Large-scale network dynamics in neural response to emotionally negative stimuli linked to serotonin 1A binding in major depressive disorder

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 PET using [ 11 C]CUMI-101 (CUMI) to quantify 5-HT 1A binding in midbrain raphe nuclei and 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.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms

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“…In fact, there is still controversy about the relationship between serum S‐100β levels and depression 35–37 . Although anxiety disorder and depression disorder have overlapping biological mechanisms such as decreased serotonin levels in the brain, the changes of neurotransmitters in the brain are not completely consistent 38–40 . Depression disorder is associated with decreased levels of dopamine and norepinephrine, 41,42 while anxiety disorder is associated with increased levels of these substances 33,43,44 .…”

“…[35][36][37] Although anxiety disorder and depression disorder have overlapping biological mechanisms such as decreased serotonin levels in the brain, the changes of neurotransmitters in the brain are not completely consistent. [38][39][40] Depression disorder is associated with decreased levels of dopamine and norepinephrine, 41,42 while anxiety disorder is associated with increased levels of these substances. 33,43,44 No significant difference was seen in the levels of 5-HT in S100β knockout mice and wildtype controls, while S-100β depletion led to a significant decrease of norepinephrine in the hippocampus (À12%) as well as in the residual cortex.…”

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