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

Molecular Psychiatry volume 26, pages 2393–2401 (2021)Cite this article

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Abstract

Serotonergic dysfunction is implicated in major depressive disorder (MDD), but the mechanisms of this relationship remain elusive. Serotonin 1A (5-HT1A) 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-HT1A 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 [11C]CUMI-101 (CUMI) to quantify 5-HT1A 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-HT1A binding. However, greater hippocampal inhibition of amygdala, thalamus, IFG and dmPFC correlated with hippocampal 5-HT1A binding. Correlation between hippocampal 5-HT1A 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-HT1A 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.

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Fig. 1: Organization of clusters responsive to negative vs. neutral images into 13 nodes.
Fig. 2: Causal connectivity in MDD related to hippocampal 5-HT1A.
Fig. 3: Hippocampal 5-HT1A in MDD vs. HV.

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Authors and Affiliations

  1. Department of Psychiatry, Columbia University, New York, NY, USA

    Noam Schneck, Jeffrey M. Miller, Francesca Zanderigo, M. Elizabeth Sublette, Barbara Stanley, Ainsley Burke & J. John Mann

  2. Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, USA

    Noam Schneck, Harry Rubin Falcone, Jeffrey M. Miller, Francesca Zanderigo, M. Elizabeth Sublette, Barbara Stanley, Ainsley Burke & J. John Mann

  3. Department of Biomedical Engineering, Columbia University, New York, NY, USA

    Tao Tu & Paul Sajda

  4. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Maria A. Oquendo

  5. Department of Psychology, Columbia University, New York, NY, USA

    Kevin Ochsner

  6. Data Science Institute, Columbia University, New York, NY, USA

    Paul Sajda

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Correspondence to Noam Schneck.

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Conflict of interest

JJM receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene and has stock options in Qualitas Health, a start- up developing a PUFA supplement. PS is the majority owner and Chairman of the Board of Neuromatters LLC, a brain computer interface neuromarketing and gaming company. MAO receives royalties for the commercial use of the Columbia-Suicide Severity Rating Scale. Her family owns stock in Bristol Myers Squibb. The remaining authors have no conflicts of interests to declare.

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Schneck, N., Tu, T., Falcone, H.R. et al. Large-scale network dynamics in neural response to emotionally negative stimuli linked to serotonin 1A binding in major depressive disorder. Mol Psychiatry 26, 2393–2401 (2021). https://doi.org/10.1038/s41380-020-0733-5

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