides novel insights that could inform more targeted and effective treatments for depression and anxiety.