Abstract
Serotonergic dysfunction is implicated in major depressive disorder (MDD), but the mechanisms of this relationship remain elusive. Serotonin 1A (5-HT(1A)) autoreceptors regulate brain-wide serotonin neuron firing and are positioned to assert large-scale effects on negative emotion. Here we investigated the relationship between raphe 5-HT(1A) binding and brain-wide network dynamics of negative emotion. 22 healthy-volunteers (HV) and 27 medication-free participants with MDD underwent positron emission tomography (PET) using [(11)C]CUMI-101 (CUMI) to quantify 5-HT(1A) binding in midbrain raphe nuclei and functional magnetic resonance imaging (fMRI) scanning during emotionally negative picture viewing. Causal connectivity across regions responsive to negative emotion was estimated in the fMRI data using a multivariate dynamical systems model. During negative picture viewing, MDD subjects demonstrated significant hippocampal inhibition of amygdala, basal-ganglia, thalamus, orbital frontal cortex, inferior frontal gyrus and dorsomedial prefrontal cortex (IFG, dmPFC). MDD-related connectivity was not associated with raphe 5-HT(1A) binding. However, greater hippocampal inhibition of amygdala, thalamus, IFG and dmPFC correlated with hippocampal 5-HT(1A) binding. Correlation between hippocampal 5-HT(1A) binding and the hippocampal inhibition network was specific to MDD but not HV. MDD and HV groups also differed with respect to the correlation between raphe and hippocampal 5-HT(1A) binding which was more pronounced in HV. These findings suggest that increased hippocampal network inhibition in MDD is linked to hippocampal serotonergic dysfunction which may in turn arise from disrupted linkage in raphe to hippocampus serotonergic circuitry.